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HaploPainter: A tool for drawing pedigrees with complex haplotypes
Abstract
Unlabelled:
HaploPainter is a user-friendly pedigree-drawing application with special features for easy visualization of complex haplotype information. It has been developed to facilitate gene mapping in Mendelian diseases in terms of fast and reliable definition of the smallest critical interval harbouring the underlying gene defect. HaploPainter is written in Perl and may be used for visualization of haplotypes calculated by any of the common linkage programs. With special features like haplotype compression or the ability of marker section cut-out it particularly addresses the requirements for viewing large haplotypes as obtained by using for genome scans high-density marker panels of many thousands of single nucleotide polymorphisms (SNPs).
Availability:
http://haplopainter.sourceforge.net/
Contact:
holger.thiele@uni-koeln.de.
... 8 Haplotypes on chromosome 7 were reconstructed from microsatellite genotype data (Fig 4). 9 ...
... PERG is undetectable (4-12 and 4-14), shows a P50 component of short peak time (5-5 and 5-12) and a reduced N95:P50 ratio (5-5, 5-12; and Family 3, 2-3). PVEPs are abnormal in all cases and FVEPs undetectable in 1 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). See text for details. ...
... Broken lines replace blink artifacts that occur soon after b-waves in DA10 ERGs and in the On-Off ERGs in Family 3, 2-3. All 5 cases show evidence of generalized retinal dysfunction with either similar severity of rod and cone involvement (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) or rod-cone dystrophy (4-12, 5-2, 5-5; Family 3, 2-3). There is evidence of progression in 5-5 between the ages of 18 and 26 years. ...
Objective:
Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a proportion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explore their causality.
Methods:
Linkage analysis and sequencing were performed in multi-generation families and unrelated patients to identify disease-causing variants. Functional consequences were investigated in silico and confirmed experimentally using the zebrafish model.
Results:
We defined a new ADOA locus on 7q33-q35 and identified three different missense variants in SSBP1 (NM_001256510.1; c.113G>A (p.(Arg38Gln)), c.320G>A (p.(Arg107Gln)) and c.422G>A (p.(Ser141Asn))) in affected individuals from two families and two singletons with ADOA and variable retinal degeneration. The mutated arginine residues are part of a basic patch that is essential for single-strand DNA binding. The loss of a positive charge at these positions is very likely to lower the affinity of SSBP1 to ssDNA. Antisense-mediated knockdown of endogenous ssbp1 mRNA in zebrafish resulted in compromised differentiation of retinal ganglion cells. A similar effect was achieved when mutated mRNAs were administered. These findings point to an essential role of ssbp1 in retinal development and the dominant-negative nature of the identified human variants, which is consistent with the segregation pattern observed in two multi-generation families studied.
Interpretation:
SSBP1 is an essential protein for mtDNA replication and maintenance. Our data established pathogenic variants in SSBP1 as a cause of ADOA and variable retinal degeneration. This article is protected by copyright. All rights reserved.
... To draw pedigrees of affected families haplopainter program (http://haplopainter.sourceforge.net/about.html) [22] was used. ...
... HOPE software (https:// www3.cmbi.umcn.nl/hope/) [22] was used to predict the biochemical changes in structure of protein due to sequence variation. ...
Background
Primary congenital glaucoma (PCG) is a heterogeneous rare recessively inherited disorder prevalent in regions with high consanguinity. Disease phenotype is associated with increased intra ocular pressure and is a major cause of childhood blindness. Sequence variations in Cytochrome P450 1B1 ( CYP1B1 ) gene are a major cause of PCG. Current study was conducted to screen CYP1B1 gene in highly consanguineous PCG affected families from Pakistani population consistent with the autosomal recessive pattern of PCG inheritance.
Methods
For this study, patients and controls (clinically unaffected individuals of each family) from 25 consanguineous families belonging to Punjab, Baluchistan and Khyber Pakhtunkhwa, Pakistan were recruited through ophthalmologists. DNA was isolated from collected blood samples. Genetic screening of CYP1B1 gene was done for all enrolled families. In-silico analysis was performed to identify and predict the potential disease-causing variations.
Results
Pathogenicity screening revealed sequence variants segregating with disease phenotype in homozygous or compound heterozygous form in eleven out of 25 analyzed families. We identified a total of sixteen disease causing variants among which five frameshift i.e., c.629dup (p.Gly211Argfs*13), c.287dup (p.Leu97Alafs*127), c.662dup (p.Arg222Profs*2), c.758_759insA (p.Val254Glyfs*73) and c.789dup (p.Leu264Alafs*63), two silent c.1314G>A, c.771T>G and six missense variations c.457C>G (p.Arg153Gly), c.516C>A (p.Ser172Arg), c.722T>A (p.Val241Glu), c.740T>A (p.Leu247Gln), c.1263T>A (p.Phe421Leu), and c.724G>C (p.Asp242His) are previously un reported. However two frameshift c.868dup (p.Arg290Profs*37), c.247del (p.Asp83Thrfs*12) and one missense variant c.732G>A (p.Met244Ile), is previously reported. Furthermore, six polymorphisms c.1347T>C, c.2244_2245insT, c.355G>T, c.1294G>C, c.1358A>G and c.142C>G were also identified. In the intronic region, a novel silent polymorphism i.e., g.35710_35711insT was found in homozygous state. All the newly detected disease-causing variants were negative in 96 ethnically matched controls.
Conclusion
Among twenty-five screened families, eight families (PCG50, 52–54, 58, 59, 63 and 67) were segregating disease causing variants in recessive manner. Two families (PCG049 and PCG062) had compound heterozygosity. Our data confirms genetic heterogeneity of PCG in Pakistani population however we did not find molecular variants segregating with PCG in fifteen families in coding exons and intron-exon boundaries of CYP1B1 gene. Genetic counseling was provided to families to refrain from practicing consanguinity and perform premarital screening as a PCG control measure in upcoming generations.
... HaploPainter v.1.043 was used to construct the haplotypes [21]. ...
... HaploPainter v.1.043 was used struct the haplotypes [21]. ...
Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic—microcephaly primary hereditary (MCPH)—and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT—genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.
... Interactive genealogy visualization tools that are designed to analyze disease clusters and to see disease propagation within families include PedVizApi [14], CraneFoot [36], Haploview [4], PediMap [50], and HaploPainter [47]. HaploPainter [47] visualizes genealogies and genetic recombination events below the individuals' nodes. ...
... Interactive genealogy visualization tools that are designed to analyze disease clusters and to see disease propagation within families include PedVizApi [14], CraneFoot [36], Haploview [4], PediMap [50], and HaploPainter [47]. HaploPainter [47] visualizes genealogies and genetic recombination events below the individuals' nodes. While it shares the approach of showing metadata as rows associated with nodes with Lineage, it does not take a linearization approach to make values of different generations easy to compare, it does not aggregate the network, and it does not visualize different types of attributes. ...
The majority of diseases that are a significant challenge for public and individual heath are caused by a combination of hereditary and environmental factors. In this paper we introduce Lineage, a novel visual analysis tool designed to support domain experts who study such multifactorial diseases in the context of genealogies. Incorporating familial relationships between cases with other data can provide insights into shared genomic variants and shared environmental exposures that may be implicated in such diseases. We introduce a data and task abstraction, and argue that the problem of analyzing such diseases based on genealogical, clinical, and genetic data can be mapped to a multivariate graph visualization problem. The main contribution of our design study is a novel visual representation for tree-like, multivariate graphs, which we apply to genealogies and clinical data about the individuals in these families. We introduce data-driven aggregation methods to scale to multiple families. By designing the genealogy graph layout to align with a tabular view, we are able to incorporate extensive, multivariate attributes in the analysis of the genealogy without cluttering the graph. We validate our designs by conducting case studies with our domain collaborators.
... relationships, making the search and visualization of such relationships a challenging goal. To solve this problem, R packages such as Kinship2 (Sinnwell et al. 2014), software programs like PEDHUNTER (Agarwala et al. 1998), Pelican (Dudbridge et al. 2004), CraneFoot (M€ akinen et al. 2005), HaploPainter (Thiele and N€ urnberg 2005), Graphviz (Zhao 2006), PyPedal (Cole 2007), GeneaQuilts (Bezerianos et al. 2010), PedVis (Tuttle et al. 2010), Pedimap (Voorrips et al. 2012), Helium (Shaw et al. 2014), and E-Brida (E-Brida 2018), and web-based tools for family trees like The Pedigree Tool (Lachmund et al. 2004) or for crops like maize and soybean such as PedigreeNet (Braun et al. 2019) and SoyPedi (Jeong et al. 2022) have been already developed for visualizing pedigrees. The majority of these visualization tools have been designed for breeding purposes, reason why some of them require attached databases, perform genetic calculations, and permit the upload of marker allele data. ...
Pedigree-based analyses’ prime role is to unravel relationships between individuals in breeding programs and germplasms. This is critical information for decoding the genetics underlying main inherited traits of relevance, and unlocking the genotypic variability of a species to carry out genomic selections and predictions. Despite the great interest, current lineage visualizations become quite limiting in terms of public display, exploration, and tracing of traits up to ancestral donors. PERSEUS is a user-friendly, intuitive, and interactive web-based tool for pedigree visualizations represented as directed graph networks distributed using a force-repulsion method. The visualizations do not only showcase individual relationships among accessions, but also facilitate a seamless search and download of phenotypic traits along the pedigrees. PERSEUS is a promising tool for breeders and scientists, advantageous for evolutionary, genealogy, and diversity analyses among related accessions and species.
Availability and implementation
PERSEUS is freely accessible at https://bioinformatics.cragenomica.es/perseus and GitHub code is available at https://github.com/aranzana-lab/PERSEUS.
Supplementary information
Supplementary data is available at Bioinformatics online.
... Haplopainter (http://haplopainter.sourceforge.net/index.html (accessed on 5 April 2021)) [24] was used to draw pedigrees of all families, with a unique identification number given to each family (Figures 1 and 2 and Supplementary Figures S1 and S2). In addition to the retinal phenotypes shared by affected individuals of all families, such as night blindness, poor day vision and photosensitivity, three (RP102, RP105 and RP109) out of nine families were suffering from syndromic disease. ...
Inherited retinal dystrophies (IRDs) are a heterogeneous group of degenerative disorders of the retina. Retinitis Pigmentosa (RP) is a common type of IRD that causes night blindness and loss of peripheral vision and may progress to blindness. Mutations in more than 300 genes have been associated with syndromic and non-syndromic IRDs. Recessive forms are more frequent in populations where endogamy is a social preference, such as Pakistan. The aim of this study was to identify molecular determinants of IRDs with the common presentation of night blindness in consanguineous Pakistani families. This study included nine consanguineous IRD-affected families that presented autosomal recessive inheritance of the night blindness phenotype. DNA was extracted from blood samples. Targeted exome sequencing of 344 known genes for retinal dystrophies was performed. Screening of nine affected families revealed two novel (c.5571_5576delinsCTAGATand c.471dup in EYS and SPATA7 genes, respectively) and six reported pathogenic mutations (c.304C>A, c.187C>T, c.1560C>A, c.547C>T, c.109del and c.9911_11550del in PDE6A, USH2A, USH2A, NMNAT1, PAX6 and ALMS1 genes, respectively) segregating with disease phenotype in each respective family. Molecular determinants of hereditary retinal dystrophies were identified in all screened families. Identification of novel variants aid future diagnosis of retinal dystrophies and help to provide genetic counseling to affected families.
... Haplopainter (http://haplopainter.sourceforge.net/index.html (accessed on 5 April 2021)) [24] was used to draw pedigrees of all families, with a unique identification number given to each family (Figures 1 and 2 and Supplementary Figures S1 and S2). In addition to the retinal phenotypes shared by affected individuals of all families, such as night blindness, poor day vision and photosensitivity, three (RP102, RP105 and RP109) out of nine families were suffering from syndromic disease. ...
Citation: Tehreem, R.; Chen, I.; Shah, M.R.; Li, Y.; Khan, M.A.; Afshan, K.; Chen, R.; Firasat, S. Exome Sequencing Identified Molecular Determinants of Retinal Dystrophies in Nine Consanguineous Pakistani Families
Inherited retinal dystrophies (IRDs) are a heterogeneous group of degenerative disorders of the retina. Retinitis Pigmentosa (RP) is a common type of IRD that causes night blindness and loss of peripheral vision and may progress to blindness. Mutations in more than 300 genes have been associated with syndromic and non-syndromic IRDs. Recessive forms are more frequent in populations where endogamy is a social preference, such as Pakistan. The aim of this study was to identify molecular determinants of IRDs with the common presentation of night blindness in consanguineous Pakistani families. This study included nine consanguineous IRD-affected families that presented autosomal recessive inheritance of the night blindness phenotype. DNA was extracted from blood samples. Targeted exome sequencing of 344 known genes for retinal dystrophies was performed. Screening of nine affected families revealed two novel (c.5571_5576delinsCTAGATand c.471dup in EYS and SPATA7 genes, respectively) and six reported pathogenic mutations (c.304C>A, c.187C>T, c.1560C>A, c.547C>T, c.109del and c.9911_11550del in PDE6A, USH2A, USH2A, NMNAT1, PAX6 and ALMS1 genes, respectively) segregating with disease phenotype in each respective family. Molecular determinants of hereditary retinal dystrophies were identified in all screened families. Identification of novel variants aid future diagnosis of retinal dystrophies and help to provide genetic counseling to affected families.
... Haplotype reconstruction of chromosome 17p region (2980 markers) was performed using MERLIN v1.12 [16]. The haplotypes including recombination events were visualized using HaploPainter v1.043 [17]. The ROH regions around the ASPA pathogenic variant from both the probands were taken as starting point for haplotype analysis. ...
Mild/juvenile Canavan disease (M/JCD) is less frequently reported in literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel ASPA (NM_000049.4):c.526G > A(p.Gly176Ser) variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, indicated to a possibility of founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event, such as a high fixation index, increased runs of homozygosity and identity-by-descent estimation in TDC in the absence of consanguinity; large haplotype with high linkage disequilibrium comprising the pathogenic variant; presence of a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.
... The presence and age at onset of neuropsychiatric diseases (including dementia) was also recorded. Based on this information, detailed family trees were constructed using the HaploPainter 1.043 software ( Thiele and Nürnberg, 2005 ). ...
Using exome sequencing, we analyzed 196 participants of the Cretan Aging Cohort (CAC; 95 with Alzheimer's disease [AD], 20 with mild cognitive impairment [MCI], 81 cognitively normal controls). The APOE ε4 allele was more common in AD patients (23.2%) than in controls (7.4%; p<0.01) and the PSEN2 p.Arg29His and p.Cys391Arg variants was found in three AD and one MCI patient, respectively. Also, we found the Frontotemporal Dementia (FTD)-associated TARDBP gene p.Ile383Val variant in two elderly patients diagnosed with AD and in two patients, non CAC members, with the Amyotrophic Lateral Sclerosis/FTD phenotype. Furthermore, the p.Ser498Ala variant in the positively selected GLUD2 gene was less frequent in AD patients (2.11 %) than in controls (16%; p<0.01), suggesting a possible protective effect. While the same trend was found in another local replication cohort (n=406) and in section of the ADNI cohort (n=808), this finding did not reach statistical significance and therefore it should be considered preliminary. Our results attest to the value of genetic testing to study aged adults with AD phenotype.
... The final linkage parameter for OTSC family was chosen assuming that the disease is inherited in an autosomal dominant pattern with a gene frequency of 0.01% and a phenocopy rate of 1%. Haplotypes were constructed using HaploPainter software [41]. ...
Otosclerosis (OTSC) is the primary form of conductive hearing loss characterized by abnormal bone remodelling within the otic capsule of the human middle ear. A genetic association of the RELN SNP rs3914132 with OTSC has been identified in European population. Previously, we showed a trend towards association of this polymorphism with OTSC and identified a rare variant rs74503667 in a familial case. Here, we genotyped these variants in an Indian cohort composed of 254 OTSC cases and 262 controls. We detected a significant association of rs3914132 with OTSC (OR = 0.569, 95%CI = 0.386–0.838, p = 0.0041). To confirm this finding, we completed a meta-analysis which revealed a significant association of the rs3914132 polymorphism with OTSC (Z = 6.707, p<0.0001) across different ethnic populations. Linkage analysis found the evidence of linkage at RELN locus (LOD score 2.1059) in the OTSC family which has shown the transmission of rare variant rs74503667 in the affected individuals. To understand the role of RELN and its receptors in the development of OTSC, we went further to perform a functional analysis of RELN/reelin. Here we detected a reduced RELN (p = 0.0068) and VLDLR (p = 0.0348) mRNA levels in the otosclerotic stapes tissues. Furthermore, a reduced reelin protein expression by immunohistochemistry was confirmed in the otosclerotic tissues. Electrophoretic mobility shift assays for rs3914132 and rs74503667 variants revealed an altered binding of transcription factors in the mutated sequences which indicates the regulatory role of these variations in the RELN gene regulation. Subsequently, we showed by scanning electron microscopy a change in stapes bone morphology of otosclerotic patients. In conclusion, this study evidenced that the rare variation rs74503667 and the common polymorphism rs3914132 in the RELN gene and its reduced expressions that were associated with OTSC.
... p-values were adjusted for multiple hypothesis testing utilizing the Benjamini-Hochberg method, and the false discovery rate was set at p-adj = 0.05. Pedigrees were examined and plotted using HaploPainter software v. 1.043 [22]. ...
Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10−8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.
... For LOD calculation, complete penetrance, autosomal recessive inheritance, disease-allele frequency of 0.001, no phenocopy, equal recombination frequencies in both males and females were assumed [ Table 2]. Furthermore, reconstruction of haplotypes was done by HaploPainter software (version 029. 5 (Berlin-Buch, Germany)) [18] [ Figure 1]. Polymerase chain reaction (PCR) was applied for the amplification of five DFNB3 STR markers. ...
... Multipoint LOD (logarithm of the odds) scores were calculated using MERLIN [21]. Haplotypes were generated also with MERLIN and displayed graphically using the program HaploPainter v. 1.046 [22]. ...
Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Ar-gfs*42)), which has been shown to be indispensable to AKNA's localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and common to rapidly degraded proteins. An impaired function of the PEST domains may affect the intracellular half-life of the protein. Our genetic findings compellingly substantiate the predicted candidacy, based on its newly ascribed functional features, of the multifaceted protein AKNA for association with MCPH. Keywords: autosomal recessive primary microcephaly (MCPH); AKNA; whole-exome sequencing (WES); linkage/haplotype analysis; cerebral cortex Citation: Waseem, S.S.; Moawia, A.; Budde, B.; Tariq, M.; Khan, A.; Ali, Z.; Khan, S.; Iqbal, M.; Malik, N.A.; Haque, S.u.; et al. A Homozygous AKNA Frameshift Variant Is Associated with Primary Microcephaly in a Pakistani Family. Genes 2021, 12,
... Pedigrees were drawn with HaploPainter [34] and modified to protect the anonymity of participants without altering the distribution of individuals and sex of cases. ...
Background
Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD.
Methods
Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing.
Results
We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5.
Conclusion
This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease.
... There is a wide variety of computer programs that allow the detection of autozygous regions. These can be listed as follows: a commercial software called Homozygosity Detector plugin of Illumina Genome Viewer (Fig. 2), HaploPainter software (Fig. 4) [39] which is an open-source like Genehunter, Al- legro, and SimWalk, whole-genome association, and population-based linkage analyses toolset named the PLINK [40] can be used to detect autozygous regions via identical by descent estimation. In addition "AutoZplotter" is another alternative software which takes a variant calling format (VCF) file as input and allows for manual inspection of long runs of homozygosity/autozygous regions, and is highly used/accessed in the clinical genetics field [41]. ...
Background:
In the context of medical genetics, gene hunting is the process of identifying and functionally characterizing genes or genetic variations that contribute to disease phenotypes. In this review, we would like to summarize gene hunting process in terms of historical aspects from Darwin to now. For this purpose, different approaches and recent developments will be detailed.
Summary:
Linkage analysis and association studies are the most common methods in use for explaining the genetic background of hereditary diseases and disorders. Although linkage analysis is a relatively old approach, it is still a powerful method to detect disease-causing rare variants using family-based data, particularly for consanguineous marriages. As is known that, consanguineous marriages or endogamy poses a social problem in developing countries, however, this same condition also provides a unique opportunity for scientists to identify and characterize pathogenic variants. The rapid advancements in sequencing technologies and their parallel implementation together with linkage analyses now allow us to identify the candidate variants related to diseases in a relatively short time. Furthermore, we can now go one step further and functionally characterize the causative variant through in vitro and in vivo studies and unveil the variant-phenotype relationships on a molecular level more robustly. Key Messages: Herein, we suggest that the combined analysis of linkage and exome analysis is a powerful and precise tool to diagnose clinically rare and recessively inherited conditions.
... Written informed consent was obtained from the guardians of patients and relevant family members. Pedigrees were drawn using HaploPainter v.2.0 (GPLv2) (13). Eighteen patients from the 12 families were male (53%), whereas 16 were female (47%). ...
Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MCPH5-associated gene. The founder mutation p.Trp1326* was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244* and p.Arg1019* were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm of ASPM and expanded the Pakistani MCPH cohort.
... To give further insights into regions showing strongest linkage to the trait, haplotypes were generated from SNPs covering the genomic region that showed multipoint LOD > 2. Haplotypes were created in the haplotype analysis tool simwalk2snp (Lange and Lange 2004) and visualized using Haplopainter (Thiele and Nurnberg 2005). ...
Dyslexia is a common heritable developmental disorder involving impaired reading abilities. Its genetic underpinnings are thought to be complex and heterogeneous, involving common and rare genetic variation. Multigenerational families segregating apparent monogenic forms of language-related disorders can provide useful entrypoints into biological pathways. In the present study, we performed a genome-wide linkage scan in a three-generational family in which dyslexia affects 14 of its 30 members and seems to be transmitted with an autosomal dominant pattern of inheritance. We identified a locus on chromosome 7q21.11 which cosegregated with dyslexia status, with the exception of two cases of phenocopy (LOD = 2.83). Whole-genome sequencing of key individuals enabled the assessment of coding and noncoding variation in the family. Two rare single-nucleotide variants (rs144517871 and rs143835534) within the first intron of the SEMA3C gene cosegregated with the 7q21.11 risk haplotype. In silico characterization of these two variants predicted effects on gene regulation, which we functionally validated for rs144517871 in human cell lines using luciferase reporter assays. SEMA3C encodes a secreted protein that acts as a guidance cue in several processes, including cortical neuronal migration and cellular polarization. We hypothesize that these intronic variants could have a cis -regulatory effect on SEMA3C expression, making a contribution to dyslexia susceptibility in this family.
... Mutation phase was determined by Sanger sequencing of PCR products of plasmid DNA amplification using primers: Phactr1-F1 and Phactr1-R1 (5 0 -gggtcatgaagctgagtgga-3 0 ) for rs3817735, and Phactr1-F3 (5 0 -gtgcgccttgaagctgat-3 0 ) andPhactr1-R3. Haplotypes were visualized using open-source bioinformatics tools, the Haplopainter.30 ...
A young boy with multifocal epilepsy with infantile spasms and hypsarrhythmia with minimal organic lesions of brain structures underwent DNA diagnosis using whole‐exome sequencing. A heterozygous amino‐acid substitution p.L519R in a PHACTR1 gene was identified. PHACTR1 belongs to a protein family of G‐actin binding protein phosphatase 1 (PP1) cofactors and was not previously associated with a human disease. The missense single nucleotide variant in the proband was shown to occur de novo in the paternal allele. The mutation was shown in vitro to reduce the affinity of PHACTR1 for G‐actin, and to increase its propensity to form complexes with the catalytic subunit of PP1. These properties are associated with altered subcellular localization of PHACTR1 and increased ability to induce cytoskeletal rearrangements. Although the molecular role of the PHACTR1 in neuronal excitability and differentiation remains to be defined, PHACTR1 has been previously shown to be involved in Slack channelopathy pathogenesis, consistent with our findings. We conclude that this activating mutation in PHACTR1 causes a severe type of sporadic multifocal epilepsy in the patient.
... These loci were subsequently checked in the remaining families for overlap, i.e. a positive score coinciding with the first locus. When overlaps between familial loci were observed, the individual pedigrees and haplotypes were displayed in Haplopainter [44]. The haplotypes inherited identically by descent (IBD) could be verified, although merely with incomplete penetrance. ...
Primary focal hyperhidrosis (PFH, OMIM %144110) is a genetically influenced condition characterised by excessive sweating. Prevalence varies between 1.0–6.1% in the general population, dependent on ethnicity. The aetiology of PFH remains unclear but an autosomal dominant mode of inheritance, incomplete penetrance and variable phenotypes have been reported. In our study, nine pedigrees (50 affected, 53 non-affected individuals) were included. Clinical characterisation was performed at the German Hyperhidrosis Centre, Munich, by using physiological and psychological questionnaires. Genome-wide parametric linkage analysis with GeneHunter was performed based on the Illumina genome-wide SNP arrays. Haplotypes were constructed using easyLINKAGE and visualised via HaploPainter. Whole-exome sequencing (WES) with 100x coverage in 31 selected members (24 affected, 7 non-affected) from our pedigrees was achieved by next generation sequencing. We identified four genome-wide significant loci, 1q41-1q42.3, 2p14-2p13.3, 2q21.2-2q23.3 and 15q26.3-15q26.3 for PFH. Three pedigrees map to a shared locus at 2q21.2-2q23.3, with a genome-wide significant LOD score of 3.45. The chromosomal region identified here overlaps with a locus at chromosome 2q22.1-2q31.1 reported previously. Three families support 1q41-1q42.3 (LOD = 3.69), two families share a region identical by descent at 2p14-2p13.3 (LOD = 3.15) and another two families at 15q26.3 (LOD = 3.01). Thus, our results point to considerable genetic heterogeneity. WES did not reveal any causative variants, suggesting that variants or mutations located outside the coding regions might be involved in the molecular pathogenesis of PFH. We suggest a strategy based on whole-genome or targeted next generation sequencing to identify causative genes or variants for PFH.
... This could mean the language phenotype within Branch 2 varies more meaningfully in comparison to the members of the other branches. To understand how the alleles are inherited to the 15q locus in Family 315, we computed haplotypes, using MERLIN and Haplopainter (see Figure 2; Abecasis et al., 2002;Thiele & Nürnberg, 2004). Two cross-over events delimit the 14.54-Mb linkage region in Branches 1 and 3 (see^on Figure 2). ...
Purpose
Specific language impairment (SLI) is characterized by a delay in language acquisition despite a lack of other developmental delays or hearing loss. Genetics of SLI is poorly understood. The purpose of this study is to identify SLI genetic loci through family-based linkage mapping.
Method
We performed genome-wide parametric linkage analysis in six families segregating with SLI. An age-appropriate standardized omnibus language measure was used to categorically define the SLI phenotype.
Results
A suggestive linkage region replicated a previous region of interest with the highest logarithm of odds (LOD) score of 2.40 at 14q11.2-q13.3 in Family 489. A paternal parent-of-origin effect associated with SLI and language phenotypes on a nonsynonymous single nucleotide polymorphism (SNP) in NOP9 (14q12) was reported previously. Linkage analysis identified a new SLI locus at 15q24.3-25.3 with the highest parametric LOD score of 3.06 in Family 315 under a recessive mode of inheritance. Suggestive evidence of linkage was also revealed at 4q31.23-q35.2 in Family 300, with the highest LOD score of 2.41. Genetic linkage was not identified in the other three families included in parametric linkage analysis.
Conclusions
These results are the first to report genome-wide suggestive linkage with a total language standard score on an age-appropriate omnibus language measure across a wide age range. Our findings confirm previous reports of a language-associated locus on chromosome 14q, report new SLI loci, and validate the pedigree-based parametric linkage analysis approach to mapping genes for SLI.
Supplemental Material
https://doi.org/10.23641/asha.13203218
... Genotyping of STR markers was performed through resolving PCR products on 12% nondenaturing polyacrylamide gel, followed by silver staining and visually inspecting genetic linkage analysis of DFNB loci. Haplotyping and logarithm of the odds score calculations were done either to confirm or reject linkage [Thiele, 2005]. ...
Background and objectives:
Identification of the pathogenic mutations underlying hereditary hearing loss (HL) is difficult, since causative mutations in 60 different genes have so far been reported.
Methods:
A comprehensive clinical and pedigree examination was performed on a multiplex family suffering from HL. Direct sequencing of GJB2 and genetic linkage analysis of 5 other most common recessive nonsyndromic HL (ARNSHL) genes were accomplished. Next-generation sequencing (NGS) was utilized to reveal the possible genetic etiology of the disease.
Results:
NGS results showed a novel rare variant c.2977G>A (p.Asp993Asn) in the CDH23 gene. The variant, which is a missense in exon 26 of the CDH23 gene, fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Electroretinography rejects the Usher syndrome in the family.
Conclusions:
The present study shows that an accurate molecular diagnosis based on NGS technologies largely improves molecular-diagnostic outcome and thus genetic counseling, and helps to clarify the recurrence risk in deaf families.
... ng. The analysis was carried out on six family members of Family C: the father and the maternal grandparents of the affected nephew had been created with missing genotype values so that Merlin could take into account all familial relationships.To be able to visualize the haplotypes with Haplopainter (http:// haplopainter.sourceforge.net/index.html;Thiele & Nurnberg, 2005), they were computed with Merlin on a smaller region of the X evs.gs.washington.edu/EVS/), HapMap (http://hapmap.ncbi.nlm.nih.gov/), 1000Genomes (http://www.1000genomes.org/), Exome Aggregation Consortium (http://exac.broadinstitute.org/), and Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org/) were considered to be p ...
... 11 Also haplotypes were reconstructed with either of these programs and presented graphically with HaploPainter. 13 2.5 | Estimation of variant age by IBD DNA samples of 14 individuals belonging to five families were genotyped on the Axiom Precision Medicine Research Array (Thermo Fisher Scientific). Genotypes were called by the Axiom Analysis Suite v4.0 (Thermo Fisher Scientific). ...
Nonsyndromic hearing loss is an extremely heterogeneous disorder. Thus, clinical diagnostics is challenging, in particular due to differences in the etiology of hearing loss between populations. With this study, we wanted to elucidate the genetic basis of hearing loss in 61 consanguineous Egyptian families. In 25 families, linkage analysis was used as a prescreening to identify regions for targeted sequencing of candidate genes. Initially, the coding regions of 12 and later of 94 genes associated with hearing loss were enriched and subjected to massively parallel sequencing (MPS) with diagnostic yields of 36% and 75%, respectively. Causative variants were identified in 48 families (79%). They were found in 23 different genes with the majority being located in MYO15A (15.3%), SLC26A4 (9.7%), GJB2 (8.3%), and MYO7A (6.4%). As many as 32 variants were novel ones at the time of detection. Five variants were shared by two, three, or even four families. Our study provides a first survey of the mutational spectrum of deaf patients in Egypt revealing less GJB2 variants than in many European populations. It underlines the value of targeted enrichment of well‐selected deafness genes in combination with MPS in the diagnostics of this frequent and genetically heterogeneous disorder.
... Genotyping of STR markers was performed through resolving PCR products on 12% nondenaturing polyacrylamide gel followed by silver staining and visual inspection for genetic linkage analysis of DFNB loci. Haplotyping and logarithm of the odds score calculations were done either to confirm or reject linkage [Thiele and Nürnberg, 2005]. ...
Background and objectives:
Hereditary hearing loss (HL) can originate from mutations in one of many genes involved in the complex process of hearing. CABP2 mutations have been reported to cause moderate HL. Here, we report the whole exome sequencing (WES) of a proband presenting with prelingual, severe HL in an Iranian family.
Methods:
A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 2 affected members. After excluding mutations in the GJB2 gene and 7 other most common autosomal recessive nonsyndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis in the family, WES was utilized to find the possible etiology of the disease.
Results:
WES results showed a novel rare variant (c.311G>A) in the CABP2gene.This missense variant in the exon 4 of the CABP2gene meets the criteria of being pathogenic according to the American College of Medical Genetics and Genomics (ACMG) interpretation guidelines.
Conclusions:
Up to now, 3 mutations have been reported for the CABP2gene to cause moderate ARNSHL in different populations. Our results show that CABP2variantsalso cause severe ARNSHL, adding CABP2to the growing list of genes that exhibit phenotypic heterogeneity. Expanding our understanding of the mutational spectrum of HL genes is an important step in providing the correct clinical molecular interpretation and diagnosis for patients.
... Furthermore, reconstruction of haplotypes was done by HaploPainter software (version 029.5) [ Figure 1]. [18] ...
... Multipoint, logarithm of the odds (LOD) scores were calculated using MERLIN. Haplotypes were reconstructed with MERLIN and presented graphically with HaploPainter (20). The 2-yr-old sister of the patients was not presented to us initially and was genotyped for the SLC6A6 variant in the course of segregation analysis. ...
We previously reported that inactivation of the transmembrane taurine transporter (TauT or solute carrier 6a6) causes early retinal degeneration in mice. Compatible with taurine's indispensability for cell volume homeostasis, protein stabilization, cytoprotection, antioxidation, and immuno‐ and neuromodulation, mice develop multisystemic dysfunctions (hearing loss; liver fibrosis; and behavioral, heart, and skeletal muscle abnormalities) later on. Here, by genetic, cell biologic, in vivo ¹H–magnetic resonance spectroscopy and molecular dynamics simulation studies, we conducted in‐depth characterization of a novel disorder: human TAUT deficiency. Loss of TAUT function due to a homozygous missense mutation caused panretinal degeneration in 2 brothers. TAUTp.A78E still localized in the plasma membrane but is predicted to impact structural stabilization. ³H‐taurine uptake by peripheral blood mononuclear cells was reduced by 95%, and taurine levels were severely reduced in plasma, skeletal muscle, and brain. Extraocular dysfunctions were not yet detected, but significantly increased urinary excretion of 8‐oxo‐7,8‐dihydroguanosine indicated generally enhanced (yet clinically unapparent) oxidative stress and RNA oxidation, warranting continuous broad surveillance.—Preising, M. N., Görg, B., Friedburg, C., Qvartskhava, N., Budde, B. S., Bonus, M., Toliat, M. R., Pfleger, C., Altmüller, J., Herebian, D., Beyer, M., Zöllner, H. J., Wittsack, H.‐J., Schaper, J., Klee, D., Zechner, U., Nürnberg, P., Schipper, J., Schnitzler, A., Gohlke, H., Lorenz, B., Häussinger, D., Bolz, H. J. Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration. FASEB J. 33, 11507–11527 (2019). www.fasebj.org
... Genotype data quality control and data management was facilitated by the program ALOHOMORA (15). HaploPainter (16) was used for drawing pedigrees with haplotypes based on MERLIN calculations. ...
Mutations in several genes encoding ion channels can cause the long-QT (LQT) syndrome with cardiac arrhythmias, syncope and sudden death. Recently, mutations in some of these genes were also identified to cause epileptic seizures in these patients, and the sudden unexplained death in epilepsy (SUDEP) was considered to be the pathologic overlap between the two clinical conditions. For LQT-associated KCNQ1 mutations, only few investigations reported the coincidence of cardiac dysfunction and epileptic seizures. Clinical, electrophysiological and genetic characterization of a large pedigree (n = 241 family members) with LQT syndrome caused by a 12-base-pair duplication in exon 8 of the KCNQ1 gene duplicating four amino acids in the carboxyterminal KCNQ1 domain (KCNQ1dup12; p.R360_Q361dupQKQR, NM_000218.2, hg19). Electrophysiological recordings revealed no substantial KCNQ1-like currents. The mutation did not exhibit a dominant negative effect on wild-type KCNQ1 channel function. Most likely, the mutant protein was not functionally expressed and thus not incorporated into a heteromeric channel tetramer. Many LQT family members suffered from syncopes or developed sudden death, often after physical activity. Of 26 family members with LQT, seizures were present in 14 (LQTplus seizure trait). Molecular genetic analyses confirmed a causative role of the novel KCNQ1dup12 mutation for the LQT trait and revealed a strong link also with the LQTplus seizure trait. Genome-wide parametric multipoint linkage analyses identified a second strong genetic modifier locus for the LQTplus seizure trait in the chromosomal region 10p14. The linkage results suggest a two-locus inheritance model for the LQTplus seizure trait in which both the KCNQ1dup12 mutation and the 10p14 risk haplotype are necessary for the occurrence of LQT-associated seizures. The data strongly support emerging concepts that KCNQ1 mutations may increase the risk of epilepsy, but additional genetic modifiers are necessary for the clinical manifestation of epileptic seizures.
... However, due to the linkage software restraints, the cases were clustered into 27 smaller (≤24 bits) families using PEDCUT software (Liu et al., 2008). We used Haplopainter (Thiele and Nürnberg, 2005) to illustrate all 27 pedigrees (Supplementary figure 1). We then performed affected-only parametric linkage analysis in MERLIN software (Abecasis et al., 2002) using incomplete penetrance and no phenocopies for both dominant (0, 0.5, 0.5) and recessive models (0, 0, 0.5) (Durner et al., 1999). ...
Creating pedigree charts is a recurring task in biomedical research, but there are few online tools for drawing complex human pedigrees available and even fewer are free. With DrawPed we aim to close this gap. DrawPed automatically draws pedigree charts from standard PED format pedigree files. Users can also create pedigrees from scratch and interactively edit existing pedigrees. The application can display conditions not captured in a PED file such as deceased persons or suspected consanguinity of parents. Pedigree charts are displayed as SVGs, which are scalable and hence publication-ready. Pedigrees can be exported as PED files for storage, exchange, or use in other applications. DrawPed is open source and freely available at https://www.genecascade.org/DrawPed/.
MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in two siblings with microcephaly, epileptic encephalopathy and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13-, Mad2- and Rev7-binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated a newly identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early deceased patient with low-level aneuploidy, severe epileptic encephalopathy and frequent blood glucose elevations likely corresponds to complete loss-of-function, as in Mad2l1bp-/- mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.
The manuscript addresses an important topic: genetic analysis of Vitiligo. Vitiligo is a complicated condition and the genetic factors account for 80% of the risk. Linkage analysis for a four generations Chinese family identified 16p13.3p13.2 as the susceptibility locus of vitiligo, whole exome sequencing then identified PDIA2 as the new candidate gene. The association between the candidate gene and vitiligo requires further investigation.
Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XYGONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.
La enfermedad de Parkinson (EP) es común y se debe a degeneración de las neuronas dopaminérgicas en la sustancia nigra y en otras áreas del cerebro. Varios genes y mutaciones han sido implicados en ella y la mayoría de estas últimas han sido identificadas en el gen PARK2. Reportamos la evaluación de este gen PARK2 y de su región flanqueante en una gran familia de origen caucano, al suroccidente de Colombia. Los padres son primos hermanos y cuatro de sus diez hijos resultaron afectados en edad juvenil. La evaluación molecular incluyó tipificación de microsatélites (STR) y la secuencia directa de los exones del gen. Nuestros hallazgos evidenciaron la presencia en condición homocigota de la mutación c.255delA, en el exón 2 de PARK2. Además, se pudo identificar un haplotipo portado por ambos padres y presente en condición homocigota en los hijos afectados. Del mismo modo se observó una alta tasa de recombinantes en la extensión de la región cromosómica analizada. La mutación c.255delA en PARK2 ya había sido reportada previamente en familias tanto de Francia como de España. Nuestros resultados reconfirman la participación del gen PARK2 en la etiología de la enfermedad de Parkinson, en particular de la forma juvenil. Además, considerando que la mutación identificada en la familia que presentamos ya había sido previamente encontrada en poblaciones europeas, es probable que haya llegado a Colombia desde allí. Alternativamente, esta mutación pudo ocurrir de manera recurrente en un ancestro más cercano de la familia estudiada; para verificar ambas posibilidades sería necesario evaluar marcadores flanqueantes de la mutación, en los cromosomas europeos y colombianos portadores de la mutación. Tales marcadores pueden ser STR (como se reporta en este estudio) o alternativamente, SNP.
La spondyloarthrite (SpA) est une maladie multifactorielle avec une héritabilité estimée à plus de 90%, principalement en lien avec le HLA-B27. L'ensemble des facteurs de susceptibilité identifiés, incluant HLA-B27, expliquent moins du tiers de l'héritabilité. L'implication de variants rares pourrait expliquer une partie de cette héritabilité manquante. L'objectif de ce travail était d'identifier des variants rares associés à la SpA via une approche combinant analyses familiales et séquençage haut-débit. D'abord, nous avons séquencé une région de 1,4 Mb significativement liée à la SpA en 13q13 chez 71 patients et 21 témoins sains appartenant à des familles avec un score de liaison élevée dans cette région. Nous avons identifié un variant rare dans le gène FREM2 présent chez 9 malades d'une famille fortement liée à la région et non retrouvé dans d'autres familles ou cas isolés de SpA. Nous avons ensuite séquencé l'exome de 48 malades venant de 20 familles multiplex. Malheureusement, nous n'avons pas observé de variants récurrents entre les familles. Puis, nous nous sommes concentrés sur un deuxième pic de liaison génétique, déjà connu, sur le chromosome 9. L'étude de la famille la plus liée à cette région, qui comprend 12 patients, a conduit à l'identification de plusieurs variants rares codants ségrégeant avec la maladie. Cependant les études ultérieures ont montré des fréquences alléliques de ces variants équivalentes entres les cas et les témoins. Enfin, le séquençage du génome entier de 413 patients issus de 76 familles multiplex avec 4 malades ou plus a été réalisé. Nous avons identifié 1203 variants rares, codants et non synonymes et partagés par au moins tous les membres atteints d'une famille. Les analyses de validation génétique et fonctionnelle de ces variants sont en cours, tout comme l'analyse des variants non-codants. En conclusion, ces différentes approches suggèrent une importante hétérogénéité génétique de la SpA et soulignent également la difficulté de confirmer l'implication de variants rares dans les maladies complexes.
Mild/juvenile Canavan disease (M/JCD) is less frequently reported in the literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel NM_000049.4(ASPA):c.526G>A variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile-onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, led us to speculate the possibility of a founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event in TDC, such as a high fixation index, increased runs of homozygosity and identity-by-descent in the absence of consanguinity; a large haplotype with high linkage disequilibrium among markers comprising the pathogenic variant; a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.
The evolutionary conserved Polo-like kinase 4 (PLK4) is essential for centriole duplication, spindle assembly, and de novo centriole formation. In man, homozygous mutations in PLK4 lead to primary microcephaly, altered PLK4 expression is associated with aneuploidy in human embryos. Here, we report on a consanguineous four-generation family with 8 affected individuals compound heterozygous for a novel missense variant, c.881 T > G, and a deletion of the PLK4 gene. The clinical phenotype of the adult patients is mild compared to individuals with previously described PLK4 mutations. One individual was homozygous for the variant c.881G and phenotypically unaffected. The deletion was inherited by 14 of 16 offspring and thus exhibits transmission ratio distortion (TRD). Moreover, based on the already published families with PLK4 mutations, it could be shown that due to the preferential transmission of the mutant alleles, the number of affected offspring is significantly increased. It is assumed that reduced expression of PLK4 decreases the intrinsically high error rate of the first cell divisions after fertilization, increases the number of viable embryos and thus leads to preferential transmission of the deleted/mutated alleles.
Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene–brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering.
We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9–63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography.
We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca’s area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype.
Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca’s area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.
The vertebrate left–right axis is specified during embryogenesis by a transient organ: the left–right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left–right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.
Inherited retinal dystrophies (IRDs) constitute one of the most heterogeneous groups of Mendelian human disorders. Using autozygome-guided next-generation sequencing methods in 17 consanguineous pedigrees of Iranian descent with isolated or syndromic IRD, we identified 17 distinct genomic variants in 11 previously-reported disease genes. Consistent with a recessive inheritance pattern, as suggested by pedigrees, variants discovered in our study were exclusively bi-allelic and mostly in a homozygous state (in 15 families out of 17, or 88%). Out of the 17 variants identified, 5 (29%) were never reported before. Interestingly, two mutations (GUCY2D:c.564dup, p.Ala189ArgfsTer130 and TULP1:c.1199G > A, p.Arg400Gln) were also identified in four separate pedigrees (two pedigrees each). In addition to expanding the mutational spectrum of IRDs, our findings confirm that the traditional practice of endogamy in the Iranian population is a prime cause for the appearance of IRDs.
Whole exome sequencing and linkage analysis were performed in a three gener-ational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson's disease and Parkinson's disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplo-type. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenera-tive diseases beyond AD.
Introduction: Inherited retinal diseases (IRDs) are one of the most common causes of incurable blindness in children and young adults. In the Czech Republic, prior to the start of our work, these disorders had not been the subject of a systematic research. The aim of the study was to identify, clinically characterize and molecular genetically analyse Czech patients with monogenic IRDs and based on the knowledge gained subsequently implement preventive and therapeutic measures to clinical practice.
Material and methods: We have performed a comprehensive clinical examination, genealogical analysis and molecular genetic investigation in patients with IRDs and their family members. Detailed ocular examination included spectral domain optical coherence tomography, high-resolution fundus photography and autofluorescence imaging. DNA was isolated from venous blood samples or buccal cells. Causal variants were searched for using Sanger and massively parallel sequencing, and their pathogenicity was evaluated in the context of previously published data, bioinformatical analysis and segregation in available family members.
Results: In total, 103 individuals from 76 Czech families diagnosed with IRDs were characterized and their data published. Specifically, we have described clinical and molecular genetic findings in patients with retinitis pigmentosa, Usher syndrome, Danon disease, Stargardt disease, early-onset severe retinal dystrophies, congenital disorder of glycosylation type Iq, and achromatopsia. The most significant was characterization of ocular findings in the largest single-center cohort of patients suffering from Danon disease.
Conclusions: Our research helped to elucidate factors involved in the etiopathogenesis of various retinal dystrophies and highlighted the need for detailed genotype-phenotype correlations, which is important for early diagnosis, development of effective screening procedure, improvement of clinical counseling and care, implementation of preventive measures and selection of patients for targeted therapies. The project has raised awareness of IRDs among both professionals and the general public.
The SLC26A4 gene has been described as the second gene involved in most cases of autosomal recessive non-syndromic hearing loss (ARNSHL), after GJB2. Over 500 different SLC26A4 mutations have been reported, with each ethnic population having its own distinctive mutations. Here, we aimed to determine the frequency and mutation profile of the SLC26A4 gene from two different provinces (center and west) of Iran. This study included 50 nuclear families with two or more siblings segregating presumed ARNSHL. All affected tested negative for mutations in GJB2 at the DFNB1 locus and were therefore screened for autozygosity by descent using short tandem repeat polymorphisms (STRPs) of DFNB4. Sanger sequencing was performed to screen the 20 exons of the SLC26A4 gene for the families linked to this locus. In silico analyses were also performed using available software tools. Four out of 25 (16%) and 3 of 25 (12%) studied families of Isfahan and Hamedan provinces, respectively. were linked to DFNB4. Sanger sequencing led to the identification of six different mutations, one of which (c.919-2A>G) was recurrent and accounted for 31% of all mutant alleles. One out of 7 (14.3%) families with mutations were confirmed to be Pendred syndrome (PS). The SLC26A4 mutations have a high carrying rate in ARNSHL Iranian patients. The identification of a disease causing mutation can be used to establish a genotypic diagnosis and provide important information to the patients and their families.
To address issues related to unbalanced tri-allelic patterns, an example at the D10S1248 locus characterized by the sum of heights of alleles 13 and 15 approximately equal to allele 14 was intensively investigated. The coexistence of these three alleles was confirmed by profiling the rs2246512-D10S1248 marker using fluorescently labelled primers and allelic sequencing. Multi-tissue genotyping revealed that this pattern had chimeric characteristics, and pedigree analysis found that allele 13 or allele 14 were inherited to offspring independently of the other two alleles. These evidences suggest that the pattern should stem from a somatic mutation in early embryonic development and that peak height ratio is not an accurate indicator of mutation time point and direction. The rs2246538-D10S1248-rs2246512 marker was subsequently used to determine the mutation from allele 15 to allele 13. Notably, allele 13 with the lowest peak height was misidentified as a stutter peak when genotyped using next generation sequencing.
Electronic medical records are at the core of an advancing movement toward information-driven healthcare. By enhancing abilities to capture, store, and analyse vast amounts of health data, the routine use of electronic medical records is advocated as a means to improve the efficiency and quality of care provision, advance population health, empower patients, and reduce healthcare costs. However, the delivery of any benefits is threatened by a failure to understand the unique care environments of different clinical specialties, and to appropriately customise system design. This has prompted a move to the user-centred design process of health information technology. Paediatric ophthalmology is a unique field that faces particular challenges in electronic medical record adoption. As with other ophthalmic specialties, the heavy use of imaging and diagrammatic documentation is difficult to replicate electronically. As is the flexibility required to meet the demands incurred by the varying ages, developmental stages, and visual needs of each patient, reflecting a unique interface between the ophthalmic and paediatric requirements. The consideration of such requirements is essential throughout the user-centred design of effective health information technology systems. However, paucity in the evidence base surrounding electronic medical record design methodologies and system usage hinders technological development and application within paediatric ophthalmology. This research was centred on a user-centred design process, to provide an understanding of the users of electronic medical records in paediatric ophthalmology, and their requirements. Taking a mixed methods approach, this research initially explored the landscape of medical record use – gathering user- centred requirements – and concluded with the development and testing of three prototype data collection forms, for specific use cases within paediatric ophthalmology. Overall, this work articulates the specific challenges and requirements in this area, and provides the foundation for future design and adoption strategies of electronic medical record systems within paediatric ophthalmology.
Applying genetic screening in Medullary Thyroid Cancer (MTC) patients we identified an unexpected high frequency of c.2671T>G, p.Ser891Ala RET mutation carriers. Our aim was to: i) deeply characterize clinical expression of this mutation, ii) identify the presence of a founder effect in our region. Genetic analysis was performed in 251 relatives from 28 Ser891Ala kindreds, among 108 p.Ser891Ala asymptomatic carriers, 64 were submitted to thyroidectomy: mean age for 10 subjects presenting C‐cells hyperplasia was 30.2±13.7 years, raising to 37.9±10.3 in 14 subjects with micro‐MTC and to 55.0±14.7 years in 39 subjects with MTC. Age related progression across histopathological groups CCH/microMTC and MTC was statistically significant: genetic screening in Ser891Ala families could be safely postponed at the age of 14. To investigate the hypothesis of a common ancestor for Ser891Ala mutation we genotyped for 18 polymorphic microsatellite markers encompassing RET locus all subjects belonging to Ser891Ala families and we identified a founder effect, estimating the age of a common ancestor, dating back to 1493 AD. Ethnographic data collected in historical archives support laboratory results; the high prevalence of this mutation in our region could suggest the hypothesis of a population study to realize a preventive intervention in a rare neoplastic disease.
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Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~ 260 genes. Albeit that many genes are implicated in IRD, for 30‐50% of the cases the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked copy number variations, by variants in intronic or promoter regions or represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB) show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of gene coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that 7 of 189 CACNA1F‐related cases have intronic and synonymous disease causing variants leading to missplicing as validated by mini‐gene approaches. These findings highlight that gene locus sequencing may be a very efficient method in detecting disease‐causing variants in clinically well characterized patients with a diagnosis of IRD, like icCSNB.
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We developed a collaborative pedigree environment called CoPE. This environment includes a Java program for drawing
pedigrees and a standardized system for pedigree storage. Unlike other existing pedigree programs, this software is particularly
intended for epidemiologists in the sense that it allows customized automatic drawing of large numbers of pedigrees and remote
and distributed consultation of pedigrees. AVAILABILITY: At http://www.infobiogen.fr/services/CoPE
Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multipoint engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.
................ ................ ................ ................ ................ ................ ................ ............... ongenital myopathies (CM) are neuromuscular disorders classified by characteristic histopathological findings in muscle fibers. Areas devoid of oxidative enzyme activity (core lesions) are pathological hallmarks of autosomal dominant or recessive central core disease (CCD; MIM 117000) and multiminicore disease (MmD; MIM 255320). While large and solitary cores in the center and along the entire length of muscle fibers are considered typical for CCD and multiple smaller cores within muscle fibers define MmD, this classic histological distinction is complicated by the marked histological variability of core lesions. 1 Minicores and central cores have been detected concomitantly as well as separately in successive muscle biopsy specimens of single patients and in myofibers of different affected family members. 1–4 So far, mutations in
Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multi-point engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.
The hypomyelinating leukodystrophies X-linked Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher- like disease (PMLD) are characterized by nystagmus, progressive spasticity, and ataxia. In a consanguineous family with PMLD, we performed a genomewide linkage scan using the GeneChip Mapping EA 10K Array (Affymetrix) and detected a single gene locus on chromosome 1q41-q42. This region harbors the GJA12 gene, which encodes gap junction protein a12 (or connexin 46.6). Gap junction proteins assemble into intercellular channels through which signaling ions and small molecules are exchanged. GJA12 is highly expressed in oligodendrocytes, and, therefore, it serves as an excellent candidate for hypomyelination in PMLD. In three of six families with PMLD, we detected five different GJA12 mutations, including missense, nonsense, and frameshift mutations. We thereby confirm previous assumptions that PMLD is genetically heterogeneous. Although the murine Gja12 ortholog is not expressed in sciatic nerve, we did detect GJA12 transcripts in human sciatic and sural nerve tissue by reverse- transcriptase polymerase chain reaction. These results are in accordance with the electrophysiological finding of reduced motor and sensory nerve conduction velocities in patients with PMLD, which argues for a demyelinating neuropathy. In this study, we demonstrate that GJA12 plays a key role in central myelination and is involved in peripheral myelination in humans.
This paper describes a visual approach to the input of information about human families into computer data bases, making use of the GEM graphic interface on the Atari ST. Similar approaches could be used on the Apple Macintosh or on the IBM PC AT (to which it has been transferred). For occasional users of pedigree analysis programs, this approach has considerable advantages in ease of use and accessibility. An example of such use might be the analysis of risk in families with Huntington disease using linked RFLPs. However, graphic interfaces do make much greater demands on the programmers of these systems.
We have recently developed and implemented three different computer algorithms for accurate haplotyping with large numbers of codominant markers. Each of these algorithms employs likelihood criteria that correctly incorporate all intermarker recombination fractions. The three programs, HAPLO, SIMCROSS, and SIMWALK, are now available for haplotying general pedigrees. The HAPLO program will be distributed as part of the Programs for Pedigree Analysis package by Kenneth Lange. The SIMCROSS and SIMWALK programs are available by anonymous ftp from watson.hgen.pitt.edu. Each program is written in FORTRAN 77 and is distributed as source code. 15 refs.
In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.
We present two extensions to linkage analysis for genetically complex traits. The first extension allows investigators to perform parametric (LOD-score) analysis of traits caused by imprinted genes-that is, of traits showing a parent-of-origin effect. By specification of two heterozygote penetrance parameters, paternal and maternal origin of the mutation can be treated differently in terms of probability of expression of the trait. Therefore, a single-disease-locus-imprinting model includes four penetrances instead of only three. In the second extension, parametric and nonparametric linkage analysis with two trait loci is formulated for a multimarker setting, optionally taking imprinting into account. We have implemented both methods into the program GENEHUNTER. The new tools, GENEHUNTER-IMPRINTING and GENEHUNTER-TWOLOCUS, were applied to human family data for sensitization to mite allergens. The data set comprises pedigrees from England, Germany, Italy, and Portugal. With single-disease-locus-imprinting MOD-score analysis, we find several regions that show at least suggestive evidence for linkage. Most prominently, a maximum LOD score of 4.76 is obtained near D8S511, for the English population, when a model that implies complete maternal imprinting is used. Parametric two-trait-locus analysis yields a maximum LOD score of 6.09 for the German population, occurring exactly at D4S430 and D18S452. The heterogeneity model specified for analysis alludes to complete maternal imprinting at both disease loci. Altogether, our results suggest that the two novel formulations of linkage analysis provide valuable tools for genetic mapping of multifactorial traits.
Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human traits and on other model organisms, including mouse, fly, nematode and yeast. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation.
Linkage analysis software requires an input text file that describes the structure of the pedigrees to be analysed. Manual
creation of these files is tedious and error-prone, and a graphical input tool is desirable. This is currently only available
in commercial packages that include much greater functionality. We have therefore developed Pelican, a lightweight graphical
pedigree editor for rapid construction of linkage pedigree files and diagrams.
Availability: The software runs on any Java-enabled machine (version 1.2 or higher). A Java Web Start launch, class files, a demonstration
applet, source code and documentation are freely available at http://www.rfcgr.mrc.ac.uk/Software/PELICAN/
We identified three consanguineous Austrian kindreds with 15 members affected by autosomal recessive childhood-onset severe retinal dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells. A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3-q24.1 that contains the gene associated with this form of retinal dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle. A homozygous 677A-->G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic retinal dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with retinal dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C-->T (resulting in Q189X), each in the homozygous state, and 146C-->T (resulting in T49M) and 184C-->T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another retinal dehydrogenase. Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.
ALOHOMORA -A Tool for Data Conversion, Quality Control and Linkage Analysis of large-scale SNP Chip Genotype Data
- F Ruschendorf
- C Becker
- K Strauch
- A M Kaindl
- A Huebner
- A Janecke
- G Utermann
- P Nürnberg
Ruschendorf F, Becker C, Strauch K, Kaindl AM, Huebner A, Janecke A, Utermann
G, Nürnberg P. ALOHOMORA -A Tool for Data Conversion, Quality Control
and Linkage Analysis of large-scale SNP Chip Genotype Data. HGM2004 Human
Genome Meeting Berlin, Germany 4th -7th April 2004; published on line;