A Rare Chromosome Rearrangement Leading to de la Chapelle Syndrome with a Mosaic 45,X Cell Line: (46,X,psu dic(X;Y)(p22.13;q11.221)/45,X/45,psu dic(X;Y)(p22.13;q11.221)

International audienceInfertility affects about 15% of couples of childbearing age. About half of these cases can be attributed predominantly to a male factor, such as a quantitative or qualitative impairment in spermatogenesis. The first-line genetic screening for non-obstructive azoospermia is limited to karyotyping (to identify chromosome abnormalities) and Y chromosome microdeletions screening, with a view to explaining the spermatogenetic failure and evaluating the likelihood of sperm retrieval in a testicular biopsy. For patients with de la Chapelle syndrome (a 46,XX karyotype with the presence of SRY (Sex determining region Y) gene) and/or Y chromosome microdeletions, or sex chromosome mosaicism, sperm retrieval is usually unsuccessful. Here, we report a patient with de la Chapelle syndrome and a short stature caused by mosaicism and a very rare chromosome rearrangement: mos 46,X,psu dic(X;Y)/45,X/45,psu dic(X;Y). This case indicates that in de la Chapelle syndrome, X- and Y-chromosome breakpoint variability is high

A Rare Chromosome Rearrangement Leading to de la Chapelle Syndrome with a Mosaic 45,X Cell Line: (46,X,psu dic(X;Y)(p22.13;q11.221)/45,X/45,psu dic(X;Y)(p22.13;q11.221)

Infertility affects about 15% of couples of childbearing age. About half of these cases can be attributed predominantly to a male factor, such as a quantitative or qualitative impairment in spermatogenesis. The first-line genetic screening for non-obstructive azoospermia is limited to karyotyping (to identify chromosome abnormalities) and Y chromosome microdeletions screening, with a view to explaining the spermatogenetic failure and evaluating the likelihood of sperm retrieval in a testicular biopsy. For patients with de la Chapelle syndrome (a 46,XX karyotype with the presence of SRY (Sex determining region Y) gene) and/or Y chromosome microdeletions, or sex chromosome mosaicism, sperm retrieval is usually unsuccessful. Here, we report a patient with de la Chapelle syndrome and a short stature caused by mosaicism and a very rare chromosome rearrangement: mos 46,X,psu dic(X;Y)/45,X/45,psu dic(X;Y). This case indicates that in de la Chapelle syndrome, X- and Y-chromosome breakpoint variability is high

Next Generation Mapping a novel approach that enables the detection of unbalanced as well as balanced structural variants

International audienceStructural variants (SVs) include large unbalanced (CNVs) and balanced variants (insertions, inversions and translocations). Whereas the detection of unbalanced SVs has been significantly improved by technological breakthrough such as Chromosomal Microarray Analysis (CMA), the detection of balanced SVs still relies on karyotype despite its very low resolution. Massively parallel sequencing enables the detection of some SVs but its use in clinical setting is yet limited by technical and computational challenges, among which the read length. Next Generation Mapping using the Bionano system is a novel non-sequencing based technology. Long high molecular weight DNA fragments are labelled at specific sites and then stretched out into a nano-channel system for fluorescence reading. The labelling pattern is then compared to a reference genome pattern allowing for the identification of SVs without complex bioinformatic analyses. We sought to evaluate the performance of this technology and its ease of use in a routine cytogenetic laboratory. Our study includes 29 patients bearing balanced (11 translocations and 4 inversions) or unbalanced SVs (1 unbalanced translocation, 7 CNVs ranging from 500kb to 4Mb), complex chromosomal rearrangements (n=4), isochromosomes (n=2) and one case of aneuploidy, all previously identified by karyotype or CMA. The results are analysed blindly and then compared to karyotype or CMA results. Preliminary data on four samples show reliable detection of the expected SVs. This approach has the potential to improve the resolution of the pangenome detection of different sorts of SVs, and could hence complement or even replace karyotype and CMA as a unique, simple and comprehensive test. This would have a significant clinical impact for diseases in which balanced SVs are mainly involved, such as reproductive diseases and recurrent miscarriages

Unusual isochromosome 5p marker chromosome

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16p13.11 microduplication in 45 new patients: refined clinical significance and genotype-phenotype correlations.

BACKGROUND: The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care. METHODS: We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents. RESULTS: Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype. CONCLUSION: Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk

Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders

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