EMC10 – Neurodevelopmental Disorder with Dysmorphic Facies and Variable Seizures

Biallelic variants in EMC10 have been implicated in an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, intellectual disability, dysmorphic facial features, and variable seizures (MONDO:0031011). The condition typically presents in early childhood with impaired motor and cognitive milestones and distinctive facial morphology.

Genetic evidence supporting this association includes a cohort of 31 affected individuals from 16 unrelated families ([PMID:40741735]). These cases harbor pathogenic EMC10 variants encompassing frameshift, nonsense, and splice-site changes consistent with loss-of-function. A recurrent homozygous frameshift variant, c.287del (p.Gly96AlafsTer9), was identified in multiple consanguineous families, demonstrating a founder and hypermutable hotspot effect ([PMID:33531666]).

Segregation analysis across consanguineous pedigrees confirms recessive inheritance: parents are obligate heterozygous carriers while affected siblings are homozygous for EMC10 loss-of-function alleles. In one Saudi family, two affected siblings segregated a homozygous splice-acceptor variant c.679-1G>A with complete concordance and reduced EMC10 transcript levels by RT-qPCR ([PMID:32869858]).

Functional studies demonstrate that EMC10 loss‐of‐function leads to significantly decreased RNA expression and unstable truncated protein products. Patient-derived cells show markedly reduced EMC10 transcript levels, and immunohistochemical assessment of normal human brain confirms critical EMC10 expression during neurodevelopment ([PMID:32869858]; [PMID:33531666]).

Clinically, affected individuals present with global developmental delay (HP:0001263), intellectual disability (HP:0001249), abnormal facial shape (HP:0001999), microcephaly (HP:0000252), seizures (HP:0001250), gingival overgrowth (HP:0000212), and scoliosis (HP:0002650). Phenotypic variability includes mild-to-moderate cognitive impairment in classic cases versus severe, progressive disability with hypotonia and gait abnormalities in others ([PMID:40741735]; [PMID:40150819]).

Integration of genetic and experimental data supports a loss‐of‐function mechanism for EMC10 in neurodevelopment. The collective evidence meets ClinGen criteria for a Strong gene–disease association with corroborating segregation and functional assays. Future studies may elucidate genotype–phenotype correlations and therapeutic targets.

Key Take-home: Biallelic loss-of-function EMC10 variants cause an autosomal recessive neurodevelopmental syndrome with dysmorphic facies, intellectual disability, and seizures; EMC10 should be included in diagnostic gene panels for early‐onset developmental delay.

References

• Developmental neurobiology • 2025 • EMC10 Gene Variants May Cause Dual Molecular Effects on the Neuropsychiatric Disease Pattern. PMID:40741735
• Clinical genetics • 2025 • Case Report: Gingival Hyperplasia and Scoliosis as Additional Features of EMC10-Related Neurodevelopmental Disorder. PMID:40150819
• Clinical genetics • 2020 • EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay. PMID:32869858
• Genetics in medicine : official journal of the American College of Medical Genetics • 2021 • A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features. PMID:33531666

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