A Novel Silent Mutation in the L1CAM Gene Causing Fetal Hydrocephalus Detected by Whole-Exome Sequencing

Abstract

X-linked hydrocephalus (XLH), a genetic disorder, has an incidence of 1/30,000 male births. The great proportion of XLH is ascribed to loss-of-function mutations of L1 cell adhesion molecule gene (L1CAM), but silent mutations in L1CAM with pathogenic potential were rare and were usually ignored especially in whole-exome sequencing (WES) detection. In the present study, we describe a novel silent L1CAM mutation in a Chinese pregnant woman reporting continuous five times pregnancies with fetal hydrocephalus. After fetal blood sampling, we found c.453G > T (p.Gly151 = ) in the L1CAM gene of the fetus by WES; RT-PCR of the messenger RNA (mRNA) from cord blood mononuclear cells and subsequent sequence analysis identified the mutation created a potential 5′ splice site consensus sequence, which would result in an in-frame deletion of 72 bp from exon 5 and 24 amino acids of the L1CAM protein. Heterozygous mutations were confirmed in analyzing DNA and mRNA from peripheral blood mononuclear cells of the woman, and a severe L1 syndrome was confirmed by fetal ultrasound scan and MRI. Our study first indicated c.453G > T (p.Gly151 = ) in L1CAM could be disease causing for hydrocephalus, which would aid in genetic counseling for the prenatal diagnosis of hydrocephalus. Meanwhile, it suggested some silent mutations detected in WES should not be ignored; splicing predictions of these mutations were necessary.

Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study

“…The present study has 4 major strengths. First, following the advent of WES technology, it has proven to be efficient in unearthing sequence variation across the MAF spectrum in obstetric and gynecological diseases [ 25 , 37 ]. Using this method, we successfully identified novel candidate pathogenicity loci with known functional genes ABCB4 , ABCB11 [ 24 ] and ABCC2 .…”

Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy

“…This can omit some potentially pathogenic mutations. Recently, WES technology has proved to be a powerful new approach for detecting low-frequency (0.01 ≤ MAF <0.05) and rare (MAF <0.01) variations that affect human diseases, such as spontaneous preterm birth ( Huusko et al, 2018 ) and fetal hydrocephalus ( Sun et al, 2019 ). Using this method, we have also successfully revealed ANO8 as a genetic risk factor for ICP ( Liu et al, 2020 ) and identified 42 novel mutations in ABC transporter genes that are associated with ICP in 151 samples ( Liu et al, 2021 ).…”

Novel homozygous silent mutation of ITGB3 gene caused Glanzmann thrombasthenia

“…sanger.ac.uk), OMIM (http://omim.org/), PubMed (http:// www.ncbi.nlm.nih.gov/pubmed), ClinVar (https://www.ncbi. nlm.nih.gov/clinvar/), and HGMD (http://www.hgmd.cf.ac.uk/ ac/index.php) databases were used to investigate the clinical relevance of the mutations (9).…”