The genetic landscape of Lynch syndrome in the Israeli population

Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49%). Most DCVs (125/157, 80%) were noted in one or two families only. Sixteen DCVs, each detected in ≥ 5 families, and accounted for LS in 378/588 (64%) families. Constitutional mismatch repair deficiency (CMMRD) was diagnosed in 7 families. Twenty-five carriers (2.3%) had an additional DCV or risk alleles in another cancer susceptibility gene. In conclusion, MMR gene variant distribution in Israel is diverse. MSH2 is most commonly mutated due to founder DCVs. Though the 16 prevalent LS-associated DCVs were frequently detected in our cohort, none of them is frequently reported in the general population. These data should facilitate variant interpretation, spouse and cascade testing.

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Publication Details

Journal
Familial Cancer
Published
2024-11-15
DOI
https://doi.org/10.1007/s10689-024-00432-w
Citations
2
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
0.85

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article

The genetic landscape of Lynch syndrome in the Israeli population

Lior H. Katz, Chana Vinkler, Samar Mattar, Lilach Peled Peretz et al.
2 citations
Familial Cancer
Genetic factors in colorectal cancer
0.85
article

The genetic landscape of Lynch syndrome in the Israeli population

Lior H. Katz, Chana Vinkler, Samar Mattar, Lilach Peled Peretz, Menachem Schechter, Shikma Mordechai, Gabriel Lidzbarsky, Liza Douiev, Marina Kalis, Eitan Friedman, Sari Lieberman, Inbal Kedar, Aasem Abu Shtaya, Ofir Hagari-Bechar, Michal Barzily-Rokni, Elizabeth Half, Zohar Levi, Sarit Farage Barhom, Yael Goldberg, Ori Segol, Naim Abu‐Freha, Revital Bruchim, Lily Bazak, Lina Basel Salmon, Ido Laish, Gili Reznick Levi, Rinat Bernstein‐Molho, Nadra Nasser Samra, Tamar Peretz‐Yablonski, Sofia Naftaly Nathan, Stavit Shalev, Shiri Shkedi Rafid
article en
2 citations

Abstract

Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49%). Most DCVs (125/157, 80%) were noted in one or two families only. Sixteen DCVs, each detected in ≥ 5 families, and accounted for LS in 378/588 (64%) families. Constitutional mismatch repair deficiency (CMMRD) was diagnosed in 7 families. Twenty-five carriers (2.3%) had an additional DCV or risk alleles in another cancer susceptibility gene. In conclusion, MMR gene variant distribution in Israel is diverse. MSH2 is most commonly mutated due to founder DCVs. Though the 16 prevalent LS-associated DCVs were frequently detected in our cohort, none of them is frequently reported in the general population. These data should facilitate variant interpretation, spouse and cascade testing.

Familial CancerVol. 24(1)
Ben-Gurion University of the Negev (IL), Tel Aviv University (IL), Technion – Israel Institute of Technology (IL), Hebrew University of Jerusalem (IL), Emek Medical Center (IL), Sheba Medical Center (IL), Hadassah Medical Center (IL), Rabin Medical Center (IL), Assuta Medical Center (IL), Wolfson Medical Center (IL), Rambam Health Care Campus (IL), Shaare Zedek Medical Center (IL), Rebecca Sieff Hospital (IL), Maccabi Healthcare Services (IL), The Technological College of Beer Sheva (IL), Carmel Medical Center (IL)
Tel Aviv University
Good health and well-being
Openalex Percentile: Top 24%
Genetic factors in colorectal cancer
0.85
DOIOpen Access PDFOpenAlex
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