1. Exome sequencing in children of women with skewed X-inactivation identifies atypical cases and complex phenotypes
- Author
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I. Borelli, Giovanni Battista Ferrero, Alessandro Bruselles, Andrea Ciolfi, Cecilia Mancini, Marta Ferrero, Eleonora Di Gregorio, Alfredo Brusco, Elisa Giorgio, Simona Cavalieri, Elga Fabia Belligni, Antonio Amoroso, Marco Tartaglia, Elisa Biamino, Alessandro Brussino, Simone Pizzi, Evelise Riberi, Viviana Caputo, Alessandro Calcia, and Elisa Pozzi
- Subjects
0301 basic medicine ,Proband ,Male ,030105 genetics & heredity ,Gene mutation ,Bioinformatics ,Pediatrics ,Marfan Syndrome ,Craniofacial Abnormalities ,RPS6KA3 ,Genes, X-Linked ,X Chromosome Inactivation ,Exome ,Child ,ATRX ,DMD ,MECP2 ,Skewed X-inactivation ,WES ,Whole exome sequencing ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,Exome sequencing ,Genetics ,Marfanoid ,General Medicine ,Perinatology and Child Health ,Pedigree ,Phenotype ,Adolescent ,Biology ,03 medical and health sciences ,alpha-Thalassemia ,Intellectual Disability ,medicine ,Coffin-Lowry Syndrome ,Humans ,Genetic Predisposition to Disease ,Retrospective Studies ,Sequence Analysis, DNA ,medicine.disease ,030104 developmental biology ,Mutation ,Mental Retardation, X-Linked - Abstract
Background More than 100 X-linked intellectual disability (X-LID) genes have been identified to be involved in 10–15% of intellectual disability (ID). Method To identify novel possible candidates, we selected 18 families with a male proband affected by isolated or syndromic ID. Pedigree and/or clinical presentation suggested an X-LID disorder. After exclusion of known genetic diseases, we identified seven cases whose mother showed a skewed X-inactivation (>80%) that underwent whole exome sequencing (WES, 50X average depth). Results WES allowed to solve the genetic basis in four cases, two of which (Coffin-Lowry syndrome, RPS6K3 gene; ATRX syndrome, ATRX gene) had been missed by previous clinical/genetics tests. One further ATRX case showed a complex phenotype including pontocerebellar atrophy (PCA), possibly associated to an unidentified PCA gene mutation. In a case with suspected Lujan-Fryns syndrome, a c.649C>T (p.Pro217Ser) MECP2 missense change was identified, likely explaining the neurological impairment, but not the marfanoid features, which were possibly associated to the p.Thr1020Ala variant in fibrillin 1. Finally, a c.707T>G variant (p.Phe236Cys) in the DMD gene was identified in a patient retrospectively recognized to be affected by Becker muscular dystrophy (BMD, OMIM 300376). Conclusion Overall, our data show that WES may give hints to solve complex ID phenotypes with a likely X-linked transmission, and that a significant proportion of these orphan conditions might result from concomitant mutations affecting different clinically associated genes.
- Published
- 2016