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.

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

GIORGIO, ELISA;BRUSSINO, Alessandro;BIAMINO, ELISA;BELLIGNI, ELGA FABIA;CALCIA, ALESSANDRO;DI GREGORIO, ELEONORA;CAVALIERI, Simona;MANCINI, CECILIA;POZZI, ELISA;FERRERO, MARTA;RIBERI, EVELISE;BORELLI, Iolanda;AMOROSO, Antonio;FERRERO, Giovanni Battista;BRUSCO, Alfredo
Last
2017

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.
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http://www.sciencedirect.com/science/article/pii/S1090379816302823
ATRX; DMD; MECP2; RPS6KA3; Skewed X-inactivation; WES; Whole exome sequencing
Giorgio, Elisa; Brussino, Alessandro; Biamino, Elisa; Belligni, Elga Fabia; Bruselles, Alessandro; Ciolfi, Andrea; Caputo, Viviana; Pizzi, Simone; Calcia, Alessandro; Di Gregorio, Eleonora; Cavalieri, Simona; Mancini, Cecilia; Pozzi, Elisa; Ferrero, Marta; Riberi, Evelise; Borelli, Iolanda; Amoroso, Antonio; Ferrero, Giovanni Battista; Tartaglia, Marco; Brusco, Alfredo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1621163
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