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.

中文翻译：

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X连锁OAVS与ZIC3中的聚丙氨酸扩展相关的家族描述。

眼-耳-椎-椎骨频谱（OAVS）[MIM：164210]或Goldenhar综合征是与第一和第二分支弓形成的结构缺陷相关的发育障碍。OAVS的遗传起源得到了一些致病基因中罕见的有害变体的描述以及几个染色体拷贝数变异的支持。我们在这里描述了一个大家庭，其中有八名男性成员受到光谱的轻度形式（主要是耳廓缺损）的影响，带有半合子ZIC3通过家族外显子组测序检测到的变体：c.159_161dup p。（Ala55dup），导致正常的10个连续的丙氨酸残基扩展为11个丙氨酸。隔离分析显示它在所有受影响的个体中均存在，并具有隐性X连锁传播。在另一位受影响的男性中进行的全基因组测序可以排除该ZIC3变异体与该家族中另一个潜在病原体变异体之间的连锁不平衡。此外，通过筛查274名OAVS患者的队列，我们​​发现1名男性患者携带10至12个丙氨酸的扩展，这是先前在VACTERL患者中报道的一种变体。ZIC3的功能丧失型引起异型或心脏畸形。这些丙氨酸扩增变体可能会对蛋白质产生不同的影响，从而导致OAVS / VACTERL内部出现不同的表型。