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

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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 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

DisorderMOIGeneDNA Nucleotide ChangePredicted Protein ChangeProportion of Pathogenic Variants in This Gene 1Carrier FrequencyEthnicity
(Specific Region of Canada)
Reference
Sequences
References
Cree encephalitis (see Aicardi-Goutières syndrome)ARTREX1c.490C>Tp.Arg164Ter100%1/10Cree
(Quebec)
NM_033629​.5
NP_338599​.1
Crow et al [2003], Crow et al [2006]
Cree leukoencephalopathy (see Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter)AREIF2B5c.584G>Ap.Arg195His100%1/10Cree
(Northern Quebec & Manitoba)
NM_003907​.2
NP_003898​.2
Fogli et al [2002]
Fatal infantile myofibrillar myopathy (OMIM PS601419)ARCRYABc.60delCp.(Ser21AlafsTer24)100%UnknownCree
(Northern Ontario & Alberta)
NM_001885​.2
NP_001876​.1
Del Bigio et al [2011]
Immunodeficiency type 15B (OMIM 615592)ARIKBKBc.1292dupGp.(Gln432ProfsTer62)100%UnknownCree
(Manitoba & Saskatchewan)
NM_001556​.2Pannicke et al [2013]
Manitoba oculotrichoanal syndrome (see FREM1-Autosomal Recessive Disorders)ARFREM1c.824+627_c.3840-1311delp.(385_1327del)100%1/7 to 1/12Ojibway-Cree (Island Lake, Manitoba)NM_144966​.5
NP_659403​.4
Slavotinek et al [2011]
Microcephaly-micromelia syndrome (OMIM 251230)ARDONSONc.1047-9A-G_c.1047-9A>G--100%UnknownCree (Saskatchewan)NM_017613​.3Evrony et al [2017]
NephronophthisisARGLIS2c.775+1G>T--100%UnknownOjibway-Cree (Canada)NM_032575​.2Attanasio et al [2007]
Neurodevelopmental disorders with microcephly, hypotonia, and variable brain anomalies (OMIM 617481)ARPRUNE1c.521-2A>G--100%UnknownCree
(Northern Manitoba)
NM_021222​.2Hartley et al [2019]
Pyruvate carboxylase deficiencyARPCc.1828G>Ap.Ala610Thr100%Up to 1/10Ojibway-Cree
(White Dog, Ontario)
NM_000920​.3
NP_000911​.2
Carbone et al [1998]

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

1.

No additional pathogenic variants in the genes listed have been reported to date in individuals of Cree and/or Ojibway descent.

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]
  • 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]
  • 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]
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