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

Stephanie E Wallace

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

Wallace SE.

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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 Bukharan Jewish ancestry. Note: Pathogenic variants that are common worldwide due to a DNA sequence hot spot are not considered founder variants and thus are not included.

Table.

Genetic Disorders Associated with Founder Variants Common in the Bukharan Jewish Population

References

Auslender N, Bandah D, Rizel L, Behar DM, Shohat M, Banin E, Allon-Shalev S, Sharony R, Sharon D, Ben-Yosef T. Four USH2A founder mutations underlie the majority of Usher syndrome type 2 cases among non-Ashkenazi Jews. Genet Test. 2008;12:289–94. [PubMed: 18452394]
Ben-Shachar S, Zvi T, Rolfs A, Breda Klobus A, Yaron Y, Bar-Shira A, Orr-Urtreger A. A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews. Mol Genet Metab. 2012;107:608–10. [PubMed: 22947400]
Bercovich D, Elimelech A, Yardeni T, Korem S, Zlotogora J, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y. A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population. Ann Hum Genet. 2008;72:305–9. [PubMed: 18294361]
Oz-Levi D, Ben-Zeev B, Ruzzo EK, Hitomi Y, Gelman A, Pelak K, Anikster Y, Reznik-Wolf H, Bar-Joseph I, Olender T, Alkelai A, Weiss M, Ben-Asher E, Ge D, Shianna KV, Elazar Z, Goldstein DB, Pras E, Lancet D. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am J Hum Genet. 2012;91:1065–72. [PMC free article: PMC3516605] [PubMed: 23176824]
Reinstein E, Smirin-Yosef P, Lagovsky I, Davidov B, Peretz Amit G, Neumann D, Orr-Urtreger A, Ben-Shachar S, Basel-Vanagaite L. A founder mutation in ADAMTSL4 causes early-onset bilateral ectopia lentis among Jews of Bukharian origin. Mol Genet Metab. 2016;117:38–41. [PubMed: 26653794]
Zlotogora J. Mendelian Disorders Among Jews [Internet]. Israel: Department of Community Genetics Public Health Services Ministry of Health - Israel; 2015 [cited 2022 June 20]. Available from: www.health.gov.il (pdf)

Revision History

29 September 2022 (sw) Initial posting

Publication Details

Author Information and Affiliations

Stephanie E Wallace, MD

Senior Editor, GeneReviews

Clinical Professor, Department of Pediatrics
University of Washington
Seattle, Washington

Email: ude.wu@2rotide

Publication History

Initial Posting: September 29, 2022.

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NLM Citation

Wallace SE. Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Bukharan Jewish Population. 2022 Sep 29. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

Table.

Genetic Disorders Associated with Founder Variants Common in the Bukharan Jewish Population

Gene	Disorder	MOI	DNA Nucleotide Change (Alias ¹)	Predicted Protein Change (Alias ¹)	% of Pathogenic Variants in Gene ²	Carrier Frequency	Ethnicity (Specific Region)	Reference Sequences	References
ADAMTSL4	ADAMTSL4-related eye disorders	AR	c.2594G>A (2663G>A)	p.Arg865His (Arg888His)	~100% ³	1/48	Bukharan Jewish ⁴	NM_019032.6 NP_061905.2	Reinstein et al [2016]
MTHFR	Methyltetrahydrofolate reductase deficiency (OMIM 236250)	AR	c.474A>T	See footnote 5.	<100% ⁶	1/39	Bukharan Jewish (Uzbekistan)	NM_005957.5	Ben-Shachar et al [2012]
PAH	Phenylalanine hydroxylase deficiency	AR	c.533A>G	p.Glu178Gly	79%	Unknown	Bukharan Jewish	NM_000277.3 NP_000268.1	Bercovich et al [2008]
PAH	Phenylalanine hydroxylase deficiency	AR	c.842C>T	p.Pro281Leu	79%	Unknown	Bukharan Jewish	NM_000277.3 NP_000268.1	Bercovich et al [2008]
TECPR2	Hereditary spastic paraparesis	AR	c.3416delT	p.Leu1139ArgfsTer75	~100% ³	1/27	Bukharan Jewish	NM_014844.5 NP_055659.2	Oz-Levi et al [2012]
USH2A	Usher syndrome type II	AR	c.12067-2A>G	--	<100% ⁶	Unknown	Bukharan Jewish	NM_206933.4	Auslender et al [2008], Zlotogora [2015]

: Included if ≤3 pathogenic variants account for ≥50% of variants identified in a specific ethnic group

: AR = autosomal recessive; MOI = mode of inheritance

1.: Variant designation that does not conform to current naming conventions

2.: Percentage does not account for the possibility of rare de novo pathogenic variants occurring in this population.

3.: To date, no additional pathogenic variants in this gene have been reported in individuals of this ethnicity (and/or from the specified region when indicated).

4.: Individuals of Bukharan Jewish ancestry originating from Kazakhstan and Tajikistan

5.: This substitution affects the nucleotide two base pairs upstream of the donor splice site of intron 3 and is known to cause abnormal splicing.

6.: At least one additional pathogenic variant reported in this population in ≥1 family