Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome

Abstract

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.

Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next‐generation sequencing

“…Single‐nucleotide variants (SNVs) and microinsertions‐deletions (indels) were called using SAMtools (http://samtools.sourceforge.net/), based on filtered variants with a mapping quality score of >20, and were annotated using ANNOVAR (http://www.openbioinformatics.org/annovar/). For analysis of the sequencing results, the international publicly available mutation and polymorphism databases such as 1000 Genomes Project (http://www.1000genomes.org/), Exome Aggregation Consortium (ExAC) (http://exac.broadinstitute.org/), Exome Sequencing Project (ESP)(http://evs.gs.washington.edu/EVS/), and Deafness Variation Database (DVD) (http://deafness-variationdatabase.org/letter) as well as BGI self‐developed local database were employed 12 . Only variants with a frequency below 1 percent were selected.…”

A novel COL2A1 mutation causing spondyloepiphyseal dysplasia congenita in a Chinese family

“…to analyze harmful mutations. The quality control system [3][4][5][6] for identifying the candidate variants is shown in Figure 3 and Table 2.…”

A Heterozygous Novel Mutation in TFAP2A Gene Causes Atypical Branchio-Oculo-Facial Syndrome With Isolated Coloboma of Choroid: A Case Report

“…The quality control (QC) of sequence reads generated targeted NGS has been performed following the previous literature ( 14 ). The data of QC were summarized in Table S2 .…”