Severe presentation of WDR62 mutation: is there a role for modifying genetic factors?
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.
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Germany.
Cathryn J
CJ
Poulton
Rachel
R
Schot
Katja
K
Seufert
Maarten H
MH
Lequin
Andrea
A
Accogli
Giuseppe D'
GD
Annunzio
Laurent
L
Villard
Nicole
N
Philip
René
R
de Coo
Coriene
C
Catsman-Berrevoets
Ute
U
Grasshoff
Anja
A
Kattentidt-Mouravieva
Hans
H
Calf
Erika
E
de Vreugt-Gronloh
Leontine
L
van Unen
Frans W
FW
Verheijen
Niels
N
Galjart
Deborah J
DJ
Morris-Rosendahl
Grazia M S
GM
Mancini
D001483:Base Sequence; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011247:Pregnancy; D014404:Tubulin / Q000378:metabolism
D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C418662:TBCD protein, human; D014404:Tubulin; C552527:WDR62 protein, human
WDR62; lissencephaly; microcephaly