A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features

  • Genet Med. 2021 Jun;23(6):1158-1162. doi: 10.1038/s41436-021-01097-x.
Diane D Shao  1  2 ,  Rachel Straussberg  #  3  4 ,  Hind Ahmed  #  5 ,  Amjad Khan  5 ,  Songhai Tian  6 ,  R Sean Hill  2  7 ,  Richard S Smith  2 ,  Amar J Majmundar  8 ,  Najim Ameziane  9 ,  Jennifer E Neil  2  7 ,  Edward Yang  10 ,  Amal Al Tenaiji  11 ,  Saumya S Jamuar  12  13 ,  Thorsten M Schlaeger  14 ,  Muna Al-Saffar  2  15 ,  Iris Hovel  9 ,  Aisha Al-Shamsi  16 ,  Lina Basel-Salmon  4  17 ,  Achiya Z Amir  4  18 ,  Lariza M Rento  2  7 ,  Jiin Ying Lim  12  13 ,  Indra Ganesan  12 ,  Shirlee Shril  8 ,  Gilad Evrony  2  19 ,  A James Barkovich  20 ,  Peter Bauer  9 ,  Friedhelm Hildebrandt  8 ,  Min Dong  6 ,  Guntram Borck  21  22 ,  Christian Beetz  #  9 ,  Lihadh Al-Gazali  #  23 ,  Wafaa Eyaid  #  5 ,  Christopher A Walsh  #  24  25
Affiliations
  • 1. Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • 2. Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • 3. Neurogenetics Clinic, Neurology Unit, Schneider Children Medical Center, Petah Tikvah, Israel.
  • 4. Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel.
  • 5. Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Science, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia.
  • 6. Department of Urology, Boston Children's Hospital, and Department of Surgery and Department of Microbiology, Harvard Medical School, Boston, MA, USA.
  • 7. Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
  • 8. Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • 9. Centogene AG, Rostock, Germany.
  • 10. Department of Radiology, Boston Children's Hospital, Boston, MA, USA.
  • 11. Medical Institute of Medical Affairs, Sheikh Khalifa Medica City, Abu Dhabi, UAE.
  • 12. Department of Pediatrics, KK Women's and Children's Hospital, Ramat Aviv, Israel.
  • 13. SingHealth Duke-NUS Genomic Medicine Centre, Singapore, Singapore.
  • 14. Stem Cell Program, Boston Children's Hospital, Harvard Medical School, and Harvard Stem Cell Institute, Harvard University, Boston, MA, USA.
  • 15. Department of Pediatrics, United Arab Emirates University, Abu Dhabi, UAE.
  • 16. Division of Genetics, Department of Pediatrics, Tawam Hospital, Al Ain, UAE.
  • 17. Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital and Pediatric Genetics Clinic, Schneider Children's Medical Center, and Felsenstein Medical Research Center, Petah Tikvah, Israel.
  • 18. Pediatric Gastroenterology, Hepatology and Nutrition Clinic, Dana-Dwek Children's Hospital, Tel Aviv Medical Center, Ramat Aviv, Israel.
  • 19. New York University School of Medicine, Center for Human Genetics & Genomics, New York, NY, USA.
  • 20. Neuroradiology, University of California at San Francisco, San Francisco, CA, USA.
  • 21. Center for Rare Diseases (ZSE Ulm), Ulm University Medical Center, Ulm, Germany.
  • 22. genetikum, Neu-Ulm, Germany.
  • 23. Department of Pediatrics, United Arab Emirates University, Al Ain, UAE.
  • 24. Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. [email protected].
  • 25. Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 33531666 DOI: 10.1038/s41436-021-01097-x
Abstract

Purpose: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane Protein Biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10.

Methods: Using exome, genome, and Sanger Sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry.

Results: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein.

Conclusion: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.