Evaluation of novel compound variants of CEP290 in prenatally suspected case of Meckel syndrome through whole exome sequencing

Abstract

Background Meckel syndrome (MKS) is a fatal disease characterized by multisystem fibrosis during the prenatal or perinatal period. It has an autosomal recessive genetic pattern and is characterized by meningo occipital encephalocele, polycystic kidney dysplasia, polydactyly, and hepatobiliary ductal plate malformation. Germline variations in CEP290 have been shown to cause MKS4. Methods In this study, a 23‐year‐old Chinese woman who was 18 weeks pregnant was examined. The pregnancy was terminated due to occipital meningocele and enlarged cystic dysplastic kidney revealed by ultrasonography. In addition, the patient had a history of adverse pregnancy whereby the fetus presented with double kidney enlargement. Karyotype analysis and chromosomal microarray examination (CMA) were carried out using amniotic fluid samples. Whole exome sequencing (WES) was performed using tissue specimens of the aborted fetus. Results Karyotype and CMA analyses showed normal results. However, compound heterozygous mutations of CEP290 c.3175dup and CEP290 c.1201dup were detected through WES. CEP290 c.1201dup is a novel heterozygous mutation of CEP290 that has not been reported previously. Conclusions The findings of this study provide information on the correlation between MKS phenotype and genotype in CEP290 . In addition, these findings indicate that WES is an effective method for detecting genetic causes of multiple structural defects especially those showing normal karyotype and CMA results.

Prenatal phenotype analysis and mutation identification of a fetus with meckel gruber syndrome

“…It has been documented that in some cases, multiple allelism at a single locus or within a single gene can account for some of this phenotypic variability (Chang et al, 2006;Chen, 2007). Recently novel compound variants have been reported in CEP290 (Peng et al, 1935), and aggregating results regarding mutations in MKS1 have resulted in a proposed genotype-phenotype correlation linking the severity of mutations and the domains affected to diagnoses of either MKS, JBTS or BBS (Leitch et al, 2008;Luo et al, 2020; Frontiers in Genetics frontiersin.org Lin et al, 2022). Further studies are needed to not only understand the genotype-phenotype correlation in ciliopathies but also formulate efficient genetic testing so that counseling can be provided to families predisposed to developing debilitating ciliopathies.…”