Novel compound heterozygous variants in EMC1 associated with global developmental delay: a lesson from a non-silent synonymous exonic mutation

Ge Wang; Yanli Wang; Chao Gao; Wanqin Xie

doi:10.3389/fnmol.2023.1153156

Novel compound heterozygous variants in EMC1 associated with global developmental delay: a lesson from a non-silent synonymous exonic mutation

Front Mol Neurosci. 2023 Apr 28:16:1153156. doi: 10.3389/fnmol.2023.1153156. eCollection 2023.

Authors

Ge Wang^#¹, Yanli Wang^#², Chao Gao², Wanqin Xie³

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
² Department of Rehabilitation Medicine, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou, China.
³ National Health Committee Key Laboratory of Birth Defects for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.

^# Contributed equally.

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 (EMC1) 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 EMC1, 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 EMC1 have been identified in individuals with global developmental delay. Non-silent synonymous mutations should be kept in mind in genetic analysis.

Keywords: endoplasmic reticulum-membrane protein complex; gene splicing; genetic diagnosis; global developmental delay; synonymous mutation.

Grants and funding

This work was funded by Special Key Project of Henan Province Traditional Chinese Medicine Scientific Research (20-21ZY1072); Open Project of Henan Clinical Medical Research Center of Childhood Diseases (YJZX202205); and the Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province (2019SK1012).