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

Wang, Ge; Wang, Yanli; Gao, Chao; Xie, Wei

doi:10.3389/fnmol.2023.1153156

Cited by 1 publication

(1 citation statement)

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“…Five additional families with biallelic variants and 3 individuals with monoallelic de novo variants and CAVIPMR have been reported since, raising the total of families reported to date with this rare disorder to 12 families with affected 17 individuals (8 families with biallelic EMC1 variants and 4 families with de novo variants). 6 , 8 , 10 - 14 The mode of inheritance in CAVIPMR has been proposed to be dependent on the variant localization and region affected where the variants in all AR cases to date affect 1 of the 2 EMC1 domains, while variants in the AD cases cluster at interdomain region. 8 …”

Section: Introductionmentioning

confidence: 99%

Tribal Founder EMC1 Variant in 5 Kuwaiti Families Expands Phenotypic Spectrum of EMC1 -Related Disorder

Alzayed,

Alzuabi,

Alqusaimi

et al. 2024

Neurol Genet

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Background and Objectives The endoplasmic reticulum (ER) membrane protein complex is a conserved multisubunit transmembrane complex that enables energy-independent insertion of newly synthesized membrane proteins into ER membranes, mediating protein folding, phospholipid transfer from ER to mitochondria, and elimination of misfolded proteins. The first subunit of EMC (EMC1) is encoded by EMC1 . Both monoallelic de novo and biallelic EMC1 variants have been identified to cause cerebellar atrophy, visual impairment, and psychomotor retardation (CAVIPMR) [OMIM #616875]. Eight families with biallelic EMC1 variants and CAVIPMR have been reported. Here, we describe 8 individuals from 5 Kuwaiti families from the same tribe, with the previously reported homozygous pathogenic missense EMC1 variant [c.245C>T:p.(Thr82Met)] and CAVIPMR. Methods Proband exome sequencing was performed in 3 families, while targeted molecular testing for EMC1 [c.245C>T:p.(Thr82Met)] variant was performed in the other 2 families based on strong clinical suspicion and tribal origin. Sanger sequencing confirmed variant segregation with disease in all families. Results We identified 8 individuals from 5 Kuwaiti families with the homozygous pathogenic EMC1 variant [c.245C>T:p.(Thr82Met)] previously reported in a Turkish family with CAVIPMR. The variant was absent from Kuwait Medical Genetic Center database, thus unlikely to represent a population founder allelic variant. The average age at symptom onset was 11 weeks, with all families reporting either visual abnormalities, hypotonia, and/or global developmental delay (GDD) as the presenting features. Shared clinical features included GDD (8/8), microcephaly (8/8), truncal hypotonia (8/8), visual impairment (7/7), and failure to thrive (7/7). Other common features included hyperreflexia (5/6; 83%), peripheral hypertonia (3/5; 60%), dysmorphism (3/6; 50%), epilepsy (4/8; 50%), and chorea (3/8; 36%). Brain imaging showed cerebellar atrophy in 4/7 (57%) and cerebral atrophy in 3/6 (50%) individuals. Discussion The presence of exact biallelic homozygous EMC1 variant in 5 Kuwaiti families from the same tribe suggests a tribal founder allelic variant. The clinical features in this study are consistent with the phenotypic spectrum of EMC1 -associated CAVIPMR in previous reports. The presence of chorea, first noted in this study, further expands the phenotypic spectrum. Our findings emphasize the importance of targeted EMC1 variant [c.245C>T:p.(Thr82Met)] testing for infants from affected tribe who present with visual impairment, GDD, and hypotonia.

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