Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy

Am J Hum Genet. 2016 Mar 3;98(3):562-570. doi: 10.1016/j.ajhg.2016.01.011.


The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.

Keywords: EMC1; Whole-exome sequencing; cerebellar atrophy; endoplasmic reticulum (ER)-membrane complex; inter-organellar communication; intracellular transport; mitochondrial membrane; neurodegeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Amino Acid Sequence
  • Atrophy / diagnosis
  • Atrophy / genetics*
  • Cerebellum / pathology
  • Child
  • Child, Preschool
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics*
  • Endoplasmic Reticulum-Associated Degradation
  • Female
  • Genetic Association Studies
  • Genetic Variation*
  • Heterozygote
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins
  • Molecular Sequence Data
  • Muscle Hypotonia / diagnosis
  • Muscle Hypotonia / genetics*
  • Mutation
  • Pedigree
  • Protein Folding
  • Proteins / genetics*
  • Proteins / metabolism
  • Scoliosis / diagnosis
  • Scoliosis / genetics*


  • EMC10 protein, human
  • Membrane Proteins
  • Proteins