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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

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Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Cree and/or Ojibway Population

, MD and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Revision: June 1, 2023.

Estimated reading time: 3 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 Cree and/or Ojibway 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 Cree and/or Ojibway Population

GeneDisorderMOIDNA Nucleotide Change
(Alias 1)		Predicted Protein Change% of Pathogenic Variants in Gene 2 ,3Carrier FrequencyEthnicity
(Specific Region of Canada)		Reference
Sequences		Reference(s)
CRYAB Fatal infantile myofibrillar myopathy (OMIM 613869)ARc.60delCp.Ser21AlafsTer24100%UnknownCree
(N Ontario & Alberta)		 NM_001885​.3
NP_001876​.1 		Del Bigio et al [2011]
DONSON Microcephaly-micromelia syndrome (OMIM 251230)ARc.1047-9A>G
(IVS6-9A>G)		--100%UnknownCree
(N Saskatchewan)		 NM_017613​.4 Evrony et al [2017]
EIF2B5 Cree leukoencephalopathy (See Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter.)ARc.584G>Ap.Arg195His100%1/10Cree
(N Quebec & Manitoba)		 NM_003907​.3
NP_003898​.2 		Fogli et al [2002]
FREM1 Manitoba oculotrichoanal syndrome (See FREM1 Autosomal Recessive Disorders.)ARc.824+627_c.3840-1311del
(IVS7+631_IVS23-1311 del; del8-23 exon)		p.385_1327del100%1/7 to 1/12Ojibway-Cree
(Island Lake, Manitoba)		 NM_144966​.5
NP_659403​.4 		Slavotinek et al [2011]
GCDH Glutaric acidemia type 1 ARc.91+5G>T
(IVS2+5G>T)		--100%1/17Ojibway-Cree
(Island Lake, Manitoba, & NW Ontario)		 NM_000159​.4 Greenberg et al [2002]
GLIS2 Nephronophthisis-related ciliopathies ARc.775+1G>T
(IVS5+1G>T)		--100%UnknownOjibway-Cree
(Canada)		 NM_032575​.3 Attanasio et al [2007]
IKBKB Immunodeficiency 15B (OMIM 615592)ARc.1292dupGp.Gln432ProfsTer62100%1/13Cree
(Manitoba & Saskatchewan)		 NM_001556​.3
NP_001547​.1 		Pannicke et al [2013], Rubin et al [2018]
PC Pyruvate carboxylase deficiency ARc.1828G>Ap.Ala610Thr100%Up to 1/10Ojibway-Cree
(White Dog, Ontario)		 NM_000920​.4
NP_000911​.2 		Carbone et al [1998]
PRUNE1 Neurodevelopmental disorder with microcephaly, hypotonia, & variable brain anomalies (OMIM 617481)ARc.521-2A>G
(IVS4-2A>G)		--100%UnknownCree
(N Manitoba)		 NM_021222​.3 Hartley et al [2019]
SLC25A38 Sideroblastic anemia 2 (OMIM 205950)ARc.560G>Ap.Arg187Gln100%UnknownCree
(Canada)		 NM_017875​.4
NP_060345​.2 		Uminski et al [2020]
TREX1 Cree encephalitis (See Aicardi-Goutières Syndrome.)ARc.490C>Tp.Arg164Ter100%1/10Cree
(Quebec)		 NM_033629​.6
NP_338599​.1 		Crow et al [2003], Crow et al [2006]

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

AR = autosomal recessive; MOI = mode of inheritance; N = Northern; NW = Northwest

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 Cree and/or Ojibway descent (from region specified).

References

  • Attanasio M, Uhlenhaut NH, Sousa VH, O'Toole JF, Otto E, Anlag K, Klugmann C, Treier AC, Helou J, Sayer JA, Seelow D, Nürnberg G, Becker C, Chudley AE, Nürnberg P, Hildebrandt F, Treier M. Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nature Genet. 2007;39:1018–24. [PubMed: 17618285]
  • Carbone MA, MacKay N, Ling M, Cole DE, Douglas C, Rigat B, Feigenbaum A, Clarke JT, Haworth JC, Greenberg CR, Seargeant L, Robinson BH. Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Am J Hum Genet. 1998;62:1312–9. [PMC free article: PMC1377163] [PubMed: 9585612]
  • Crow YJ, Black DN, Ali M, Bond J, Jackson AP, Lefson M, Michaud J, Roberts E, Stephenson JB, Woods CG, Lebon P. Cree encephalitis is allelic with Aicardi-Goutieres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism. J. Med. Genet. 2003;40:183–7. [PMC free article: PMC1735395] [PubMed: 12624136]
  • Crow YJ, Hayward BE, Parmar R, Robins P, Leitch A, Ali M, Black DN, van Bokhoven H, Brunner HG, Hamel BC, Corry PC, Cowan FM, Frints SG, Klepper J, Livingston JH, Lynch SA, Massey RF, Meritet JF, Michaud JL, Ponsot G, Voit T, Lebon P, Bonthron DT, Jackson AP, Barnes DE, Lindahl T. Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet. 2006;38:917–20. [PubMed: 16845398]
  • Del Bigio MR, Chudley AE, Sarnat HB, Campbell C, Goobie S, Chodirker BN, Selcen D. Infantile muscular dystrophy in Canadian aboriginals is an alpha-B-crystallinopathy. Ann Neurol. 2011;69:866–71. [PMC free article: PMC3085857] [PubMed: 21337604]
  • Evrony GD, Cordero DR, Shen J, Partlow JN, Yu TW, Rodin RE, Hill RS, Coulter ME, Lam AN, Jayaraman D, Gerrelli D, Diaz DG, Santos C, Morrison V, Galli A, Tschulena U, Wiemann S, Martel MJ, Spooner B, Ryu SC, Elhosary PC, Richardson JM, Tierney D, Robinson CA, Chibbar R, Diudea D, Folkerth R, Wiebe S, Barkovich AJ, Mochida GH, Irvine J, Lemire EG, Blakley P, Walsh CA. Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome. Genome Res. 2017;27:1323–35. [PMC free article: PMC5538549] [PubMed: 28630177]
  • Fogli A, Wong K, Eymard-Pierre E, Wenger J, Bouffard JP, Goldin E, Black DN, Boespflug-Tanguy O, Schiffmann R. Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol. 2002;52:506–10. [PubMed: 12325082]
  • Greenberg CR, Prasad AN, Dilling LA, Thompson JR, Haworth JC, Martin B, Wood-Steiman P, Seargeant LE, Seifert B, Booth FA, Prasad C. Outcome of the first 3-years of a DNA-based neonatal screening program for glutaric acidemia type 1 in Manitoba and northwestern Ontario, Canada. Mol Genet Metab. 2002;75:70–8. [PubMed: 11825066]
  • Hartley JN, Simard LR, Ly V, Del Bigio MR, Frosk P. A homozygous canonical splice acceptor site mutation in PRUNE1 is responsible for a rare childhood neurodegenerative disease in Manitoba Cree families. Am J Med Genet A. 2019;179:206–18. [PubMed: 30556349]
  • Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, Rizzi M, Janda A, Hese K, Schlesier M, Holzmann K, Borte S, Laux C, Rump EM, Rosenberg A, Zelinski T, Schrezenmeier H, Wirth T, Ehl S, Schroeder ML, Schwarz K. Deficiency of innate and acquired immunity caused by an IKBKB mutation. N Engl J Med. 2013;369:2504–14. [PubMed: 24369075]
  • Rubin TS, Rockman-Greenberg C, Van Caeseele P, Cuvelier GDE, Kwan L, Schroeder ML. Newborn screening for IKBKB deficiency in Manitoba, using genetic mutation analysis. J Clin Immunol. 2018;38:742–4. [PubMed: 30288645]
  • Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, Yahyavi M, Bijlsma EK, Chu C, Musone S, Wheatley A, Kwok PY, Marles S, Fryns JP, Maga AM, Hassan MG, Gould DB, Madireddy L, Li C, Cox TC, Smyth I, Chudley AE, Zenker M. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet. 2011;48:375–82. [PMC free article: PMC4294942] [PubMed: 21507892]
  • Uminski K, Houston DS, Hartley JN, Liu J, Cuvelier GDE, Israels SJ. Clinical characterization and hematopoietic stem cell transplant outcomes for congenital sideroblastic anemia caused by a novel pathogenic variant in SLC25A38. Pediatr Blood Cancer. 2020;67:e28623. [PubMed: 32790119]

Revision History

  • 1 June 2023 (sw) Revision: added sideroblastic anemia 2
  • 16 January 2020 (sw) Revision: added glutaric acidemia type 1
  • 16 May 2019 (sw) Initial posting
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