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

Eur J Paediatr Neurol. 2017 May;21(3):475-484. doi: 10.1016/j.ejpn.2016.12.005. Epub 2016 Dec 19.


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.

Keywords: ATRX; DMD; MECP2; RPS6KA3; Skewed X-inactivation; WES; Whole exome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Child
  • Coffin-Lowry Syndrome / genetics
  • Craniofacial Abnormalities / genetics
  • Exome / genetics*
  • Genes, X-Linked / genetics
  • Genetic Predisposition to Disease
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Marfan Syndrome / genetics
  • Mental Retardation, X-Linked / genetics
  • Mutation
  • Pedigree
  • Phenotype
  • Retrospective Studies
  • Sequence Analysis, DNA
  • X Chromosome Inactivation / genetics*
  • alpha-Thalassemia / genetics

Supplementary concepts

  • ATR-X syndrome
  • Lujan Fryns syndrome