EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay.

Muhammad Umair,Abdulaziz Asiri,Taghrid Aloraini,Yusra Alyafee,Majid Alfadhel,Ahmed Alfares,Abeer Al Tuwaijri,Senay Kafkas,Muhammad Talal Alrifai,Marwa Abdelhakim,Robert Hoehndorf,Lamia Alsubaie,Kheloud M Alhamoudi,Mariam Ballow,Azza Thamer Althagafi

doi:10.1111/cge.13842

Abstract

In recent years, several genes have been implicated in the variable disease presentation of global developmental delay (GDD) and intellectual disability (ID). The endoplasmic reticulum membrane protein complex (EMC) family is known to be involved in GDD and ID. Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders. EMC10 is a bone marrow‐derived angiogenic growth factor that plays an important role in infarct vascularization and promoting tissue repair. However, this gene has not been previously associated with human disease. Herein, we describe a Saudi family with two individuals segregating a recessive neurodevelopmental disorder. Both of the affected individuals showed mild ID, speech delay, and GDD. Whole‐exome sequencing (WES) and Sanger sequencing were performed to identify candidate genes. Further, to elucidate the functional effects of the variant, quantitative real‐time PCR (RT‐qPCR)‐based expression analysis was performed. WES revealed a homozygous splice acceptor site variant (c.679‐1G>A) in EMC10 (chromosome 19q13.33) that segregated perfectly within the family. RT‐qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients, indicating the pathogenicity of the identified variant. For the first time in the literature, the EMC10 gene variant was associated with mild ID, speech delay, and GDD. Thus, this gene plays a key role in developmental milestones, with the potential to cause neurodevelopmental disorders in humans.

Highlights

The endoplasmic reticulum (ER) is a diverse cell organelle whose physical behavior and function greatly impact cell physiology
We characterized this clinical phenotype using whole-exome sequencing (WES) and identified a potential pathogenic homozygous variant in the EMC10 gene located on chromosome 19q13.33
Other systemic examinations were unremarkable, except for mild hirsutism. Clinical descriptions of both affected individuals are provided in Table 1. 3.2 Whole-exome sequencing and Sanger sequencing WES was performed for single affected individuals (IV-1), as described previously.[11,12]

Summary

Introduction

The endoplasmic reticulum (ER) is a diverse cell organelle whose physical behavior and function greatly impact cell physiology. In most cases, their functions remain unknown.[1,3] One of these complexes, the ER membrane protein complex (EMC), is an abundant, multi-subunit protein complex found in all eukaryotic kingdoms.[4] The EMC family was first identified in yeast as a multi-protein transmembrane complex composed of ten subunits, where it was though to be responsible for eliminating misfolded membrane proteins.[1] The EMC may facilitate interactions between mitochondria and the ER, modulating the processing and folding of different proteins.[5] It plays a key role in the stability of different transmembrane proteins, such as rhodopsin, which has been reported to cause retinal degeneration in Drosophila.[6] The loss of ER‒mitochondria crosstalk has been previously associated with Alzheimer’s disease (AD) type 3 and 4 (PSEN1: OMIM 607822; PSEN2: OMIM 600759), recessive cerebellar atrophy, visual impairment, psychomotor retardation (EMC1: OMIM 616875), dominant amyotrophic lateral sclerosis (ALS) type 8 (VAPB: OMIM 608627), juvenile ALS type 16 (SIGMAR1; OMIM 601978), Parkinson’s disease type 1 and 4 (SNCA: OMIM 163890), and Charcot-Marie-Tooth disease (CMT) type 2A2A (MFN2; OMIM 608507).[7] Despite advances in molecular genetic technologies, the function of the EMC and the pathways associated with human disease remain to be fully elucidated.[8] we report a single family with two siblings affected by mild ID, speech delay, and GDD We characterized this clinical phenotype using whole-exome sequencing (WES) and identified a potential pathogenic homozygous variant in the EMC10 gene located on chromosome 19q13.33

Methods

Results

Conclusion