Exome sequencing in children of women with skewed X-inactivation identifies atypical cases and complex phenotypes

Elisa Giorgio, Alessandro Brussino, Elisa Biamino, Elga Fabia Belligni, Alessandro Bruselles, Andrea Ciolfi, Viviana Caputo, Simone Pizzi, Alessandro Calcia, Eleonora Gregorio, Simona Cavalieri, Cecilia Mancini, Elisa Pozzi, Marta Ferrero, Evelise Riberi, Iolanda Borelli, Antonio Amoroso, Giovanni Battista Ferrero, Marco Tartaglia, Alfredo Brusco

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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.

Original languageEnglish
JournalEuropean Journal of Paediatric Neurology
Publication statusE-pub ahead of print - Dec 19 2016


  • Journal Article


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