Fine Breakpoint Mapping by Genome Sequencing Reveals the First Large X Inversion Disrupting the NHS Gene in a Patient with Syndromic Cataracts.

Inversions are structural variants that are generally balanced. However, they could lead to gene disruptions or have positional effects leading to diseases. Mutations in the NHS gene cause Nance-Horan syndrome, an X-linked disorder characterised by congenital cataracts and dental anomalies. Here, we aimed to characterise a balanced pericentric inversion X(p22q27), maternally inherited, in a child with syndromic bilateral cataracts by breakpoint mapping using whole-genome sequencing (WGS). 30× Illumina paired-end WGS was performed in the proband, and breakpoints were confirmed by Sanger sequencing. EdU assays and FISH analysis were used to assess skewed X-inactivation patterns. RNA expression of involved genes in the breakpoint boundaries was evaluated by droplet-digital PCR. We defined the breakpoint position of the inversion at Xp22.13, with a 15 bp deletion, disrupting the unusually large intron 1 of the canonical NHS isoform, and also perturbing topologically-associated domains (TADs). Moreover, a microhomology region of 5 bp was found on both sides. RNA analysis confirmed null and reduced NHS expression in the proband and his unaffected mother, respectively. In conclusion, we report the first chromosomal inversion disrupting NHS, fine-mapped by WGS. Our data expand the clinical spectrum and the pathogenic mechanisms underlying the NHS defects.

MECP2 Duplications in Symptomatic Females: Report on 3 Patients Showing the Broad Phenotypic Spectrum.

Xq28 microduplications including the MECP2 gene constitute a 100% penetrant X-linked syndrome in males caused by overexpression of normal MeCP2 protein. A small number of cases of affected females have been reported. This can be due to the location of the duplicated material into an autosome, but it can also be due to the location of the duplicated material into one of the X chromosomes and random or unfavorable skewed X chromosome inactivation, which is much more likely to occur but may be underdiagnosed because of the resulting broad phenotypic spectrum. In order to contribute to the phenotypic delineation of Xq28 microduplications including MECP2 in symptomatic females, the authors present clinical and molecular data on 3 patients illustrating the broad phenotypic spectrum. Our finding underlines the importance of quantitative analysis of MECP2 in females with intellectual disability and raises the question of the indication in females with borderline intellectual performances or learning difficulties.

Two cases of deletion 2q37 associated with segregation of an unbalanced translocation 2;21: choanal atresia leading to misdiagnosis of CHARGE syndrome.

CONTEXT: The phenotypic variability of patients with syndromes presenting with dysmorphism makes clinical diagnosis difficult, leading to an exhaustive genetic study to determine the underlying mechanism so that a proper diagnosis could be established. OBJECTIVE: To genetically characterize siblings, the older sister diagnosed with Albright hereditary osteodystrophy and the younger one with CHARGE syndrome. DESIGN: Clinical case report. METHODS: Clinical, biochemical, and radiological studies were performed on the family. In addition, molecular genetic studies including sequencing of GNAS, typing of microsatellites on 2q and 21q, and multiplex ligation-dependent probe amplification of subtelomeric regions were performed, as well as confirmatory fluorescent in situ hybridization analysis. RESULTS: The genetic analysis revealed that both sisters presented a 2q37 deletion due to the maternal unbalanced segregation of a 2;21 translocation. CONCLUSIONS: This is the first report of a 2q37 deletion where differential diagnosis of CHARGE syndrome is needed due to the appearance of choanal atresia.