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Short report
Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews
  1. Rivka Birnbaum1,
  2. Shlomit Ezer2,
  3. Nava Shaul Lotan1,
  4. Avital Eilat1,
  5. Keren Sternlicht3,
  6. Lilach Benyamini3,
  7. Orit Reish3,4,
  8. Tzipora Falik-Zaccai5,
  9. Gali Ben-Gad6,
  10. Raya Rod7,
  11. Reeval Segel8,
  12. Katherine Kim9,10,
  13. Barabra Burton11,
  14. Catherine E Keegan12,
  15. Mallory Wagner12,
  16. Lindsay B Henderson13,
  17. Nofar Mor14,
  18. Ortal Barel14,
  19. Yoel Hirsch15,16,
  20. Vardiella Meiner2,17,
  21. Orly Elpeleg2,17,
  22. Tamar Harel2,17,
  23. Hagar Mor-Shakad1,2
  1. 1Department of Genetics, Hadassah Medical Center, Jerusalem, Israel
  2. 2Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
  3. 3Genetics Institute, Shamir Medical Center, Tzrifin, Israel
  4. 4Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  5. 5Institute of Human Genetics, Western Galilee Hospital-Nahariya, Nahariya, Israel
  6. 6Department of Child Development, Galilee Medical Center, Nahariya, Israel
  7. 7The Center for Child Development and Pediatric Neurology, Western Galilee Hospital-Naharyia, Nahariya, Israel
  8. 8Genetics, Shaare-Zedek, Jerusalem, Israel
  9. 9Genetics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
  10. 10Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  11. 11Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
  12. 12Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
  13. 13GeneDx, Gaithersburg, Maryland, USA
  14. 14The Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel
  15. 15Research, Dor Yeshroim, Brooklyn, New York, USA
  16. 16Dor Yeshorim, New York, New York, USA
  17. 17Department of Genetics, Hadassah Medical Center, Jerusalem, Jerusalem, Israel
  1. Correspondence to Dr Hagar Mor-Shakad, Department of Genetics, Hadassah Medical Center, Jerusalem, 12000, Israel; hagarmor{at}


Background Neurodevelopmental disorders (NDDs) impact both the development and functioning of the brain and exhibit clinical and genetic variability. RAP and RAB proteins, belonging to the RAS superfamily, are identified as established contributors to NDDs. However, the involvement of SGSM (small G protein signalling modulator), another member of the RAS family, in NDDs has not been previously documented.

Methods Proband-only or trio exome sequencing was performed on DNA samples obtained from affected individuals and available family members. The variant prioritisation process focused on identifying rare deleterious variants. International collaboration aided in the identification of additional affected individuals.

Results We identified 13 patients from 8 families of Ashkenazi Jewish origin who all carried the same homozygous frameshift variant in SGSM3 gene. The variant was predicted to cause a loss of function, potentially leading to impaired protein structure or function. The variant co-segregated with the disease in all available family members. The affected individuals displayed mild global developmental delay and mild to moderate intellectual disability. Additional prevalent phenotypes observed included hypotonia, behavioural challenges and short stature.

Conclusions An Ashkenazi Jewish homozygous founder variant in SGSM3 was discovered in individuals with NDDs and short stature. This finding establishes a connection between another member of the RAS family and NDDs. Additional research is needed to uncover the specific molecular mechanisms by which SGSM3 influences neurodevelopmental processes and the regulation of growth.

  • Genetic Research
  • Human Genetics
  • Genetic Variation

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  • TH and HM-S contributed equally.

  • Contributors HM-S and RB designed the study and wrote the paper. TH supervised the study and contributed to writing the paper. RB recognised this disease as a new clinical entity with the families A–E. SE performed Sanger validation for families A–C. OE provided genetic consultation and evaluation for families A and D. VM provided genetic consultation and evaluation for family B. RS and AE provided genetic consultation and evaluation for family C. TF-Z and GB-G provided genetic consultation and evaluation for family D and performed Sanger segregation. NM and OB analysed the exome sequencing of family D and reported the SGSM3 variants. RR performed neurological evaluation of proband in family D. KS, LB and OR provided genetic consultation and evaluation for family E. NSL provided genetic consultation and evaluation for family F. KK and BB provided genetic consultation and evaluation for family G. CEK and MW provided genetic consultation and evaluation for family H. YH performed segregation in family H. LBH performed the GeneDx database search, contacted referring physicians of families G and H and reviewed the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.