Abstract：
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 Ca2+ 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.
摘要：
颅面畸形,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，其特征是发育迟缓和/或智力障碍的临床三联症，典型的面部完形与短头畸形,浓密的眉毛，synphrys,超端粒,宽鼻梁,鼻子短,以及多个椎骨和肋骨畸形，如两裂和融合的肋骨和异常的椎体分割和融合。TMCO1中的双等位基因功能丧失变体引起CFSMR1。我们报告了两名无关的埃及患者，其表型提示CFSMR。患者1的单个全外显子组测序和患者2的TMCO1的Sanger测序揭示了相同的纯合TMCO1无义变体c.187C>T/p。（Arg63*）在两个受影响的个体中；患者的健康父母是该变体的杂合携带者。患者1和2的先天性听力损失是在受CFSMR影响的个体中偶尔发现的。Camptodactyly和syndactyly，在患者2中注意到，在CFSMR中没有或很少报道。文献综述显示，包括本文报道的患者在内，共有30例具有临床可识别和独特的CFSMR1表型的个体。他们都携带双等位基因TMCO1变体。在来自14个家庭的30名患者中报告了六种不同的TMCO1变体，包括三个废话，两个2-bp的缺失，和剪接供体位点变体。所有疾病相关的TMCO1变体可能代表无效等位基因,导致不存在编码的蛋白质。TMCO1已被提议充当Ca2+通道，而其他数据显示TMCO1作为线粒体蛋白和内质网转位的组成部分，对于多遍膜蛋白的生物发生很重要的细胞机制。RAB5IF/C20orf24最近被确定为颅面畸形的致病基因，骨骼异常,和智力发育受损综合征-2（CFSMR2；OMIM#616994）。RAB5IF/C20orf24和TMCO1的异型二聚化及其相互依赖性可能表明CFSMR背后的ER-线粒体相互作用的病理生理作用。
