Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome.
Meckel syndrome (MKS) is a pre- or perinatal multisystemic ciliopathic lethal disorder with an autosomal recessive mode of inheritance. Meckel syndrome is usually manifested with meningo-occipital encephalocele, polycystic kidney dysplasia, postaxial polydactyly and hepatobiliary ductal plate malformation. Germline variants in CEP290 cause MKS4. In this study, we investigated a 35-years-old Chinese female who was 17+1 weeks pregnant. She had a history of adverse pregnancy of having foetus with multiple malformations. We performed ultrasonography and identified the foetus with occipital meningoencephalocele and enlarged cystic dysplastic kidneys. So, she decided to terminate her pregnancy and further genetic molecular analysis was performed. We identified the aborted foetus without postaxial polydactyly. Histological examination of foetal kidney showed cysts in kidney and thinning of the renal cortex with glomerular atrophy. Whole exome sequencing identified a novel homozygous variant (c.2144T>G; p.L715* ) in exon 21 of the CEP290 in the foetus. Sanger sequencing confirmed that both the parents of the foetus were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters of the foetus as well as in the 100 healthy individuals. Western blot analysis showed that this variant leads to the formation of truncated CEP290 protein with the molecular weight of 84 KD compared with the wild-type CEP290 protein of 290 KD. Hence, it is a loss-of-function variant. We also found that the mutant cilium appears longer in length than the wild-type cilium. Our present study reported the first variant of CEP290 associated with MKS4 in Chinese population.
['Zhang|Rui|R|', 'Chen|Shaoyun|S|', 'Han|Peng|P|', 'Chen|Fangfang|F|', 'Kuang|Shan|S|', 'Meng|Zhuo|Z|', 'Liu|Junnian|J|', 'Sun|Ruliang|R|', 'Wang|Zhiwei|Z|', 'He|Xiaohong|X|', 'Li|Yong|Y|', 'Guan|Yuanning|Y|', 'Yue|Zhengfang|Z|', 'Li|Chen|C|', 'Kumar Dey|Subrata|S|', 'Zhu|Yuanfang|Y|', 'Banerjee|Santasree|S|0000-0003-2481-4562']
D000328:Adult D000951:Antigens, Neoplasm D044466:Asians D001483:Base Sequence D018797:Cell Cycle Proteins D002925:Ciliary Motility Disorders D003598:Cytoskeletal Proteins D004677:Encephalocele D005260:Female D005333:Fetus D006720:Homozygote D006801:Humans D007668:Kidney D008297:Male D009154:Mutation D010375:Pedigree D007690:Polycystic Kidney Diseases D012174:Retinitis Pigmentosa D016216:Ultrasonography, Prenatal D000073359:Whole Exome Sequencing
homozygous novel variant CEP290 gene Meckel syndrome loss-of-function