Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Druze Population

Wallace SE, Bean LJH.

Publication Details

Estimated reading time: 9 minutes

A founder variant is a pathogenic variant observed at high frequency in a specific population due to the presence of the variant in a single ancestor or small number of ancestors. The presence of a founder variant can affect the approach to molecular genetic testing. When one or more founder variants account for a large percentage of all pathogenic variants found in a population, testing for the founder variant(s) may be performed first.

The table below includes common founder variants – here defined as three or fewer variants that account for >50% of the pathogenic variants identified in a single gene in individuals of a specific ancestry – in individuals of Druze ancestry. Note: (1) Pathogenic variants that are common worldwide due to a DNA sequence hot spot are not considered founder variants and thus are not included. (2) Disorders with a carrier frequency ≤1/200 are not included.

Table Icon

Table.

Genetic Disorders Associated with Founder Variants Common in the Druze Population

References

  • Avnat E, Shapira G, Shoval S, Israel-Elgali I, Alkelai A, Shuldiner AR, Gonzaga-Jauregui C, Zidan J, Maray T, Shomron N, Friedman E. Comprehensive genetic analysis of Druze provides insights into carrier screening. Genes (Basel). 2023;14:937. [PMC free article: PMC10137689] [PubMed: 37107695]

  • Bach G, Moskowitz SM, Tieu PT, Matynia A, Neufeld EF. Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. Am J Hum Genet. 1993;53:330-8. [PMC free article: PMC1682364] [PubMed: 8328452]

  • Bargal R, Avidan N, Olender T, Ben Asher E, Zeigler M, Raas-Rothschild A, Frumkin A, Ben-Yoseph O, Friedlender Y, Lancet D, Bach G. Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum Mutat. 2001;17:397-402. [PubMed: 11317355]

  • Chuang JL, Wynn RM, Moss CC, Song JL, Li J, Awad N, Mandel H, Chuang DT. Structural and biochemical basis for novel mutations in homozygous Israeli maple syrup urine disease patients: a proposed mechanism for the thiamin-responsive phenotype. J Biol Chem. 2004;279:17792-800. [PubMed: 14742428]

  • DeBarber AE, Kalfon L, Fedida A, Fleisher Sheffer V, Ben Haroush S, Chasnyk N, Shuster Biton E, Mandel H, Jeffries K, Shinwell ES, Falik-Zaccai TC. Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment. J Lipid Res. 2018;59:2214-22. [PMC free article: PMC6210902] [PubMed: 30135217]

  • Estrada-Cuzcano A., Neveling K., Kohl S, Banin E, Rotenstreich Y, Sharon D, Falik-Zaccai TC, Hipp S, Roepman R, Wissinger B, Letteboer SJF, Mans DA, and 12 others. Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement. Am J Hum Genet. 2012;90:102-9. [PMC free article: PMC3257957] [PubMed: 22177090]

  • Falik-Zaccai TC, Kalfon L, Klar A, Elisha M, Ben Hurvitz H, Weingarten G, Chechik E, Fleisher Sheffer V, Haj Yahya R, Meidan G, Gross-Kieselstein E, Bauman D, Hershkovitz S, Yaron Y, Orr-Urtreger A, Wertheimer E. Two novel mutations identified in familial cases with Donohue syndrome. Mol Genet Genomic Med. 2014;2:64–72. [PMC free article: PMC3907912] [PubMed: 24498630]

  • Falik-Zaccai TC, Kfir N, Frenkel P, Cohen C, Tanus M, Mandel H, Shihab S, Morkos S, Aaref S, Summar ML, Khayat M. Population screening in a Druze community: the challenge and the reward. Genet Med. 2008a;10:903-9. [PubMed: 19092443]

  • Falik-Zaccai TC, Khayat M, Luder A, Frenkel P, Magen D, Brik R, Gershoni-Baruch R, Mandel H. A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:46-56. [PubMed: 19308961]

  • Falik-Zaccai TC, Laskar M, Kfir N, Nasser W, Slor H, Khayat M. Cockayne syndrome type II in a Druze isolate in Northern Israel in association with an insertion mutation in ERCC6. Am J Med Genet A. 2008b;146A:1423-9. [PubMed: 18446857]

  • Fares F, Axelord Ran S, David M, Zelnik N, Hecht Y, Khairaldeen H, Lerner A. Identification of two mutations for ataxia telangiectasia among the Druze community. Prenat Diagn. 2004;24:358-62. [PubMed: 15164409]

  • Friederich MW, Timal S, Powell CA, Dallabona C, Kurolap A, Palacios-Zambrano S, Bratkovic D, Derks TGJ, Bick D, Bouman K, Chatfield KC, Damouny-Naoum N, Dishop MK, Falik-Zaccai TC, Fares F, Fedida A, Ferrero I, Gallagher RC, Garesse R, Gilberti M, González C, Gowan K, Habib C, Halligan RK, Kalfon L, Knight K, Lefeber D, Mamblona L, Mandel H, Mory A, Ottoson J, Paperna T, Pruijn GJM, Rebelo-Guiomar PF, Saada A, Sainz B Jr, Salvemini H, Schoots MH, Smeitink JA, Szukszto MJ, Ter Horst HJ, van den Brandt F, van Spronsen FJ, Veltman JA, Wartchow E, Wintjes LT, Zohar Y, Fernández-Moreno MA, Baris HN, Donnini C, Minczuk M, Rodenburg RJ, Van Hove JLK. Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder. Nat Commun. 2018;9:4065. [PMC free article: PMC6170436] [PubMed: 30283131]

  • Fromovich-Amit Y, Zivelin A, Rosenberg N, Tamary H, Landau M, Seligsohn U. Characterization of mutations causing factor VII deficiency in 61 unrelated Israeli patients. J Thromb Haemost. 2004;2:1774-81. [PubMed: 15456489]

  • Geyer O, Wolf A, Levinger E, Harari-Shacham A, Walton DS, Shochat C, Korem S, Bercovich D. Genotype/phenotype correlation in primary congenital glaucoma patients from different ethnic groups of the Israeli population. Am J Ophthalmol. 2011;151:263-71.e1. [PubMed: 21168818]

  • Issler N, Afonso S, Weissman I, Jordan K, Cebrian-Serrano A, Meindl K, Dahlke E, Tziridis K, Yan G, Robles-López JM, Tabernero L, Patel V, Kesselheim A, Klootwijk ED, Stanescu HC, Dumitriu S, Iancu D, Tekman M, Mozere M, Jaureguiberry G, Outtandy P, Russell C, Forst AL, Sterner C, Heinl ES, Othmen H, Tegtmeier I, Reichold M, Schiessl IM, Limm K, Oefner P, Witzgall R, Fu L, Theilig F, Schilling A, Shuster Biton E, Kalfon L, Fedida A, Arnon-Sheleg E, Ben Izhak O, Magen D, Anikster Y, Schulze H, Ziegler C, Lowe M, Davies B, Böckenhauer D, Kleta R, Falik Zaccai TC, Warth R. A founder mutation in EHD1 presents with tubular proteinuria and deafness. J Am Soc Nephrol. 2022;33:732-45. [PMC free article: PMC8970462] [PubMed: 35149593]

  • Kalfon L, Baydany M, Samra N, Heno N, Segal Z, Eran A, Yulevich A, Fellig Y, Mandel H, Falik-Zaccai TC. Congenital hypotonia: cracking a saga of consanguineous kindred harboring four genetic variants. Mol Genet Genomic Med. 2022;10:e1849. [PMC free article: PMC8801141] [PubMed: 34970863]

  • Kalinsky H, Funes A, Zeldin A, Pel-Or Y, Korostishevsky M, Gershoni-Baruch R, Farrer LA, Bonne-Tamir B. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Hum Mutat. 1998;11:145-51. [PubMed: 9482578]

  • Landsberger D, Meiner V, Reshef A, Levy Y, van der Westhuyzen DR, Coetzee GA, Leitersdorf E. A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect. Am J Hum Genet. 1992;50:427-433. [PMC free article: PMC1682466] [PubMed: 1734722]

  • Lefeber DJ, de Brouwer AP, Morava E, Riemersma M, Schuurs-Hoeijmakers JH, Absmanner B, Verrijp K, van den Akker WM, Huijben K, Steenbergen G, van Reeuwijk J, Jozwiak A, Zucker N, Lorber A, Lammens M, Knopf C, van Bokhoven H, Grünewald S, Lehle L, Kapusta L, Mandel H, Wevers RA. Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation. PLoS Genet. 2011;7:e1002427. [PMC free article: PMC3248466] [PubMed: 22242004]

  • Leitersdorf E, Safadi R, Meiner V, Reshef A, Bjorkhem I, Friedlander Y, Morkos S, Berginer VM. Cerebrotendinous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics. Am J Hum Genet. 1994;55:907–15. [PMC free article: PMC1918342] [PubMed: 7977352]

  • Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet. 2001;29:337-41. [PubMed: 11687800]

  • Mizuguchi T, Nakashima M, Kato M, Yamada K, Okanishi T, Ekhilevitch N, Mandel H, Eran A, Toyono M, Sawaishi Y, Motoi H, Shiina M, Ogata K, Miyatake S, Miyake N, Saitsu H, Matsumoto N. PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder. J Hum Genet. 2017;62:525-9. [PubMed: 28077841]

  • Mory A, Dagan E, Illi B, Duquesnoy P, Mordechai S, Shahor I, Romani S, Hawash-Moustafa N, Mandel H, Valente EM, Amselem S, Gershoni-Baruch R. A nonsense mutation in the human homolog of Drosophila rogdi causes Kohlschutter-Tonz syndrome. Am J Hum Genet. 2012;90:708-14. [PMC free article: PMC3322231] [PubMed: 22482807]

  • Raas-Rothschild A, Cormier-Daire V, Bao M, Genin E, Salomon R, Brewer K, Zeigler M, Mandel H, Toth S, Roe B, Munnich A, Canfield WM. Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC). J Clin Invest. 2000;105:673-81. [PMC free article: PMC289169] [PubMed: 10712439]

  • Rafi MA, Luzi P, Zlotogora J, Wenger DA. Two different mutations are responsible for Krabbe disease in the Druze and Moslem Arab populations in Israel. Hum Genet. 1996;97:304-8. [PubMed: 8786069]

  • Reznick Levi G, Goldberg Y, Segev H, Maza I, Gorelik Y, Laish I, Levi Z, Kedar I, Naftali Nathan S, Sharon Swartzman N, Abu Freha N, Paritsky M, Rennert G, Baris Feldman H, Paperna T, Weiss K, Half EE. High prevalence of MUTYH associated polyposis among minority populations in Israel, due to rare founder pathogenic variants. Dig Liver Dis. 2023;55:880-7. [PubMed: 36740502]

  • Sharkia R, Mahajnah M, Zalan A, Athamna M, Azem A, Badarneh K, Faris F. Comparative screening of FMF mutations in various communities of the Israeli society. Eur J Med Genet. 2013;56:351-5. [PubMed: 23602951]

  • Sharon D, Ben-Yosef T, Goldenberg-Cohen N, Pras E, Gradstein L, Soudry S, Mezer E, Zur D, Abbasi AH, Zeitz C, Cremers FPM, Khan MI, Levy J, Rotenstreich Y, Birk OS, Ehrenberg M, Leibu R, Newman H, Shomron N, Banin E, Perlman I. A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC). Hum Mutat. 2020;41:140-9. [PubMed: 31456290]

  • Sprecher E, Bergman R, Richard G, Lurie R, Shalev S, Petronius D, Shalata A, Anbinder Y, Leibu R, Perlman I, Cohen N, Szargel R. Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin. Nature Genet. 2001;29:134-6. [PubMed: 11544476]

  • Steinberg-Shemer O, Goldberg TA, Yacobovich J, Levin C, Koren A, Revel-Vilk S, Ben-Ami T, Kuperman AA, Zemer VS, Toren A, Kapelushnik J, Ben-Barak A, Miskin H, Krasnov T, Noy-Lotan S, Dgany O, Tamary H. Characterization and genotype-phenotype correlation of patients with Fanconi anemia in a multi-ethnic population. Haematologica. 2020;105:1825-34. [PMC free article: PMC7327661] [PubMed: 31558676]

  • Tappino B, Biancheri R, Mort M, Regis S, Corsolini F, Rossi A, Stroppiano M, Lualdi S, Fiumara A, Bembi B, Di Rocco M, Cooper DN, Filocamo M. Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease. Hum Mutat. 2010;31:E1894-914. [PMC free article: PMC3052420] [PubMed: 20886637]

  • Weiss K, Ekhilevitch N, Cohen L, Bratman-Morag S, Bello R, Martinez AF, Hadid Y, Shlush LI, Kurolap A, Paperna T, Mory A, Baris HN, Muenke M. Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population. Eur J Med Genet. 2020; 63:103643. [PubMed: 30922925]

  • Wynn RM, Chuang JL, Sansaricq C, Mandel H, Chuang DT. Biochemical basis of type IB (E1beta) mutations in maple syrup urine disease. A prevalent allele in patients from the Druze kindred in Israel. J Biol Chem. 2001;276:36550-6. [PubMed: 11448970]

Revision History

  • 28 September 2023 (sw) Revision: added ABCA4, EHD1, FANCA, HOGA1, MUTYH, NGLY1, and RDH5; updated reference sequences
  • 16 December 2021 (ha) Revision: added Falik-Zaccai et al [2008a]
  • 7 November 2019 (sw) Initial posting