Intellectual disability syndrome associated with a homozygous founder variant in SGSM3 in Ashkenazi Jews

Rivka Birnbaum, Shlomit Ezer, Nava Shaul Lotan, Avital Eilat, Keren Sternlicht, Lilach Benyamini, Orit Reish, Tzipora Falik-Zaccai, Gali Ben-Gad, Raya Rod, Reeval Segel, Katherine Kim, Barabra Burton, Catherine E. Keegan, Mallory Wagner, Lindsay B. Henderson, Nofar Mor, Ortal Barel, Yoel Hirsch, Vardiella MeinerOrly Elpeleg, Tamar Harel, Hagar Mor-Shakad

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)289-293
Number of pages5
JournalJournal of Medical Genetics
Issue number3
Early online date13 Oct 2023
StatePublished - 21 Feb 2024
Externally publishedYes

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