Damaging variants in FOXI3 cause microtia and craniofacial microsomia.

Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.

颅面短小畸形（CFM）表现为一系列颅面畸形，从伴有或不伴有耳道闭锁的单纯小耳畸形到下颌骨、上颌骨、眼眶、面部软组织和/或面神经发育不全。CFM的遗传病因在很大程度上仍然未知。 我们对病因不明的小耳畸形和CFM患者及家系进行了基因组测序和连锁分析。通过在体外表达野生型和突变型蛋白质来评估有害错义变异的功能影响。 我们研究了一个患有小耳畸形的5代家系，确定FOXI3基因的一个错义变异（p.Arg236Trp）是致病原因（优势对数比 = 3.33）。随后，我们从另外3个家系中鉴定出6名患有小耳畸形 - CFM谱系表型的个体，其FOXI3基因存在有害变异，FOXI3是外胚层和神经嵴发育的调节因子。在伴有耳道闭锁的单纯小耳畸形病例中发现了核定位序列的错义变异，并发现其影响FOXI3的亚细胞定位。在患有小耳畸形和下颌骨发育不全（CFM）的患者中发现了功能缺失变异，这表明FOXI3存在剂量敏感性。 FOXI3基因的有害变异是CFM的第二常见遗传病因，导致所有病例中的1%，包括我们队列中13%的家族性病例。