Department of Genetics, Harvard Medical School, Boston, Massachusetts; Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
Hum Mutat. 2013 Oct;34(10):1347-51. doi: 10.1002/humu.22367. Epub 2013 Jul 11.
Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.
小耳畸形是一种罕见的先天性外耳畸形，在某些情况下具有遗传病因。我们确定了一个三代家系，该家系双侧小耳畸形伴听力损失呈常染色体显性遗传。受影响的家庭成员的外显子组测序仅发现了七个共享的、罕见的、杂合的、非同义变异，包括一个蛋白截断变异、HOXA2 无义变化 (c.703C>T, p.Q235*)。该 HOXA2 变异在家族中与小耳畸形和听力损失共分离，在 NHLBI 外显子组测序计划中对 6500 个人进行测序或在本研究中对 218 个对照个体进行测序时均未发现。HOXA2 通过小鼠模型被证明对中耳和外耳的发育至关重要，并且之前与常染色体隐性双侧小耳畸形相关。我们的数据扩展了这些结论，并将 HOXA2 单倍不足定义为常染色体显性非综合征性小耳畸形的第一个遗传原因。
