Exome sequencing in children of women with skewed X-inactivation identifies atypical cases and complex phenotypes.
Eur J Paediatr Neurol
; 21(3): 475-484, 2017 May.
Article
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| MEDLINE
| ID: mdl-28027854
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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Inactivación del Cromosoma X
/
Exoma
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Discapacidad Intelectual
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Adolescent
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Child
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Humans
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Male
Idioma:
En
Revista:
Eur J Paediatr Neurol
Asunto de la revista:
NEUROLOGIA
/
PEDIATRIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Italia