Department of Cardiology, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Genetics, Harvard Medical School, Boston, MA.
Hansjörg Wyss Department of Plastic and Reconstructive Surgery, NYU Langone Medical Center, New York, NY.
Genet Med. 2023 Jan;25(1):143-150. doi: 10.1016/j.gim.2022.09.005. Epub 2022 Oct 19.
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.
颅面裂畸形（CFM）代表了一系列颅面畸形，范围从孤立性小耳畸形伴或不伴听骨闭锁到下颌骨、上颌骨、眼眶、面部软组织和/或面神经发育不良。CFM 的遗传原因在很大程度上仍不清楚。
我们对患有小耳畸形和未知遗传病因的 CFM 的患者和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来评估有害错义变异的功能后果。
我们研究了一个有 5 代的家系，该家系患有小耳畸形，确定了 FOXI3 中的错义变异（p.Arg236Trp）是疾病的原因（对数优势比=3.33）。随后，我们在另外 3 个家系中发现了 6 名小耳畸形-CFM 表型的个体，这些家系携带有 FOXI3 的破坏性变异，FOXI3 是外胚层和神经嵴发育的调节剂。在孤立性小耳畸形伴听骨闭锁的病例中发现了核定位序列中的错义变异，这些变异影响了 FOXI3 的亚细胞定位。在小耳畸形伴下颌骨发育不良（CFM）的患者中发现了功能丧失变异，这表明 FOXI3 的剂量敏感性。
FOXI3 的破坏性变异是 CFM 的第二大常见遗传原因，占所有病例的 1%，包括我们队列中家族性病例的 13%。
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