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Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Newfoundland and Labrador Populations

, MD and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Revision: August 17, 2023.

Estimated reading time: 4 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 Newfoundlander and/or Labradorian 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 Newfoundland and/or Labrador Population

GeneDisorderMOIDNA Nucleotide Change
(Alias 1)		Predicted Protein ChangeProportion of Pathogenic Variants in Gene 2Carrier FrequencyEthnicity
(Specific Region)		Reference
Sequences		References
APC Familial adenomatous polyposis, attenuated ADc.221-1G>A
(IVS2-1G>A)		--~80%NANewfoundland NM_00038​.6 Spirio et al [1999], Woods et al [2010]
BBS1 Bardet-Biedl syndrome ARc.1169T>Gp.Met390Arg~100% 31/67Newfoundland
(southwest)		 NM_024649​.5
NP_078925​.3 		Fan et al [2004]
CDH1 Hereditary diffuse gastric cancer ADc.2398delCp.Arg800AlafsTer16Most familiesNANewfoundland NM_004360​.5
NP_004351​.1 		Kaurah et al [2007]
CLDN14 Deafness, AR 29 (OMIM 614035)ARc.488C>Tp.Ala163Val~100% 31/44Newfoundland NM_144492​.3
NP_652763​.1 		Pater et al [2017]
CLN6 Neuronal ceroid lipofuscinosis 6 (OMIM 601780)ARc.268_271dupAACGp.Val91GlufsTer42~100% 3UnknownNewfoundland
(southern coast)		 NM_017882​.3
NP_060352​.1 		Moore et al [2008]
F13A1 Factor XIIIA deficiency (OMIM 613225)ARc.691-1G>A
(IVS5-1G>A)		--86%UnknownNewfoundland & Labrador NM_000129​.4 Scully et al [2018]
F8 Hemophilia A XLc.6104T>Cp.Val2035Ala74%UnknownNewfoundland & Labrador (Twillingate) NM_000132​.4
NP_000123​.1 		Scully et al [2018]
MEN1 Multiple endocrine neoplasia type 1 ADc.1378C>Tp.Arg460Ter~100%NANewfoundland
(Burin Peninsula)		 NM_130799​.2
NP_570711​.1 		Olufemi et al [1998]
MSH2 Lynch syndrome ADDeletion of exon 8--<30%NANewfoundland NG_007110​.2 Stuckless et al [2007], Woods et al [2010]
c.942+3A>T
(IVS5+3A>T)		--~30%-60%Newfoundland
(northeast coast)		 NM_000251​.3
RLBP1 Newfoundland rod cone dystrophy (OMIM 607476)ARc.141+2T>C
(IVS3+2T>C)		--~20%UnknownNewfoundland NM_000326​.5 Eichers et al [2002]
c.141G>A 4
(IVS3-1G>A)		--~80%1/106
STAR Lipoid congenital adrenal hyperplasia (OMIM 201710)ARc.562C>Tp.Arg188Cys~100% 3UnknownNewfoundland & Labrador NM_000349​.3
NP_000340​.2 		Tsai et al [2016]
TMEM43 Arrhythmogenic right ventricular cardiomyopathy ADc.1073C>Tp.Ser358Leu~100% 3NANewfoundland NM_024334​.3
NP_077310​.1 		Merner et al [2008], Milting et al [2015]
TPP1 Neuronal ceroid lipofuscinosis 2 (OMIM 204500)ARc.509-1G>C
(IVS5-1G>C)		--33%UnknownNewfoundland
(southern coast)		 NM_000391​.4 Moore et al [2008]
c.851G>Tp.Gly284Val42%Newfoundland
(east coast)		 NM_000391​.4
NP_000382​.3
c.1424delCp.Ser475TrpfsTer1311%Newfoundland
(northern coast)
VAMP1 Spastic ataxia 1 (See Hereditary Ataxia Overview.)ADc.340+2T>G
(IVS4+2T>G)		--~100% 3NANewfoundland NM_014231​.5 Bourassa et al [2012]

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

1.

Does not conform to standard HGVS nomenclature

2.

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

3.

To date, additional pathogenic variants in this gene have not been reported in individuals of Newfoundlander and/or Labradorian descent.

4.

DNA nucleotide change introduces new splice site and does not result in predicted protein change.

References

  • Bourassa CV, Meijer IA, Merner ND, Grewal KK, Stefanelli MG, Hodgkinson K, Ives EJ, Pryse-Phillips W, Jog M, Boycott K, Grimes DA, Goobie S, Leckey R, Dion PA, Rouleau GA. VAMP1 mutation causes dominant hereditary spastic ataxia in Newfoundland families. Am J Hum Genet. 2012;91:548–52. [PMC free article: PMC3511983] [PubMed: 22958904]
  • Eichers ER, Green JS, Stockton DW, Jackman CS, Whelan J, McNamara JA, Johnson GJ, Lupski JR, Katsanis N. Newfoundland rod-cone dystrophy, an early-onset retinal dystrophy, is caused by splice-junction mutations in RLBP1. Am J Hum Genet. 2002;70:955-64. [PMC free article: PMC379124] [PubMed: 11868161]
  • Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL, May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL, Beales PL, Katsanis N, Davidson WS, Leroux MR. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet. 2004;36:989-93. [PubMed: 15314642]
  • Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, Suriano G, Zaor S, Van Manen L, Gilpin C, Nikkel S, Connolly-Wilson M, Weissman S, Rubinstein WS, Sebold C, Greenstein R, Stroop J, Yim D, Panzini B, McKinnon W, Greenblatt M, Wirtzfeld D, Fontaine D, Coit D, Yoon S, Chung D, Lauwers G, Pizzuti A, Vaccaro C, Redal MA, Oliveira C, Tischkowitz M, Olschwang S, Gallinger S, Lynch H, Green J, Ford J, Pharoah P, Fernandez B, Huntsman D. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297:2360-72. [PubMed: 17545690]
  • Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD, Kupprion C, Ramadanova K, Thierfelder L, McKenna W, Gallagher B, Morris-Larkin L, Bassett AS, Parfrey PS, Young TL. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:809-21. [PMC free article: PMC2427209] [PubMed: 18313022]
  • Milting H, Klauke B, Christensen AH, Müsebeck J, Walhorn V, Grannemann S, Münnich T, Šarić T, Rasmussen TB, Jensen HK, Mogensen J, Baecker C, Romaker E, Laser KT, zu Knyphausen E, Kassner A, Gummert J, Judge DP, Connors S, Hodgkinson K, Young TL, van der Zwaag PA, van Tintelen JP, Anselmetti D. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. Eur Heart J. 2015;36:872-81. [PubMed: 24598986]
  • Moore SJ, Buckley DJ, MacMillan A, Marshall HD, Steele L, Ray PN, Nawaz Z, Baskin B, Frecker M, Carr SM, Ives E, Parfrey PS. The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland. Clin Genet. 2008;74:213-22. [PubMed: 18684116]
  • Olufemi SE, Green JS, Manickam P, Guru SC, Agarwal SK, Kester MB, Dong Q, Burns AL, Spiegel AM, Marx SJ, Collins FS, Chandrasekharappa SC. Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland. Hum Mutat. 1998;11:264-9. [PubMed: 9554741]
  • Pater JA, Benteau T, Griffin A, Penney C, Stanton SG, Predham S, Kielley B, Squires J, Zhou J, Li Q, Abdelfatah N, O'Rielly DD, Young TL. A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect. Hum Genet. 2017;136:107-18. [PMC free article: PMC5215284] [PubMed: 27838790]
  • Scully MF, Stoffman J, Boyd S. The unusual pattern of hereditary bleeding disorders in the province of Newfoundland and Labrador-Canada's most Eastern Province. Transfus Apher Sci. 2018;57:713-6. [PubMed: 30455155]
  • Spirio L, Green J, Robertson J, Robertson M, Otterud B, Sheldon J, Howse E, Green R, Groden J, White R, Leppert M. The identical 5' splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect. Hum Genet. 1999;105:388-98. [PubMed: 10598803]
  • Stuckless S, Parfrey PS, Woods MO, Cox J, Fitzgerald GW, Green JS, Green RC. The phenotypic expression of three MSH2 mutations in large Newfoundland families with Lynch syndrome. Fam Cancer. 2007;6:1-12. [PubMed: 17039271]
  • Tsai SL, Green J, Metherell LA, Curtis F, Fernandez B, Healey A, Curtis J. Primary Adrenocortical Insufficiency Case Series: Genetic Etiologies More Common than Expected. Horm Res Paediatr. 2016;85:35-42. [PubMed: 26650942]
  • Woods MO, Younghusband HB, Parfrey PS, Gallinger S, McLaughlin J, Dicks E, Stuckless S, Pollett A, Bapat B, Mrkonjic M, de la Chapelle A, Clendenning M, Thibodeau SN, Simms M, Dohey A, Williams P, Robb D, Searle C, Green JS, Green RC. The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut. 2010;59:1369-77. [PMC free article: PMC3047452] [PubMed: 20682701]

Revision History

  • 17 August 2023 (sw) Revision: added BBS1 and updated reference sequences
  • 30 April 2020 (sw) Initial posting
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