Identification of a likely pathogenic structural variation in the LAMA1 gene by Bionano optical mapping

Min Chen,Liya Wang,Yanmei Yang,Min Zhang,Minyue Dong,Yeqing Qian,Bei Liu,Yixi Sun

doi:10.1038/s41525-020-0138-z

Abstract

Recent advances in Bionano optical mapping (BOM) provide a great insight into the determination of structural variants (SVs), but its utility in identification of clinical likely pathogenic variants needs to be further demonstrated and proved. In a family with two consecutive pregnancies affected with ventriculomegaly, a splicing likely pathogenic variant at the LAMA1 locus (NM_005559: c. 4663 + 1 G > C) inherited from the father was identified in the proband by whole-exome sequencing, and no other pathogenic variant associated with the clinical phenotypes was detected. SV analysis by BOM revealed an ~48 kb duplication at the LAMA1 locus in the maternal sample. Real-time quantitative PCR and Sanger sequencing further confirmed the duplication as c.859-153_4806 + 910dup. Based on these variants, we hypothesize that the fetuses have Poretti-Boltshauser syndrome (PBS) presenting with ventriculomegaly. With the ability to determine single nucleotide variants and SVs, the strategy adopted here might be useful to detect cases missed by current routine screening methods. In addition, our study may broaden the phenotypic spectrum of fetuses with PBS.

Highlights

Accurate molecular diagnosis of genetic disorders is crucial to families with history of diseases and couples with consecutive abnormal fetuses showing similar phenotypes
We identified two likely pathogenic variants at the LAMA1 locus in a family with two consecutive pregnancies affected with ventriculomegaly by using Bionano optical mapping (BOM) together with whole-exome sequencing (WES), chromosome microarray (CMA), and Sanger sequencing
The splicing variant was been reported. It spanned from exons 7 to 33, which encoded present in 27.3% of all reads covering this position in the proband several Laminin EGF-like domains and partial domain I

Summary

Introduction

Accurate molecular diagnosis of genetic disorders is crucial to families with history of diseases and couples with consecutive abnormal fetuses showing similar phenotypes. A de novo genome assembly is derived from many copies of a native DNA molecule, which allows BOM to detect CNVs, translocations and inversions, as well as other complex SVs10,12. PBS is associated with biallelic pathogenic variants in the LAMA1 gene located on 18p11.31.

Results

Conclusion