Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and consequently which of the three major SOX5 protein isoforms are affected. One intragenic deletion involving only untranslated exons was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene

Expression of Fragile Sites Triggers Intrachromosomal Mammalian Gene Amplification and Sets Boundaries to Early Amplicons

International audienceDrug-selected intrachromosomal gene amplification by breakage-fusion-bridge (BFB) cycles is well documented in mammalian cells, but factors governing this mechanism are not clear. Here, we show that only some clastogenic drugs induce drug resistance through intrachromosomal amplification. We strictly correlate triggering of BFB cycles to induction of fragile site expression. We demonstrate a dual role for fragile sites in intrachromosomal amplification: a site telomeric to the selected gene is involved in initiation, while a centromeric site defines the size and organization of early amplified units. The positions of fragile sites relative to boundaries of amplicons found in human cancers support the hypothesis that fragile sites play a key role in the amplification of at least some oncogenes during tumor progression

Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B

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Molecular characterization of a de novo 6q24.2q25.3 duplication interrupting UTRN in a patient with arthrogryposis.

International audienceChromosome 6q duplications have been documented repeatedly, allowing the delineation of a "6q duplication syndrome," characterized by hypertelorism, downslanting palpebral fissures, tented upper lip, short neck, severe mental and growth retardation, and joint contractures. Most reported cases result from malsegregation of a reciprocal translocation leading to a terminal 6q duplication and partial monosomy of another chromosome. Only 11 cases of de novo pure duplication have been reported so far. The breakpoints do not appear to be recurrent, but in most cases they have not been characterized molecularly, precluding genotype-phenotype correlation. We report on an 8-year-old girl with a phenotype consistent with mild 6q duplication syndrome, including characteristic physical findings, mild mental retardation, and joint contractures. She carries a 13 Mb de novo 6q24.2q25.3 duplication, diagnosed by high-resolution karyotype and confirmed by array-CGH. Molecular characterization of the duplicated segment with quantitative PCR showed that the proximal breakpoint is localized within the UTRN gene, encoding utrophin, the autosomal homologue of dystrophin. We discuss the possible implication of UTRN in arthrogryposis associated with duplications spanning the 6q23q26 region

2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features?

International audienceBACKGROUND: Genome-wide screening of patients with mental retardation using array comparative genomic hybridisation (CGH) has identified several novel imbalances. With this genotype-first approach, the 2q22.3q23.3 deletion was recently described as a novel microdeletion syndrome. The authors report two unrelated patients with a de novo interstitial deletion mapping in this genomic region and presenting similar "pseudo-Angelman" phenotypes, including severe psychomotor retardation, speech impairment, epilepsy, microcephaly, ataxia, and behavioural disabilities. METHODS: The microdeletions were identified by array CGH using oligonucleotide and bacterial artificial chromosome (BAC) arrays, and further confirmed by fluorescence in situ hybridisation (FISH) and semi-quantitative polymerase chain reaction (PCR). RESULTS: The boundaries and sizes of the deletions in the two patients were different but an overlapping region of about 250 kb was defined, which mapped to 2q23.1 and included two genes: MBD5 and EPC2. The SIP1 gene associated with the Mowat-Wilson syndrome was not included in the deleted genomic region. DISCUSSION: Haploinsufficiency of one of the deleted genes (MBD5 or EPC2) could be responsible for the common clinical features observed in the 2q23.1 microdeletion syndrome, and this hypothesis needs further investigation

Identification of gene copy number variations in patients with mental retardation using array-CGH: Novel syndromes in a large French series.

International audienceArray-CGH has revealed a large number of copy number variations (CNVs) in patients with multiple congenital anomalies and/or mental retardation (MCA/MR). According to criteria recently listed, pathogenicity was clearly suspected for some CNVs but benign CNVs, considered as polymorphisms, have complicated the interpretation of the results. In this study, genomic DNAs from 132 French patients with unexplained mental retardation were analysed by genome wide high-resolution Agilent 44K oligonucleotide arrays. The results were in accordance with those observed in previous studies: the detection rate of pathogenic CNVs was 14.4%. A non-random involvement of several chromosomal regions was observed. Some of the microimbalances recurrently involved regions (1q21.1, 2q23.1, 2q32q33, 7p13, 17p13.3, 17p11.2, 17q21.31) corresponding to known or novel syndromes. For all the pathogenic CNVs, further cases are needed to allow more accurate genotype-phenotype correlations underscoring the importance of databases to group patients with similar molecular data

An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease

International audienceImportance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes.Objective: To identify novel genes and mechanisms associated with familial CSVD.Design, setting, and participants: This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset <age 55 years and ≥1 first-degree relative with CSVD) were referred to the French cerebrovascular referral center between 2013 and 2023. The large-scale gnomAD structural variant database and 467 healthy individuals of French ancestry were used as a control group.Main outcomes and measures: A pathogenic AluYa5 insertion was identified within the COL4A1 3'UTR in the 2 large families with CSVD. Reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), Western blot, and long-read RNA sequencing were used to investigate outcomes associated with the insertion using patient fibroblasts. Clinical and magnetic resonance imaging features of probands with variants and available relatives were assessed.Results: Among 246 probands (141 females [57.3%]; median [IQR] age at referral, 56 [49-64] years), 7 patients of French ancestry carried the insertion. This insertion was absent in 467 healthy French individuals in a control group (odds ratio, ∞; 95% CI, 2.78 to ∞; P = 5 × 10-4) and 10 847 individuals from the gnomAD structural variant database (odds ratio, ∞; 95% CI, 64.77 to ∞; P = 2.42 × 10-12). In these 7 patients' families, 19 family members with CSVD carried the insertion. RT-qPCR and Western blot showed an upregulation of COL4A1 mRNA (10.6-fold increase; 95% CI, 1.4-fold to 17.1-fold increase) and protein levels (2.8-fold increase; 95% CI, 2.1-fold to 3.5-fold increase) in patient vs control group fibroblasts. Long-read RNA sequencing data showed that the insertion was associated with perturbation in the use of canonical COL4A1 polyadenylation signals (approximately 87% of isoforms transcribed from the wild type allele vs 5% of isoforms transcribed from the allele with the insertion used the 2 distal canonical polyadenylation signals). The main clinical feature of individuals with CSVD was the recurrence of pontine ischemic lesions starting at an early age (17 of 19 patients [89.5%]).Conclusions and relevance: This study found a novel mechanism associated with COL4A1 upregulation and a highly penetrant adult-onset CSVD. These findings suggest that quantitative alterations of the cerebrovascular matrisome are associated with CSVD pathogenesis, with diagnostic and therapeutic implications