Description of a family with X-linked oculo-auriculo-vertebral spectrum associated with polyalanine tract expansion in ZIC3

Aurélien Trimouille, Angèle Tingaud-Sequeira, Didier Lacombe, Tina Duelund Hjortshøj, Sven Kreiborg, Hanne Buciek Hove, Caroline Rooryck

10 Citationer (Scopus)

Abstract

Oculo-auriculo-vertebral spectrum (OAVS) [MIM:164210], or Goldenhar syndrome, is a developmental disorder associating defects of structures derived from the first and second branchial arches. The genetic origin of OAVS is supported by the description of rare deleterious variants in a few causative genes, and several chromosomal copy number variations. We describe here a large family with eight male members affected by a mild form of the spectrum, mostly auricular defects, harboring a hemizygous ZIC3 variant detected by familial exome sequencing: c.159_161dup p.(Ala55dup), resulting in an expansion of the normal 10 consecutive alanine residues to 11 alanines. Segregation analysis shows its presence in all the affected individuals, with a recessive X-linked transmission. Whole-genome sequencing performed in another affected male allowed to exclude linkage disequilibrium between this ZIC3 variant and another potential pathogenic variant in this family. Furthermore, by screening of a cohort of 274 OAVS patients, we found 1 male patient carrying an expansion of 10 to 12 alanines, a variant previously reported in patient presenting with VACTERL. Loss-of-function variants of ZIC3 are causing heterotaxy or cardiac malformations. These alanine expansion variants could have a different impact on the protein and thereby resulting in a different phenotype within the OAVS/VACTERL.

OriginalsprogEngelsk
TidsskriftClinical Genetics
Vol/bind98
Udgave nummer4
Sider (fra-til)384-389
Antal sider6
ISSN0009-9163
DOI
StatusUdgivet - okt. 2020

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