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Severe presentation of WDR62 mutation: Is there a role for modifying genetic factors?
Author(s) -
Poulton Cathryn J.,
Schot Rachel,
Seufert Katja,
Lequin Maarten H.,
Accogli Andrea,
Annunzio Giuseppe D',
Villard Laurent,
Philip Nicole,
de Coo René,
CatsmanBerrevoets Coriene,
Grasshoff Ute,
KattentidtMouravieva Anja,
Calf Hans,
de VreugtGronloh Erika,
van Unen Leontine,
Verheijen Frans W.,
Galjart Niels,
MorrisRosendahl Deborah J.,
Mancini Grazia M. S.
Publication year - 2014
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36611
Subject(s) - genetics , missense mutation , mutation , biology , gene duplication , phenotype , microcephaly , polymicrogyria , allele , proband , intellectual disability , gene , neuroscience , epilepsy
Mutations in WDR62 are associated with primary microcephaly; however, they have been reported with wide phenotypic variability. We report on six individuals with novel WDR62 mutations who illustrate this variability and describe three in greater detail. Of the three, one lacks neuromotor development and has severe pachygyria on MRI, another has only delayed speech and motor development and moderate polymicrogyria, and the third has an intermediate phenotype. We observed a rare copy number change of unknown significance, a 17q25qter duplication, in the first severely affected individual. The 17q25 duplication included an interesting candidate gene, tubulin cofactor D ( TBCD ), crucial in microtubule assembly and disassembly. Sequencing of the non‐duplicated allele showed a TBCD missense mutation, predicted to cause a deleterious p.Phe1121Val substitution. Sequencing of a cohort of five patients with WDR62 mutations, including one with an identical mutation and different phenotype, plus 12 individuals with diagnosis of microlissencephaly and another individual with mild intellectual disability (ID) and a 17q25 duplication, did not reveal TBCD mutations. However, immunostaining with tubulin antibodies of cells from patients with both WDR62 and TBCD mutation showed abnormal tubulin network when compared to controls and cells with only the WDR62 mutation. Therefore, we propose that genetic factors contribute to modify the severity of the WDR62 phenotype and, although based on suggestive evidence, TBCD could function as one of such factors. © 2014 Wiley Periodicals, Inc.