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Schematic of X chromosome and genes in the Xq27.3-q28 region. Region of deletion is highlighted by the red box. Shown are the OMIM-disease associated genes in green and all RefSeq genes in blue within the deletion region of 144,270,614-154,845,961 bp (hg19). Image was adapted from http://genome.ucsc.edu/cgi-bin/hgTracks.
Source publication
Background
Global developmental delay and mental retardation are associated with X-linked disorders including Hunter syndrome (mucopolysaccharidosis type II) and Fragile X syndrome (FXS). Single nucleotide mutations in the iduronate 2-sulfatase (IDS) gene at Xq28 most commonly cause Hunter syndrome while a CGG expansion in the FMR1 gene at Xq27.3 i...
Context in source publication
Context 1
... array showed a ~10.6 megabase deletion at Xq27.3q28 (144,270,845,961 bp) encompassed within BAC clones CTD- 3109C8 to CTD-2341N11 (Figure 2). This deletion resulted in hemizygosity for 113 RefSeq genes including the FMR1 and iduronate 2-sulfatase (IDS) genes which are associated with Fragile X syndrome (FXS) and Hunter syndrome, respectively (Figure 3). OMIM disease-associated genes within the deletion region in- cluded: FMR1, AFF2 (FMR2), IDS, MAMLD1, MTM1, NSDHL, ATP2B3, FAM58A, SLC6A8, ABCD1, L1CAM, AVPR2, NAA10, HCFC1, MECP2, OPN1LW, OPN1MW, FLNA, EMD, RPL10, TAZ, GDI1, G6PD, IKBKG (NEMO), DKC1, F8, RAB39B, CLIC2, and TMLHE. ...Citations
... Male patients show more severe clinical features than females, which resemble as Hunter syndrome and Fragile X syndrome [10,11]. However, female patients harboring Xq27.3q28 deletion demonstrate variable clinical manifestations [9,12,13]. ...
Background
Partial trisomy 13q is a less common chromosomal abnormality with a great clinical variability, among them, isolated partial trisomy 13q is extremely rare. Here, we report two new unrelated cases of partial trisomy 13q in Chinese families aiming to emphasize the genotype–phenotype correlation in partial trisomy 13q.
Methods
Enrolled in this study were two unrelated cases of partial 13q trisomy from two families in Quanzhou region South China. Karyotpe and single-nucleotide polymorphism (SNP) array analysis were employed to identify chromosome abnormalities and copy number variants in the families.
Results
A 72.9-Mb duplication in 13q14.11q34 region was identified using SNP array analysis in Patient 1 with an intellectual disability, developmental delay, seizures, gastric perforation, and other congenital malformations from a family with paternal inv(13)(p12q14.1). SNP array detection in Patient 2 revealed a 92.4-Mb duplication in 13q12.11q34 region combined with an 8.4-Mb deletion in Xq27.3q28 region with intellectual disability, developmental delay, cleft palate, and duplication of the cervix and the vagina. No chromosomal abnormality was elicited from the parents of Patient 2.
Conclusions
In this study, we presented two new unrelated cases of partial trisomy 13q with variable features in Chinese population, which may enrich the spectrum of the phenotypes partial trisomy 13q and further confirm the genotype–phenotype correlation.
... In clinical practice, microdeletions often extend into adjacent genes that also cause intellectual disability, especially AFF2 located 550 kb downstream and IDS (mucopolysaccharidosis II) 1.5 Mb downstream. These larger deletions can present with additional clinical features related to the neighboring genes, as in proximal deletions including SOX3 [97] and distal deletions including IDS [98][99][100][101][102][103][104][105][106][107]. ...
FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.
... Since the girl confirmed comorbidity of Turner syndrome and MPS II, the authors conclude that the partial deletion of the long arm of chromosome X from the father caused Turner syndrome while the manifestation of MPS II was caused by a 5-nucleotide deletion in the maternal IDS gene [53]. Vice versa, another report shows that a heterozygous 10.6 Mb deletion of Xq27.3q28 including IDS gene among others did not lead to the manifestation of MPS II in a four-year-old girl with global developmental delay because the deleterious X chromosome was subject to highly skewed X-inactivation [54]. It is of note that the Xq27-28 region is often involved in genomic rearrangements. ...
Mucopolysaccharidosis Type II (MPS II) is an X-linked recessive genetic disorder that primarily affects male patients. With an incidence of 1 in 100,000 male live births, the disease is one of the orphan diseases. MPS II symptoms are caused by mutations in the lysosomal iduronate-2-sulfatase (IDS) gene. The mutations cause a loss of enzymatic performance and result in the accumulation of glycosaminoglycans (GAGs), heparan sulfate and dermatan sulfate, which are no longer degradable. This inadvertent accumulation causes damage in multiple organs and leads either to a severe neurological course or to an attenuated course of the disease, although the exact relationship between mutation, extent of GAG accumulation and disease progression is not yet fully understood. This review is intended to present current diagnostic procedures and therapeutic interventions. In times when the genetic profile of patients plays an increasingly important role in the assessment of therapeutic success and future drug design, we chose to further elucidate the impact of genetic diversity within the IDS gene on disease phenotype and potential implications in current diagnosis, prognosis and therapy. We report recent advances in the structural biological elucidation of I2S enzyme that that promises to improve our future understanding of the molecular damage of the hundreds of IDS gene variants and will aid damage prediction of novel mutations in the future.
... A similar picture is seen for Patient 2, who presented an unbalanced translocation between chromosomes X and 21, with a pseudo dicentric derivative chromosome harboring an Xq loss. While Xq monosomies have already been associated with premature ovarian insufficiency and some other mild phenotypic characteristics (Beke et al., 2013;Marshall et al., 2013;Papoulidis et al., 2018), our patient's phenotype includes other important skeletal, cardiac and neuropsychomotor alterations as well as dysmorphic features that have never been reported in cases of Xq monosomies. ...
Patients with unbalanced X‐autosome translocations are rare and usually present a skewed X‐chromosome inactivation (XCI) pattern, with the derivative chromosome being preferentially inactivated, and with a possible spread of XCI into the autosomal regions attached to it, which can inactivate autosomal genes and affect the patients' phenotype. We describe three patients carrying different unbalanced X‐autosome translocations, confirmed by G‐banding karyotype and array techniques. We analyzed their XCI pattern and inactivation spread into autosomal regions, through HUMARA, ZDHHC15 gene assay and the novel 5‐ethynyl‐2′‐deoxyuridine (EdU) incorporation assay, and identified an extremely skewed XCI pattern toward the derivative chromosomes for all the patients, and a variable pattern of late‐replication on the autosomal regions of the derivative chromosomes. All patients showed phenotypical overlap with patients presenting deletions of the autosomal late‐replicating regions, suggesting that the inactivation of autosomal segments may be responsible for their phenotype. Our data highlight the importance of the XCI spread into autosomal regions for establishing the clinical picture in patients carrying unbalanced X‐autosome translocations, and the incorporation of EdU as a novel and precise tool to evaluate the inactivation status in such patients.
... Single nucleotide mutations in the iduronate 2-sulfatase (IDS) gene at Xq28 most commonly cause Hunter syndrome, which can cause developmental delays (Marshall et al., 2013). ...
Background:
There is a strong evidence for genetic factors as the main causes of Autism Spectrum Disorders (ASD). To date, hundreds of genes have been identified either by copy number variations (CNVs) and/or single nucleotide variations. However, despite all the findings, the genetics of these disorders have not been totally explored.
Methods:
Thus, the aim of our work was to identify rare CNVs and genes present in these regions in ASD children, using a high-resolution comparative genomic hybridization technique and quantitative PCR (qPCR) approach.
Results:
Our results have shown 60-70 chromosomal aberrations per patient. We have initially selected 66 CNVs that have been further assessed using qPCR. Finally, we have validated 22 CNVs including 11 deletions and 11 duplications. Ten CNVs are de novo, 11 are inherited and one of unknown origin of transmission. Among the CNVs detected, novel ASD candidate genes PJA2, SYNPO, APCS, and TAC1 have been identified in our group of Lebanese patients. In addition, previously described CNVs have been identified containing genes such as SHANK3, MBP, CHL1, and others.
Conclusion:
Our study broadens the population spectrum of studied ASD patients and adds new candidates at the list of genes contributing to these disorders.
... The phenomenon of random inactivation of this chromosome, in the female sex, also inactivates part of the mutated X chromosomes, with consequent reduction of clinical manifestations of the disease (Willemsen et al., 2001). Although the symptomatology of FXS in women is less common, the process of unfavorable random inactivation may justify the phenotype (Marshall et al., 2013). ...
X-Fragile Syndrome (FXS) is the most common cause of inherited intellectual disability and the second of genetic origin, with an estimated prevalence of 1/4000 men and 1/6000 women. The etiology is associated with a trinucleotide expansion of CGG sequences and hypermethylation of the promoter region of the FMR1 (Fragile-X Mental Retardation-1) gene, located in the Xq27.3 region. Symptoms occur due to lack of Fragile X Mental Retardation Protein (FMRP), essential for dendrites growth and synaptic function. This syndrome is commonly underdiagnosed in children and adolescents due to the high phenotypic variability of patients and the need for a complex and high cost laboratory diagnosis. This research aims to evaluate individuals referred by the public health system of Goiás presenting intellectual deficiency suggestive of FXS and submitted to molecular diagnosis by PCR. Thirty-one patients, ranging in age from 4 to 41 years, were analyzed. It was possible to detect molecular alterations in the FMR1 gene in 6 patients with complete mutations, consistent with the observed phenotypes. The use of molecular techniques associated with capillary electrophoresis in an automatic genetic analyser demonstrated rapid and efficient investigation of CGG repeats in the FMR1 gene. Its inclusion in the public health service, in addition to universalizing access to genetic tests in Brazil, bridging the gap between effective diagnosis and the technologies available until now, has supported families in clarifying the etiology and assessing the risk of recurrence through genetic counselling.
... Her 5.9-Mb deletion extended proximally from FMR1 , and XCI was skewed (17: 83). Complete skewing with preferential inactivation of the deleted X chromosome was detected in another patient with a 10.6-Mb deletion encompassing FMR1, AFF2, IDS, and 110 additional RefSeq genes, who displayed global DD, mild muscular hypotonia, and growth measurements in the normal range [Marshall et al., 2013]. ...
Fragile X syndrome (FXS) is one of the most common causes of intellectual disability/developmental delay (ID/DD), especially in males. It is caused most often by CGG trinucleotide repeat expansions, and less frequently by point mutations and partial or full deletions of the FMR1 gene. The wide clinical spectrum of affected females partly depends on their X-inactivation status. Only few female ID/DD patients with microdeletions including FMR1 have been reported. We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet they presented with ID/DD as well as speech delay, macrocephaly and other features attributable to FXS. No signs of autism were present. Here, we further delineate the clinical spectrum of female patients with microdeletions. FMR1 expression studies gave no evidence for an absolute threshold below which signs of FXS present. Since FMR1 expression is known to be highly variable between unrelated females, and since FMR1 mRNA levels have been suggested to be more similar among family members, we further explored the possibility of an intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were significantly lower than in their respective mothers, which was shown to be specific for patients with microdeletions containing FMR1.
Since it is extremely difficult to establish an animal model for human chromosomal abnormalities, induced pluripotent stem cells (iPSCs) provide a powerful alternative to study underlying mechanisms of these disorders and identify potential therapeutic interventions. In this study we established iPSCs from a young girl with a hemizygous deletion of Xq27.3-q28 who exhibited global developmental delay and intellectual disability from early in infancy. The deletion site on the X chromosome includes Fragile X Mental Retardation 1 (FMR1), the gene responsible for fragile X syndrome, which likely contributes to the patient's neurodevelopmental abnormalities. The FMR1 gene was expressed in approximately half of the iPSC clones we generated while it was absent in the other half due to the random inactivation of normal and abnormal X chromosomes. The normal or absent expression pattern of the FMR1 gene was not altered when the iPSCs were differentiated into neural progenitor cells (NPCs). Moreover, chromosome reactivating reagents such as 5-aza-2-deoxycytidine, trichostatin A, and UNC0638, were tested in an attempt to reactivate the suppressed FMR1 gene in affected iPSC-NPCs. The affected and control isogenic iPSCs developed in this study are ideal models with which to identify downstream consequences caused by the Xq27.3-q28 deletion and also to provide tools for high-throughput screening to identify compounds potentially improving the well-being of this patient population.
A heterozygous deletion at Xq27.3q28 including FMR1 , AFF2 , and IDS causing intellectual disability and characteristic facial features is very rare in females, with only 10 patients having been reported. Here, we examined two female patients with different clinical features harboring Xq27.3q28 deletion and determined the chromosomal breakpoints. Moreover, we assessed X chromosome inactivation (XCI) in peripheral blood from both patients. Both patients had almost overlapping deletion at Xq27.3q28, however the more severe patient (Patient 1) showed skewed XCI of the normal X chromosome (79:21) whereas the milder patient (Patient 2) showed random XCI. Therefore, deletion at Xq27.3q28 critically affected brain development, and the ratio of XCI of the normal X chromosome greatly affected the clinical characteristics of patients with deletion at Xq27.3q28. Since the chromosomal breakpoints were determined, we analyzed a change in chromatin domains termed Topologically Associated Domains (TADs) using published Hi‐C data on the Xq27.3q28 region, and found that only patient 1 had a possibility of a drastic change in TADs. The altered chromatin topologies on the Xq27.3q28 region might affect clinical features of patient 1 by changing the expression of genes just outside the deletion and/or the XCI establishment during embryogenesis resulted in skewed XCI.
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Girls with pathogenic variants in FMR1, the gene responsible for Fragile X syndrome, have received relatively little attention in the literature. The reports of girls with trinucleotide expansions or deletions affecting FMR1 describe variable phenotypes; having normal intelligence and no severe neurologic sequelae is not uncommon. We reviewed epilepsy genetics research databases for girls with FMR1 pathogenic variants and seizures to characterize the spectrum of epilepsy phenotypes. We identified 4 patients, 3 of whom had drug-resistant focal epilepsy. Two had severe developmental and epileptic encephalopathy with late-onset epileptic spasms. Our findings demonstrate that FMR1 loss-of-function variants can result in severe neurologic phenotypes in girls. Similar cases may be missed because clinicians may not always perform Fragile X testing in girls, particularly those with severe neurodevelopmental impairment or late-onset spasms.
