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

Stephanie E Wallace

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

Wallace SE.

Estimated reading time: 12 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 Romani 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 Romani Population

References

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11 August 2022 (sw) Initial posting

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Stephanie E Wallace, MD

Senior Editor, GeneReviews

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

Email: ude.wu@2rotide

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Initial Posting: August 11, 2022.

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Wallace SE. Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Romani Population. 2022 Aug 11. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

Table.

Genetic Disorders Associated with Founder Variants Common in the Romani Population

Gene	Disorder	MOI	DNA Nucleotide Change	Predicted Protein Change	% of Pathogenic Variants in Gene ¹	Carrier Frequency	Ethnicity (Specific Subpopulation; Specific Region)	Reference Sequences	References
ABCC2	Dubin-Johnson syndrome (OMIM 237500)	AR	c.1013_1014delTG	p.Val338GlufsTer14	~100% ²	Unknown	Romani (Slovakia)	NM_000392.5 NP_000383.2	Slachtova et al [2016]
ANO10	Cerebellar ataxia (OMIM 613728)	AR	c.1150_1151delTT	p.Leu384AsnfsTer91	~100% ²	1/33	Romani (Romania)	NM_018075.5 NP_060545.3	Chamova et al [2012]
ASPA	Canavan disease	AR	c.654C>A	p.Cys218Ter	~100% ²	Unknown	Romani	NM_000049.4 NP_000040.1	Shaag et al [1995]
ATM	Ataxia-telangiectasia	AR	c.9007_9034del28	p.Asn3003AspfsTer6	~100% ²	1/36	Romani (Spain)	NM_000051.4 NP_000042.3	Mancebo et al [2007], Carranza et al [2017]
ATP7B	Wilson disease	AR	c.3207C>A	p.His1069Gln	~100% ²	1/17	Romani (Feredjelli; Bulgaria)	NM_000053.4 NP_000044.2	Todorov et al [2005], Mihaylova et al [2007]
BCKDHA	Maple syrup urine disease	AR	c.117delC	p.Arg40GlyfsTer23	~100% ²	1/71	Romani (SE Portugal)	NM_000709.4 NP_000700.1	Quental et al [2008]
BIN1	Centronuclear myopathy, type 2 (OMIM 255200)	AR	c.700C>T	p.Arg234Cys	~100% ²	1/29	Romani (Spain)	NM_139343.3 NP_647593.1	Cabrera-Serrano et al [2018]
CD8A	CD8 deficiency (OMIM 608957)	AR	c.331G>A	p.Gly111Ser	~100% ²	1/250	Romani (Spain)	NM_001768.7 NP_001759.3	Mancebo et al [2008]
CDC73	Hyperparathyroidism-jaw tumor syndrome (See CDC73-Related Disorders.)	AD	c.766_767delGT	p.Val256LysfsTer10	<100%	NA	Romani (Portugal)	NM_024529.5 NP_078805.3	Cavaco et al [2004]
CFTR	Cystic fibrosis	AR	c.1521_1523delCTT	p.Phe508del	~100% ²	Unknown	Romani (Bulgaria)	NM_000492.4 NP_000483.3	Angelicheva et al [1997]
CHEK2	CHEK2-related tumor disposition	AD	c.596dupA	p.Tyr199Ter	<100%	NA	Romani (Portugal)	NM_007194.4 NP_009125.1	Pires et al [2021]
CHRNE	Congenital myasthenia	AR	c.1327delG	p.Glu443LysfsTer64	~100% ²	1/27	Romani	NM_000080.4 NP_000071.1	Kalaydjieva et al [2001], Hantaï et al [2004], Morar et al [2004]
CRLF1	Cold-induced sweating syndrome / Crisponi syndrome	AR	c.713dupC	p.Pro239AlafsTer91	~100% ²	Unknown	Romani (Spain)	NM_004750.5 NP_004741.1	Buers et al [2020]
CTDP1	Congenital cataracts, facial dysmorphism, and neuropathy	AR	c.863+389C>T	--	~100% ²	1/69	Romani	NM_004715.5	Varon et al [2003]
CTDP1	Congenital cataracts, facial dysmorphism, and neuropathy	AR	c.863+389C>T	--	~100% ²	1/14	Romani (Rudari)	NM_004715.5	Varon et al [2003]
CYP1B1	Primary congenital glaucoma (OMIM 231300)	AR	c.1159G>A	p.Glu387Lys	~100% ²	1/9	Romani (Slovakia)	NM_000104.4 NP_000095.2	Plásilová et al [1999], Kalaydjieva et al [2001], Azmanov et al [2011]
			c.1159G>A	p.Glu387Lys	52%	Unknown	Romani
			c.1168C>T	p.Arg390Cys	28%	Unknown	Romani
EIF2AK4	Pulmonary arterial hypertension	AR	c.3344C>T	p.Pro1115Leu	~100% ²	Unknown	Romani (Iberian Peninsula)	NM_001013703.4 NP_001013725.2	Tenorio et al [2015]
EXOSC3	Pontocerebellar hypoplasia	AR	c.92G>C	p.Gly31Ala	~100% ²	1/23	Romani (Czech Republic)	NM_016042.4 NP_057126.2	Schwabova et al [2013]
EXOSC8	Pontocerebellar hypoplasia, type 1C (OMIM 616081)	AR	c.815G>C	p.Ser272Thr	~100% ²	1/33	Romani	NM_181503.3 NP_852480.1	Boczonadi et al [2014]
FANCA	Fanconi anemia	AR	c.295C>T	p.Gln99Ter	~100% ²	1/64-1/70	Romani (Spain)	NM_000135.4 NP_000126.2	Callén et al [2005]
GALK1	Galactokinase deficiency (OMIM 230200)	AR	c.82C>A	p.Pro28Thr	~100% ²	1/16	Romani (Lom)	NM_000154.2 NP_000145.1	Kalaydjieva et al [1999], Morar et al [2004]
GALK1	Galactokinase deficiency (OMIM 230200)	AR	c.82C>A	p.Pro28Thr	~100% ²	1/29	Romani (all Vlax)	NM_000154.2 NP_000145.1	Kalaydjieva et al [1999], Morar et al [2004]
GJB2	GJB2-related autosomal recessive nonsyndromic hearing loss	AR	c.71G>A	p.Trp24Ter	79%	NA	Romani (Spain)	NM_004004.5 NP_003995.2	Alvarez et al [2005]
GJB2		AR	c.71G>A	p.Trp24Ter	93%	NA	Romani (Czech Republic)	NM_004004.5 NP_003995.2	Seeman et al [2004]
GLB1	GM1 gangliosidosis	AR	c.176G>A	p.Arg59His	~100% ²	1/10	Romani (Rudari)	NM_000404.4 NP_000395.3	Sinigerska et al [2006]
GLB1	GM1 gangliosidosis	AR	c.176G>A	p.Arg59His	~100% ²	1/52	Romani	NM_000404.4 NP_000395.3	Sinigerska et al [2006]
GNE	GNE myopathy	AR	c.1853T>C	p.Ile618Thr	99%	1/60	Romani (Bulgaria)	NM_001128227.3 NP_001121699.1	Chamova et al [2015]
GRM1	Spinocerebellar ataxia 13 (OMIM 614831)	AR	c.2652_2660+2delGAATGCCAAGTinsTGCCAAGG	--	~100% ²	1/40	Romani (Bowlmakers; Bulgaria)	NM_001278064.2	Guergueltcheva et al [2012]
HK1	Hereditary motor and sensory neuropathy, Russe type (OMIM 605285)	AR	c.-40237G>C	--	~100% ²	1/158	Romani (Bulgaria)	NG_012077.1	Hantke et al [2009]
HK1		AR	c.-40237G>C	--	~100% ²	Unknown	Romani (Spain)	NG_012077.1	Sevilla et al [2013]
ITGA2B	Glanzmann thrombasthenia (OMIM 273800)	AR	c.1544+1G>A	--	~100% ²	Unknown	Romani (Manouche; France)	NM_000419.5	Fiore et al [2011]
LAMB3	Junctional epidermolysis bullosa	AR	c.1133-22G>A	--	~100% ²	1/2	Romani (Romungro; Hungary)	NM_000228.3	Mayer et al [2016]
LTBP2	Primary congenital glaucoma (OMIM 613086)	AR	c.895C>T	p.Arg299Ter	~100% ²	1/42	Romani (Bulgaria)	NM_000428.3 NP_000419.1	Azmanov et al [2011]
MARVELD2	Deafness, AR type 49 (OMIM 610153)	AR	c.1331+2T>C	--	~100% ²	1/26	Romani (Slovakia)	NM_001038603.3	Mašindová et al [2015]
MARVELD2	Deafness, AR type 49 (OMIM 610153)	AR	c.1331+2T>C	--	~100% ²	1/10	Romani (Hungary)	NM_001038603.3	Mašindová et al [2015]
MFSD8	Neuronal ceroid lipofuscinosis, type 7	AR	c.881C>A	p.Thr294Lys	~100% ²	Unknown	Romani (Czech Republic)	NM_152778.3 NP_689991.1	Kousi et al [2009]
NDRG1	Hereditary motor and sensory neuropathy, type 4D (OMIM 601455)	AR	c.442C>T	p.Arg148Ter	~100% ²	1/6	Romani (Lom)	NM_006096.4 NP_006087.2	Kalaydjieva et al [2001], Morar et al [2004], Guergueltcheva et al [2006]
NDRG1		AR	c.442C>T	p.Arg148Ter	~100% ²	1/22	Romani	NM_006096.4 NP_006087.2
PAH	Phenylalanine hydroxylase deficiency	AR	c.1066-11G>A	--	87.5%	Unknown	Romani (Spain)	NM_000277.3	Desviat et al [1997]
PAH	Phenylalanine hydroxylase deficiency	AR	c.754C>T	p.Arg252Trp	~100% ²	Unknown	Romani (Slovakia)	NM_000277.3 NP_000268.1	Kalanin et al [1994]
PDHX	Pyruvate dehydrogenase E3-binding protein deficiency (OMIM 245349)	AR	c.1336C>T	p.Arg446Ter	~100% ²	1/150	Romani	NM_003477.3 NP_003468.2	Ivanov et al [2014]
PKD2	Polycystic kidney disease	AD	c.916C>T	p.Arg306Ter	<100%	NA	Romani (Bulgaria)	NM_000297.4 NP_000288.1	Kalaydjieva et al [2001]
RNF220	Hypomyelinating leukodystrophy, type 23 (OMIM 619688)	AR	c.1094G>A	p.Arg365Gln	~100% ²	Unknown	Romani	NM_018150.4 NP_060620.2	Sferra et al [2021]
SERPINC1	Antithrombin III deficiency (OMIM 613118)	AD AR	c.391C>T	p.Leu131Phe	<100%	1/36	Romani (NE Hungary)	NM_000488.4 NP_000479.1	Bereczky et al [2021]
SGCG	Limb-girdle muscular dystrophy, type 2C (OMIM 253700)	AR	c.848G>A	p.Cys283Tyr	~100% ²	1/18	Romani (Darakchii)	NM_000231.3 NP_000222.2	Piccolo et al [1996], Kalaydjieva et al [2001], Morar et al [2004]
SGCG	Limb-girdle muscular dystrophy, type 2C (OMIM 253700)	AR	c.848G>A	p.Cys283Tyr	~100% ²	1/16	Romani (Turgovzi)	NM_000231.3 NP_000222.2
SH3TC2	SH3TC2-related hereditary motor and sensory neuropathy	AR	c.3325C>T	p.Arg1109Ter	85%	1/25	Romani (Spain)	NM_024577.4 NP_078853.2	Claramunt et al [2007], Sevilla et al [2013]
SH3TC2	SH3TC2-related hereditary motor and sensory neuropathy	AR	c.2211_2213delCCC	p.Cys737Ter	12%	1/25	Romani (Spain)	NM_024577.4 NP_078853.2	Claramunt et al [2007], Sevilla et al [2013]
SHOX	SHOX deficiency disorders	AD AR	c.508G>C	p.Ala170Pro	<100%	Unknown	Romani (Spain)	NM_000451.3 NP_000442.1	Barca-Tierno et al [2011]
SLC12A3	Gitelman syndrome (OMIM 263800)	AR	c.1180+1G>T	--	~75%	Unknown	Romani (Europe)	NM_000339.3	Coto et al [2004]
SLC12A3	Gitelman syndrome (OMIM 263800)	AR	c.1939G>A	p.Val647Met	~25%	Unknown	Romani (Europe)	NM_000339.3 NP_000330.3	Gil-Peña et al [2017]
SLC22A12	Renal hypouricemia (OMIM 220150)	AR	c.1245_1253delGGCAGGGCT	p.Ala416_Leu418del	~25%	1/52	Romani (Czech Republic, Slovakia, & Spain)	NM_144585.4 NP_653186.2	Gabrikova et al [2015], Stiburkova et al [2016]
SLC22A12	Renal hypouricemia (OMIM 220150)	AR	c.1400C>T	p.Thr467Met	~75%	1/18	Romani (Czech Republic, Slovakia, & Spain)	NM_144585.4 NP_653186.2	Gabrikova et al [2015], Stiburkova et al [2016]
TMEM70	Mitochondrial complex V deficiency nuclear type 2 (OMIM 614052)	AR	c.317-2A>G	--	~100% ²	Unknown	Romani	NM_017866.6	Cízková et al [2008]
UFM1	Hypomyelinating leukodystrophy, type 14 (OMIM 617899)	AR	c.-273_-271delTCA	--	~100% ²	1/22	Romani (Europe)	NM_001286704.2	Hamilton et al [2017]
VWF	von Willebrand disease type 3	AR	c.3931C>T	p.Gln1311Ter	<100%	Unknown	Romani (Spain)	NM_000552.5 NP_000543.3	Casaña et al [2000]

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

: AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable; NE = northeast; SE = southeast

1.: This percentage does not account for the possibility of rare de novo pathogenic variants occurring in this population.

2.: To date, additional pathogenic variants in this gene have not been reported in individuals of the Romani subpopulation and/or Romani from the specified region where indicated.