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Severe presentation of WDR62 mutation: Is there a role for modifying genetic factors?
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Personen und Körperschaften: | , , , , , , , , , , , , , , , , , , |
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Titel: |
Severe presentation of WDR62 mutation: Is there a role for modifying genetic factors? |
In: | American Journal of Medical Genetics Part A, 164, 2014, 9, S. 2161-2171 |
veröffentlicht: |
Wiley
|
Umfang: | 2161-2171 |
ISSN: |
1552-4825 1552-4833 |
DOI: | 10.1002/ajmg.a.36611 |
Zusammenfassung: | <jats:sec><jats:label /><jats:p>Mutations in <jats:italic>WDR62</jats:italic> are associated with primary microcephaly; however, they have been reported with wide phenotypic variability. We report on six individuals with novel <jats:italic>WDR62</jats:italic> 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 (<jats:italic>TBCD</jats:italic>), crucial in microtubule assembly and disassembly. Sequencing of the non‐duplicated allele showed a <jats:italic>TBCD</jats:italic> missense mutation, predicted to cause a deleterious p.Phe1121Val substitution. Sequencing of a cohort of five patients with <jats:italic>WDR62</jats:italic> 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 <jats:italic>TBCD</jats:italic> mutations. However, immunostaining with tubulin antibodies of cells from patients with both <jats:italic>WDR62</jats:italic> and <jats:italic>TBCD</jats:italic> mutation showed abnormal tubulin network when compared to controls and cells with only the <jats:italic>WDR62</jats:italic> mutation. Therefore, we propose that genetic factors contribute to modify the severity of the <jats:italic>WDR62</jats:italic> phenotype and, although based on suggestive evidence, TBCD could function as one of such factors. © 2014 Wiley Periodicals, Inc.</jats:p></jats:sec> |
Format: | E-Article |
Quelle: | Wiley (CrossRef) |
Sprache: | Englisch |