Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Eur J Med Genet. 2023 Mar;66(3):104715. doi: 10.1016/j.ejmg.2023.104715. Epub 2023 Jan 25.
Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1; OMIM#213980) is a rare autosomal recessive disorder characterized by the clinical triad of developmental delay and/or intellectual disability, a typical facial gestalt with brachycephaly, highly-arched bushy eyebrows, synophrys, hypertelorism, wide nasal bridge, and short nose, as well as multiple vertebrae and rib malformations, such as bifid and fused ribs and abnormal vertebral segmentation and fusion. Biallelic loss-of-function variants in TMCO1 cause CFSMR1. We report on two unrelated Egyptian patients with a phenotype suggestive of CFSMR. Single whole-exome sequencing in patient 1 and Sanger sequencing of TMCO1 in patient 2 revealed the same homozygous TMCO1 nonsense variant c.187C > T/p.(Arg63*) in both affected individuals; patients' healthy parents were heterozygous carriers of the variant. Congenital hearing loss in patients 1 and 2 is an occasional finding in individuals affected by CFSMR. Camptodactyly and syndactyly, which were noted in patient 2, have not or rarely been reported in CFSMR. Review of the literature revealed a total of 30 individuals with the clinically recognizable and unique phenotype of CFSMR1, including the patients reported here, who all carried biallelic TMCO1 variants. Six different TMCO1 variants have been reported in the 30 patients from 14 families, comprising three nonsense, two 2-bp deletions, and a splice donor site variant. All disease-associated TMCO1 variants likely represent null alleles resulting in absence of the encoded protein. TMCO1 has been proposed to act as a Ca channel, while other data revealed TMCO1 as a mitochondrial protein and a component of the translocon at the endoplasmic reticulum, a cellular machinery important for the biogenesis of multi-pass membrane proteins. RAB5IF/C20orf24 has recently been identified as causative gene for craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2; OMIM#616994). Heterodimerization of RAB5IF/C20orf24 and TMCO1 and their interdependence may suggest a pathophysiological role of ER-mitochondria interaction underlying CFSMR.
颅面发育不良、骨骼异常和智力发育障碍综合征-1（CFSMR1；OMIM#213980）是一种罕见的常染色体隐性遗传疾病，其特征为发育迟缓或智力障碍三联征，典型的面部特征为短头畸形、浓密拱形眉毛、连眉、远视、宽鼻梁和短鼻，以及多个椎体和肋骨畸形，如叉骨和融合肋骨以及异常的椎体分段和融合。TMCO1 的双等位基因功能丧失变异导致 CFSMR1。我们报告了两例具有 CFSMR 表型的埃及无关患者。对患者 1 进行全外显子组测序，对患者 2 进行 TMCO1 的 Sanger 测序，均在两名受累个体中发现相同的纯合 TMCO1 无义变异 c.187C>T/p.(Arg63*)；患者健康父母为该变异的杂合携带者。患者 1 和 2 均存在先天性听力损失，这是 CFSMR 受影响个体的偶发发现。患者 2 出现的并指和蹼状指，在 CFSMR 中鲜有报道。文献复习共发现 30 例具有 CFSMR1 临床可识别且独特表型的个体，包括本文报告的患者，他们均携带双等位基因 TMCO1 变异。14 个家系的 30 名患者共报道了 6 种不同的 TMCO1 变异，包括 3 种无义变异、2 种 2bp 缺失和 1 种剪接供体位点变异。所有与疾病相关的 TMCO1 变异可能代表无功能等位基因，导致编码蛋白缺失。TMCO1 被提议作为 Ca 通道，而其他数据显示 TMCO1 为线粒体蛋白和内质网转位复合物的组成部分，该复合物对于多跨膜蛋白的生物发生至关重要。RAB5IF/C20orf24 最近被鉴定为颅面发育不良、骨骼异常和智力发育障碍综合征-2（CFSMR2；OMIM#616994）的致病基因。RAB5IF/C20orf24 和 TMCO1 的异二聚化及其相互依赖性可能提示 ER-线粒体相互作用在 CFSMR 中的病理生理学作用。
Proc Natl Acad Sci U S A. 2009-12-14
Am J Med Genet A. 2018-12-17
Eur J Hum Genet. 2014-9
Am J Med Genet A. 2014-2
Elife. 2020-8-21
Zotero 插件