Lin Tingting, Ma Yongyi, Zhou Danni, Sun Liwei, Chen Ke, Xiang Yezhou, Tong Keya, Jia Chaoli, Jiang Kean, Liu Dongyun, Huang Guoning
Chongqing Key Laboratory of Human Embryo Engineering, Chongqing, China.
Chongqing Clinical Research Center for Reproductive Medicine, Chongqing, China.
Front Genet. 2022 Mar 14;13:843931. doi: 10.3389/fgene.2022.843931. eCollection 2022.
Meckel syndrome (MKS), also known as the Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of the primary cilia during early embryogenesis. The diagnostic criteria are based on clinical variability and genetic heterogeneity. Mutations in the gene constitute approximately 7% of all MKS cases. Herein, we present a non-consanguineous couple with three abnormal pregnancies as the fetuses showed MKS-related phenotypes of the central nervous system malformation and postaxial polydactyly. Whole-exome sequencing identified two novel heterozygous mutations of : c.350C>A and c.1408-14A>G. The nonsense mutation c.350C>A produced a premature stop codon and induced the truncation of the MKS1 protein (p.S117*). Reverse-transcription polymerase chain reaction (RT-PCR) showed that c.1408-14A>G skipped exon 16 and encoded the mutant MKS1 p.E471Lfs*92. Functional studies showed that these two mutations disrupted the B9-C2 domain of the MKS1 protein and attenuated the interactions with B9D2, the essential component of the ciliary transition zone. The couple finally got a healthy baby through preimplantation genetic testing for monogenic disorder (PGT-M) with haplotype linkage analysis. Thus, this study expanded the mutation spectrum of and elucidated the genetic heterogeneity of in clinical cases.
梅克尔综合征（MKS），也称为梅克尔-格鲁伯综合征，是一种严重的多效性常染色体隐性发育障碍，由早期胚胎发育过程中初级纤毛功能障碍引起。诊断标准基于临床变异性和遗传异质性。该基因的突变约占所有MKS病例的7%。在此，我们报道了一对非近亲夫妇，他们有三次异常妊娠，因为胎儿表现出与MKS相关的中枢神经系统畸形和轴后多指的表型。全外显子测序确定了该基因的两个新的杂合突变：c.350C>A和c.1408-14A>G。无义突变c.350C>A产生了一个提前终止密码子，并导致MKS1蛋白截短（p.S117*）。逆转录聚合酶链反应（RT-PCR）显示，c.1408-14A>G跳过了第16外显子，并编码突变的MKS1 p.E471Lfs*92。功能研究表明，这两个突变破坏了MKS1蛋白的B9-C2结构域，并减弱了与纤毛过渡区重要成分B9D2的相互作用。这对夫妇最终通过单基因疾病植入前基因检测（PGT-M）和单倍型连锁分析得到了一个健康的婴儿。因此，本研究扩展了该基因的突变谱，并阐明了临床病例中该基因的遗传异质性。
