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

, MD and , PhD.

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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 Inuit 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 Inuit Population

DisorderMOIGeneDNA
Nucleotide
Change
Predicted
Protein
Change
Proportion of
Pathogenic
Variants in
This Gene
Carrier
Frequency
Ethnicity
(Specific
Region)
Reference
Sequences
References
ATP8B1 deficiencyARATP8B1c.1660G>Ap.Asp554Asn~100% 11/4 to 1/20InuitNM_005603​.5
NP_005594​.1
Andersen et al [2006]
CLPB deficiencyARCLPBc.803C>Tp.Thr268Met~100% 11/31InuitNM_030813​.5
NP_110440​.1
Saunders et al [2015]
Congenital sucrase–isomaltase deficiency (OMIM 222900)ARSIc.273_274delAG--~100% 11/4Inuit
(Nunavut)
NM_001041​.3Marcadier et al [2015]
Glycogen storage disease type IIIARAGLc.4456delT--~100% 11/25Inuit
(Nunavik)
NM_000642​.2Rousseau-Nepton et al [2015]
Infantile sialic acid storage disease (see Free Sialic Acid Storage Disorders)ARSLC17A5c.526-2A>G--~100% 11/129InuitNM_012434​.4Lines et al [2014]
Hereditary breast & ovarian cancer (see BRCA1- & BRCA2-Associated Hereditary Breast & Ovarian Cancer)ADBRCA1c.115T>Gp.Cys39Gly>95%1/100 to 1/10Inuit
(Ammassalik)
NM_007294​.3
NP_009225​.1
Hansen et al [2009], Harboe et al [2009], Hansen et al [2010]
Lynch syndrome & mismatch repair deficiency syndrome (OMIM 276300)AD
AR
PMS2c.2002A>G 2--~100% 11/16Inuit
(Nunavik)
NM_000535​.6Li et al [2015]
Propionic acidemiaARPCCBc.1538_1540dupCCCp.Ala513_Arg514insPro~88%1/20InuitNM_000532​.4Ravn et al [2000]

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

1.

Additional pathogenic variants in this gene have not been reported to date in individuals of Inuit descent.

2.

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

References

  • Andersen S, Okkels H, Krarup H, Laurberg P. Geographical clustering and maintained health in individuals harbouring the mutation for Greenland familial cholestasis: A population-based study. Scand J Gastroenterol. 2006;41:445–50. [PubMed: 16635913]
  • Hansen TV, Ejlertsen B, Albrechtsen A, Bergsten E, Bjerregaard P, Hansen T, Myrhøj T, Nielsen PB, Timmermans-Wielenga V, Andersen MK, Jønson L, Nielsen FC. A common Greenlandic Inuit BRCA1 RING domain founder mutation. Breast Cancer Res Treat. 2009;115:69–76. [PubMed: 18500671]
  • Hansen TV, Jønson L, Albrechtsen A, Steffensen AY, Bergsten E, Myrhøj T, Ejlertsen B, Nielsen FC. Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families: implications for genetic screening of Greenlandic Inuit families with high risk for breast and/or ovarian cancer. Breast Cancer Res Treat. 2010;124:259–64. [PubMed: 20437199]
  • Harboe TL, Eiberg H, Kern P, Ejlertsen B, Nedergaard L, Timmermans-Wielenga V, Nielsen IM, Bisgaard ML. A high frequent BRCA1 founder mutation identified in the Greenlandic population. Fam Cancer. 2009;8:413–9. [PubMed: 19504351]
  • Li L, Hamel N, Baker K, McGuffin MJ, Couillard M, Gologan A, Marcus VA, Chodirker B, Chudley A, Stefanovici C, Durandy A, Hegele RA, Feng BJ, Goldgar DE, Zhu J, De Rosa M, Gruber SB, Wimmer K, Young B, Chong G, Tischkowitz MD, Foulkes WD. A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype. J Med Genet. 2015;52:348–52. [PubMed: 25691505]
  • Lines MA, Rupar CA, Rip JW, Baskin B, Ray PN, Hegele RA, Grynspan D, Michaud J, Geraghty MT. Infantile sialic acid storage disease: two unrelated Inuit cases homozygous for a common novel SLC17A5 mutation. JIMD Rep. 2014;12:79–84. [PMC free article: PMC3897797] [PubMed: 23900835]
  • Marcadier JL, Boland M, Scott CR, Issa K, Wu Z, McIntyre AD, Hegele RA, Geraghty MT, Lines MA. Congenital sucrase–isomaltase deficiency: identification of a common Inuit founder mutation. CMAJ. 2015;187:102–7. [PMC free article: PMC4312148] [PubMed: 25452324]
  • Ravn K, Chloupkova M, Christensen E, Brandt NJ, Simonsen H, Kraus JP, Nielsen IM, Skovby F, Schwartz M. High incidence of propionic acidemia in Greenland is due to a prevalent mutation, 1540insCCC, in the gene for the β-subunit of propionyl CoA carboxylase. Am J Hum Genet. 2000;67:203–6. [PMC free article: PMC1287078] [PubMed: 10820128]
  • Rousseau-Nepton I, Okubo M, Grabs R., FORGE Canada Consortium. Mitchell J, Polychronakos C, Rodd C. A founder AGL mutation causing glycogen storage disease type IIIa in Inuit identified through whole-exome sequencing: a case series. CMAJ. 2015;187:E68–73. [PMC free article: PMC4312169] [PubMed: 25602008]
  • Saunders C, Smith L, Wibrand F, Ravn K, Bross P, Thiffault I, Christensen M, Atherton A, Farrow E, Miller N, Kingsmore SF, Ostergaard E. CLPB variants associated with autosomal-recessive mitochondrial disorder with cataract, neutropenia, epilepsy, and methylglutaconic aciduria. Am J Hum Genet. 2015;96:258–65. [PMC free article: PMC4320254] [PubMed: 25597511]
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