Description of a family with X-linked oculo‐auriculo‐vertebral spectrum associated with polyalanine tract expansion in ZIC3
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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 (WGS) 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 one 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 OAV spectrum/VACTERL.
Original language | English |
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Journal | Clinical Genetics |
Volume | 98 |
Issue number | 4 |
Pages (from-to) | 384-389 |
ISSN | 0009-9163 |
DOIs | |
Publication status | Published - 2020 |
ID: 244328442