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Burden of Rare Copy Number Variants in Microcephaly: A Brazilian Cohort of 185 Microcephalic Patients and Review of the Literature

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Giovanna Tolezano at University of São Paulo
Giovanna Tolezano
Giovanna Civitate Bastos at University of São Paulo
Giovanna Civitate Bastos
Silvia Costa at University of São Paulo
Silvia Costa
Bruna Lucheze Freire
Bruna Lucheze Freire
Bruna Lucheze Freire
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Abstract and Figures

Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients with microcephaly and evaluated microcephalic patients carrying < 200 kb CNVs documented in the DECIPHER database. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed, OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200 kb CNVs, at least one known microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates, including OTUD7A, BBC3, CNTN6, and NAA15. In the review, we compiled 957 known microcephaly genes and 58 genomic CNV loci, comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and provided a useful resource for future research on the field of neurodevelopment.
Rare CNVs detected in 39 microcephalic Brazilian patients regarding their a pathogenicity classification, b variant type, c pattern of CNV inheritance, and d chromosomal location
Rare CNVs detected in 39 microcephalic Brazilian patients regarding their a pathogenicity classification, b variant type, c pattern of CNV inheritance, and d chromosomal location
… 
Overlapping copy number changes highlighting new candidate genes for microcephaly detected in Brazilian patients or in prioritized microcephalic DECIPHER patients carrying < 200 kb CNVs. Genomic features of each overlapping segment are displayed with the encompassed protein-coding genes (GENCODE v36 track). Blue lines indicate duplications, red lines indicate deletions, and aqua green areas highlight the proposed candidate genes; darker tracks denote known CNV syndromes already associated with a reduction in brain size. Patients’ DECIPHER IDs are shown; T2 corresponds to “Table 2”, and T4 to “Table 4” (images derived from the UCSC Genome Browser, up to July 2021). a 3p26.3 deletions encompassing the CNTN6 and CHL1 genes, among others, with superposition with the chromosome 3pter-p25 deletion syndrome region. b Overlapping segments at 3q27.1q27.2. The AP2M1 gene was fully deleted in patient 421,069. In patient 421,075 one of the CNV breakpoints was located proximally to the 5’ UTR of this gene. c Four patients carried 4p16.3 deletions, partially overlapping the Wolf-Hirschhorn syndrome region. Three CNVs encompass the NSD2 and NELFA genes, and one includes only NELFA. d Two 4q31.3 deletions encompassing the NAA15 gene. e Two 14q11.2 duplications including the CHD8 gene. f Two 19q13.32 overlapping duplications; one of them includes three candidate genes for microcephaly, NPAS1, KPTN, and BBC3, and the other CNV includes only BBC3. g 22q13.33 deletions encompassing the SHANK3 gene; the segments overlap the Phelan-McDermid syndrome region, typically associated with macrocephaly, but not with microcephaly
Overlapping copy number changes highlighting new candidate genes for microcephaly detected in Brazilian patients or in prioritized microcephalic DECIPHER patients carrying < 200 kb CNVs. Genomic features of each overlapping segment are displayed with the encompassed protein-coding genes (GENCODE v36 track). Blue lines indicate duplications, red lines indicate deletions, and aqua green areas highlight the proposed candidate genes; darker tracks denote known CNV syndromes already associated with a reduction in brain size. Patients’ DECIPHER IDs are shown; T2 corresponds to “Table 2”, and T4 to “Table 4” (images derived from the UCSC Genome Browser, up to July 2021). a 3p26.3 deletions encompassing the CNTN6 and CHL1 genes, among others, with superposition with the chromosome 3pter-p25 deletion syndrome region. b Overlapping segments at 3q27.1q27.2. The AP2M1 gene was fully deleted in patient 421,069. In patient 421,075 one of the CNV breakpoints was located proximally to the 5’ UTR of this gene. c Four patients carried 4p16.3 deletions, partially overlapping the Wolf-Hirschhorn syndrome region. Three CNVs encompass the NSD2 and NELFA genes, and one includes only NELFA. d Two 4q31.3 deletions encompassing the NAA15 gene. e Two 14q11.2 duplications including the CHD8 gene. f Two 19q13.32 overlapping duplications; one of them includes three candidate genes for microcephaly, NPAS1, KPTN, and BBC3, and the other CNV includes only BBC3. g 22q13.33 deletions encompassing the SHANK3 gene; the segments overlap the Phelan-McDermid syndrome region, typically associated with macrocephaly, but not with microcephaly
… 
Distribution of the genes detected in the microcephaly associated-CNVs into four categories: known genes in which point mutations cause microcephaly, candidate genes with previous supporting evidence of association with microcephaly, known genes associated with macrocephaly, and novel candidate genes for microcephaly
Distribution of the genes detected in the microcephaly associated-CNVs into four categories: known genes in which point mutations cause microcephaly, candidate genes with previous supporting evidence of association with microcephaly, known genes associated with macrocephaly, and novel candidate genes for microcephaly
… 
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Vol.:(0123456789)
1 3
Journal of Autism and Developmental Disorders (2024) 54:1181–1212
https://doi.org/10.1007/s10803-022-05853-z
ORIGINAL PAPER
Burden ofRare Copy Number Variants inMicrocephaly: ABrazilian
Cohort of185 Microcephalic Patients andReview oftheLiterature
GiovannaCantiniTolezano1· GiovannaCivitateBastos1· SilviaSouzadaCosta1· BrunaLuchezeFreire2·
ThaisKataokaHomma2· RachelSayuriHonjo3· GuilhermeLopesYamamoto1,3· MariaRitaPassos‑Bueno1·
CeliaPriszkulnikKoimann1· ChongAeKim3· AngelaMariaVianna‑Morgante1·
AlexanderAugustodeLimaJorge2· DéboraRomeoBertola1,3· CarlaRosenberg1·
AnaCristinaVictorinoKrepischi1,4
Accepted: 26 November 2022 / Published online: 11 December 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number
variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular
basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV
syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients
with microcephaly and evaluated microcephalic patients carrying < 200kb CNVs documented in the DECIPHER data-
base. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed,
OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian
patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200kb CNVs, at least one known
microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly
genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates,
including OTUD7A, BBC3, CNTN6, and NAA15. In the review, we compiled 957 known microcephaly genes and 58 genomic
CNV loci, comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including
microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA
diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and
provided a useful resource for future research on the field of neurodevelopment.
Keywords CMA· CNV· Microcephaly· Neurodevelopmental disorders· OTUD7A· BBC3· CNTN6· NAA15
Microcephaly is a condition of abnormal brain development
clinically defined by a head circumference (HC) at least two
standard deviations (SD) below the mean for an age and sex-
matched control (Boonsawat etal., 2019; der Hagen etal.,
2014; Gilmore & Walsh, 2013). It is considered an important
risk factor for intellectual disability and developmental delay
and can occur in both syndromic and nonsyndromic forms,
affecting approximately 2–3% of the population worldwide
(Boonsawat etal., 2019; Capkova etal., 2019).
Giovanna Cantini Tolezano, Giovanna Civitate Bastos and Ana
Cristina Victorino Krepischi have contributed equally to this work.
* Ana Cristina Victorino Krepischi
ana.krepischi@ib.usp.br
1 Department ofGenetics andEvolutionary Biology,
Human Genome andStem-Cell Research Center, Institute
ofBiosciences, University ofSão Paulo, 106 Rua do Matão,
SãoPaulo, SP05508-090, Brazil
2 Unidade de Endocrinologia Genética (LIM25), Hospital
das Clínicas da Faculdade de Medicina da Universidade
de São Paulo, 455 Avenida Doutor Arnaldo, SãoPaulo,
SP01246-903, Brazil
3 Unidade de Genética doInstituto da Criança, Hospital das
Clínicas da Faculdade de Medicina da Universidade de
São Paulo, 647 Avenida Doutor Enéas Carvalho de Aguiar,
SãoPaulo, SP05403-900, Brazil
4 Institute ofBiosciences, University ofSão Paulo, 277 Rua do
Matão, SãoPaulo, SP05508-090, Brazil
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Multifactorial occurrences are believed to interact to the pathogenesis, as demonstrated in studies with congenital Zika syndrome discordant twins [8]. From a genetic perspective, 58 copy number variant (CNV) syndromes and 957 genes have been associated with this phenotype [9]. Up to May 2023, 1187 entries that included microcephaly with a known molecular basis were reported in the OMIM database, which comprises CNV syndromes and monogenic disorders. ...
... They had undergone karyotyping, and all of them were primarily referred to CMA. In this previous study, clinically relevant CNVs classified as pathogenic/likely pathogenic were detected in seven cases (including two sibships) [9]. We proceed in the present study with the WES analysis of the families in which the index cases were CMA negative (n = 34) or carried VUS (n = 7) or risk factors CNV (n = 1). ...
... uk/ ac/ index. php) databases); (b) evaluating variants mapped to a specific list of genes known to be associated with microcephaly, global developmental delay, and/or ID [9]; and (c) performing an HPO-based analysis [19]. Additional analyses were conducted using the in silico pathogenic prediction tools FATHMM, FATHMM-MKL, MutationAssessor, Muta-tionTaster, Polyphen2, and SIFT from the dbNSFP Functional Prediction database (http:// datab ase. ...
Clinical Characterization and Underlying Genetic Findings in Brazilian Patients with Syndromic Microcephaly Associated with Neurodevelopmental Disorders
Article
Full-text available
  • Jan 2024
  • MOL NEUROBIOL
Microcephaly is characterized by an occipitofrontal circumference at least two standard deviations below the mean for age and sex. Neurodevelopmental disorders (NDD) are commonly associated with microcephaly, due to perturbations in brain development and functioning. Given the extensive genetic heterogeneity of microcephaly, managing patients is hindered by the broad spectrum of diagnostic possibilities that exist before conducting molecular testing. We investigated the genetic basis of syndromic microcephaly accompanied by NDD in a Brazilian cohort of 45 individuals and characterized associated clinical features, as well as evaluated the effectiveness of whole-exome sequencing (WES) as a diagnostic tool for this condition. Patients previously negative for pathogenic copy number variants underwent WES, which was performed using a trio approach for isolated index cases (n = 31), only the index in isolated cases with parental consanguinity (n = 8) or affected siblings in familial cases (n = 3). Pathogenic/likely pathogenic variants were identified in 19 families (18 genes) with a diagnostic yield of approximately 45%. Nearly 86% of the individuals had global developmental delay/intellectual disability and 51% presented with behavioral disturbances. Additional frequent clinical features included facial dysmorphisms (80%), brain malformations (67%), musculoskeletal (71%) or cardiovascular (47%) defects, and short stature (54%). Our findings unraveled the underlying genetic basis of microcephaly in half of the patients, demonstrating a high diagnostic yield of WES for microcephaly and reinforcing its genetic heterogeneity. We expanded the phenotypic spectrum associated with the condition and identified a potentially novel gene (CCDC17) for congenital microcephaly.
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... As expected, based on theory prediction and observation in model organisms, deletions (haploinsufficiency) are more common and penetrant than duplications (triplosensitivity) for extreme developmental phenotypes [28,69]; in the investigated DECIPHER cohort, over 75% of the CNVs that met our criteria were deletions. This present study and our previous review of CNVs in microcephaly [70] generated a map of CNV loci associated with alterations in head size (Figure 2). A total of 67 loci were gathered, harboring 77 CNVs (58 deletions and 19 duplications), reinforcing the relevance of CNVs, mostly deletions, in neurodevelopmental phenotypes [28,69]. ...
Rare CNVs and Known Genes Linked to Macrocephaly: Review of Genomic Loci and Promising Candidate Genes
Article
Full-text available
  • Dec 2022
Macrocephaly frequently occurs in single-gene disorders affecting the PI3K-AKT-MTOR pathway; however, epigenetic mutations, mosaicism, and copy number variations (CNVs) are emerging relevant causative factors, revealing a higher genetic heterogeneity than previously expected. The aim of this study was to investigate the role of rare CNVs in patients with macrocephaly and review genomic loci and known genes. We retrieved from the DECIPHER database de novo <500 kb CNVs reported on patients with macrocephaly; in four cases, a candidate gene for macrocephaly could be pinpointed: a known microcephaly gene –TRAPPC9, and three genes based on their functional roles – RALGAPB, RBMS3, and ZDHHC14. From the literature review, 28 pathogenic CNV genomic loci and over 300 known genes linked to macrocephaly were gathered. Among the genomic regions, 17 CNV loci (~61%) exhibited mirror phenotypes, that is, deletions and duplications having opposite effects on head size. Identifying structural variants affecting head size can be a preeminent source of information about pathways underlying brain development. In this study, we reviewed these genes and recurrent CNV loci associated with macrocephaly, as well as suggested novel potential candidate genes deserving further studies to endorse their involvement with this phenotype.
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Genetic diagnosis of fetal microcephaly at a single tertiary center in China
Article
Full-text available
  • May 2023
Background: Microcephaly is common in patients with neuropsychiatric problems, and it is usually closely related to genetic causes. However, studies on chromosomal abnormalities and single-gene disorders associated with fetal microcephaly are limited. Objective: We investigated the cytogenetic and monogenic risks of fetal microcephaly and evaluated their pregnancy outcomes. Methods: We performed a clinical evaluation, high-resolution chromosomal microarray analysis (CMA), and trio exome sequencing (ES) on 224 fetuses with prenatal microcephaly and closely followed the pregnancy outcome and prognosis. Results: Among 224 cases of prenatal fetal microcephaly, the diagnosis rate was 3.74% (7/187) for CMA and 19.14% (31/162) for trio-ES. Exome sequencing identified 31 pathogenic or likely pathogenic (P/LP) single nucleotide variants (SNVs) in 25 genes associated with fetal structural abnormalities in 37 microcephaly fetuses; 19 (61.29%) of which occurred de novo. Variants of unknown significance (VUS) was found in 33/162 (20.3%) fetuses. The gene variant involved included the single gene MPCH 2 and MPCH 11, which is associated with human microcephaly, and HDAC8, TUBGCP6, NIPBL, FANCI, PDHA1, UBE3A, CASK, TUBB2A, PEX1, PPFIBP1, KNL1, SLC26A4, SKIV2L, COL1A2, EBP, ANKRD11, MYO18B, OSGEP, ZEB2, TRIO, CLCN5, CASK, and LAGE3. The live birth rate of fetal microcephaly in the syndromic microcephaly group was significantly higher than that in the primary microcephaly group [62.9% (117/186) vs 31.56% (12/38), p = 0.000]. Conclusion: We conducted a prenatal study by conducting CMA and ES for the genetic analysis of fetal microcephaly cases. CMA and ES had a high diagnostic rate for the genetic causes of fetal microcephaly cases. In this study, we also identified 14 novel variants, which expanded the disease spectrum of microcephaly-related genes.
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CHL1 deletion is associated with cognitive and language disabilities – Case report and review of literature
Article
Full-text available
  • May 2021
Background There is a small, but growing number of reports of pediatric patients with terminal deletions at 3p26.3 involving only the cell adhesion molecule L1-like (CHL1) gene that has been found to have language delays and intellectual disability. Here we report a one month of age patient who developed seizures and tone abnormalities, with persistent and prominent gross and fine motor delays. The patient has microcephaly and deficits in language and cognitive delays, similar to what has been seen in previous case reports. Methods Chromosome and microarray comparative genomic hybridization (aCGH) analysis was performed to identify clinically significant copy number variants (CNVs). In addition, Fluorescent in-situ hybridization (FISH) was performed to confirm the aCGH findings. Results Chromosome analysis revealed an apparently normal (46,XX) female karyotype. Microarray CGH analysis revealed a 639 kb loss at 3p26.3 from 62199 to 701052 base pairs encompassing the whole CHL1 gene that was confirmed by FISH. Parental follow-up revealed the deletion as maternal in origin. Conclusion This case report adds to the limited body of literature that exists on this terminal deletion at 3p26.3 that involves CHL1 gene, and supports prior proposals of an emerging CHL1 microdeletion syndrome that results in language and cognitive delays. Further studies are needed to understand the degree of phenotypic heterogeneity associated with CHL1 gene deletion and whether the size of the deletion or presence of additional copy number variants (CNVs) which were seen in other case reports help predict the expected phenotype for a patient.
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8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature
Article
Full-text available
  • Apr 2021
To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.
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Molecular Genetics of Microcephaly Primary Hereditary: An Overview
Article
Full-text available
  • Apr 2021
  • BSRCCS
MicroCephaly Primary Hereditary (MCPH) is a rare congenital neurodevelopmental disorder characterized by a significant reduction of the occipitofrontal head circumference and mild to moderate mental disability. Patients have small brains, though with overall normal architecture; therefore, studying MCPH can reveal not only the pathological mechanisms leading to this condition, but also the mechanisms operating during normal development. MCPH is genetically heterogeneous, with 27 genes listed so far in the Online Mendelian Inheritance in Man (OMIM) database. In this review, we discuss the role of MCPH proteins and delineate the molecular mechanisms and common pathways in which they participate.
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Investigating Genetic Factors Contributing to Variable Expressivity of Class I 17p13.3 Microduplication
Article
Full-text available
  • Feb 2021
17p13.3 microduplications are rare copy number variations (CNVs) associated with variable phenotypes, including facial dysmorphism, developmental delay, intellectual disability, and autism. Typically, when a recognized pathogenic CNV is identified, other genetic factors are not considered. We investigated via whole-exome sequencing the presence of additional variants in four carriers of class I 17p13.3 microduplications. A 730 kb 17p13.3 microduplication was identified in two half-brothers with intellectual disability, but not in a third affected half-brother or blood cells from their normal mother (Family A), thus leading to the hypothesis of maternal germline mosaicism. No additional pathogenic variants were detected in Family A. Two affected siblings carried maternally inherited 450 kb 17p13.3 microduplication (Family B); the three carriers of the microduplication exhibited microcephaly and learning disability/speech impairment of variable degrees. Exome analysis revealed a variant of uncertain significance in RORA, a gene already linked to autism, in the autistic boy; his sister was heterozygous for a CYP1B1 pathogenic variant that could be related to her congenital glaucoma. Besides, both siblings carried a loss-of-function variant in DIP2B, a candidate gene for intellectual disability, which was inherited from their father, who also exhibited learning disability in childhood. In conclusion, additional pathogenic variants were revealed in two affected carriers of class I 17p13.3 microduplication (Family B), probably adding to their phenotypes. These results provided new evidence regarding the contribution of RORA and DIP2B to neurocognitive deficits, and highlighted the importance of full genetic investigation in carriers of CNV syndromes with variable expressivity. Finally, we suggest that microcephaly may be a rare clinical feature also related to the presence of the class I 17p13.3 microduplication.
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TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development
Article
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Thousand and one amino acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen‐activated protein kinase (MAPK) pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function, and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function, and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties and growth problems. This article is protected by copyright. All rights reserved.
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Prenatal diagnosis and ultrasonographic findings of partial trisomy of chromosome 6q: A case report and review of the literature
Article
Full-text available
  • Jan 2021
Rationale: Partial trisomy of the long arm of chromosome 6 syndrome is a rare chromosomal disorder with distinctive phenotypic expressivity, in which cytogenetic abnormalities are usually reported in infancy and childhood. Ultrasonographic findings on trisomy of the distal long arm of chromosome 6 in previous studies are limited. Patient concerns: A 32-year-old, gravida 6, para 1, pregnant woman who had 4 spontaneous abortions underwent a clinical ultrasound examination at 26 weeks of gestation. Diagnoses: Ultrasonographic findings were microcephaly, an acoustic image of a transparent septum, a flat nasal bridge, right pulmonary artery stenosis, and a single umbilical artery. Cytogenetic and single-nucleotide polymorphism array analyses were performed to estimate genetic factors of this diagnosis by amniocentesis. Interventions: After genetic counseling, the patient and her husband opted to terminate the pregnancy. Outcomes: Cytogenetic examination of the fetus showed the karyotype 46,XX,der(20)t(6;20)(q24;p13). The single-nucleotide polymorphism (SNP) array showed a 22.104-Mb duplication of 6q24.3q27 and a 0.784-Mb deletion of 20p13. Lessons: Ultrasonographic findings of fetal abnormalities, including microcephaly, an acoustic image of a transparent septum, a flat nasal bridge, right pulmonary artery stenosis, and a single umbilical artery, may be related to a 22.104-Mb duplication of 6q24.3q27 and a 0.784-Mb deletion of 20p13. More ultrasonographic and genotype studies are required to extend the phenotypic characterization of partial trisomy 6q syndrome.
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Deep exploration of a CDKN1C mutation causing a mixture of Beckwith-Wiedemann and IMAGe syndromes revealed a novel transcript associated with developmental delay
Article
Full-text available
  • Dec 2020
Background Loss-of-function mutations in CDKN1C cause overgrowth, that is, Beckwith-Wiedemann syndrome (BWS), while gain-of-function variants in the gene’s PCNA binding motif cause a growth-restricted condition called IMAGe syndrome. We report on a boy with a remarkable mixture of both syndromes, with developmental delay and microcephaly as additional features. Methods Whole-exome DNA sequencing and ultra-deep RNA sequencing of leucocyte-derived and fibroblast-derived mRNA were performed in the family. Results We found a maternally inherited variant in the IMAGe hotspot region: NM_000076.2( CDKN1C ) c.822_826delinsGAGCTG. The asymptomatic mother had inherited this variant from her mosaic father with mild BWS features. This delins caused tissue-specific frameshifting resulting in at least three novel mRNA transcripts in the boy. First, a splice product causing CDKN1C truncation was the likely cause of BWS. Second, an alternative splice product in fibroblasts encoded IMAGe-associated amino acid substitutions. Third, we speculate that developmental delay is caused by a change in the alternative CDKN1C-201 (ENST00000380725.1) transcript, encoding a novel isoform we call D (UniProtKB: A6NK88). Isoform D is distinguished from isoforms A and B by alternative splicing within exon 1 that changes the reading frame of the last coding exon. Remarkably, this delins changed the reading frame back to the isoform A/B type, resulting in a hybrid D–A/B isoform. Conclusion Three different cell-type-dependent RNA products can explain the co-occurrence of both BWS and IMAGe features in the boy. Possibly, brain expression of hybrid isoform D–A/B is the cause of developmental delay and microcephaly, a phenotypic feature not previously reported in CDKN1C patients.
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A cross-disorder dosage sensitivity map of the human genome
Article
  • Aug 2022
  • CELL
Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.
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Congenital chromoanagenesis in the routine postnatal chromosomal microarray analyses
Article
  • May 2021
Chromosomal microarray analyses (CMA) have greatly increased both the yield and diagnostic accuracy of postnatal analysis; it has been used as a first‐tier cytogenetic test in patients with intellectual disability, autism spectrum disorder, and multiple congenital abnormalities. During the last 15 years, we performed CMA in approximately 8,000 patients with neurodevelopmental and/or congenital disorders, of which 13 (0.16%) genetically catastrophic complex chromosomal rearrangements were identified. These ultrarare rearrangements showed clustering of breakpoints, characteristic of chromoanagenesis events. Al1 13 complex events display underlying formation mechanisms, originating either by a synchronization of the shattering of clustered chromosome regions in which regional asynchrony of DNA replication may be one of the main causes of disruption. We provide an overview of the copy number profiling in these patients. Although several previous studies have suggested that chromoanagenesis is often a genetic disease source in postnatal diagnostic screening, due to either the challenge of clinical interpretation of these complex rearrangements or the limitation of microarray resolution relative to the small size and complexity of chromogenic induced chromosome abnormalities, bringing further attention and to study its occurrence in the clinical setting is extremely important.
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What a finding of gene copy number variation can add to the diagnosis of developmental neuropsychiatric disorders
Article
  • Jun 2021
  • CURR OPIN GENET DEV
Among medical disciplines, diagnosis in psychiatry depends highly upon descriptive signs and symptoms, rather than biomarkers. Clear descriptions of specific genetic etiologies have been lacking; genomic technologies, however, are rapidly changing that landscape. Notably, chromosomal microarrays—which detect gene copy number variants (CNVs)—are a recommended standard of care for neurodevelopmental disorders. As a result, an increasing number of patients now receive a clinical diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and an identified genetic etiological variant. However, psychiatric and genetic diagnoses are frequently communicated and managed as two disconnected diagnostic parameters. Here, we advocate for a transition model, allowing the integration of genetic etiological information—starting with diagnostically proven CNVs—within the DSM-5 classification framework.
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