Novel Compound Heterozygous Variants in Associated with Global Developmental Delay: a Lesson from a Non-silent Synonymous Exonic Mutation

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2023 May 15

PMID 37187958

Authors

Ge Wang

Yanli Wang

Chao Gao

Wanqin Xie

Affiliations

Soon will be listed here.

Abstract

Background: The endoplasmic reticulum-membrane protein complex (EMC) as a molecular chaperone is required for the proper synthesis, folding and traffic of several transmembrane proteins. Variants in the subunit 1 of EMC () have been implicated in neurodevelopmental disorders.

Methods: Whole exome sequencing (WES) with Sanger sequencing validation was performed for a Chinese family, including the proband (a 4-year-old girl who displayed global developmental delay, severe hypotonia and visual impairment), her affected younger sister and her non-consanguineous parents. RT-PCR assay and Sanger sequencing were used to detect abnormal RNA splicing.

Results: Novel compound heterozygous variants in , including the maternally inherited chr1: 19566812_1956800delinsATTCTACTT[hg19];NM_015047.3:c.765_777delins ATTCTACTT;p.(Leu256fsTer10) and the paternally inherited chr1:19549890G> A[hg19];NM_015047.3:c.2376G>A;p.(Val792=) are identified in the proband and her affected sister. RT-PCR assay followed by Sanger sequencing reveals that the c.2376G>A variant leads to aberrant splicing, with retention of intron 19 (561bp) in the mature mRNA, which is presumed to introduce a premature translational termination codon (p.(Val792fsTer31)).

Conclusion: Novel compound heterozygous variants in have been identified in individuals with global developmental delay. Non-silent synonymous mutations should be kept in mind in genetic analysis.

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