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Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Costa Rican 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 more than 50% of the pathogenic variants identified in a single gene in individuals of a specific ancestry – in individuals of Costa Rican 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 Costa Rican Population

GeneDisorderMOIDNA Nucleotide ChangePredicted Protein Change% of Pathogenic Variants in Gene 1Carrier FrequencyEthnicityReference SequencesReferences
ATM Ataxia-telangiectasia ARc.5908C>Tp.Gln1970Ter61%UnknownCosta Rican NM_000051​.4
NP_000042​.3 		Telatar et al [1998]
c.7449G>Ap.Trp2483Ter12%
c.4507C>Tp.Gln1503Ter10%
ATP7B Wilson disease ARc.3809A>Gp.Asn1270Ser61%1/72 2Costa Rican NM_000053​.4
NP_000044​.2 		Shah et al [1997]
CLN6 Ceroid lipofuscinosis (OMIM 601780)ARc.214G>Tp.Glu72Ter~85%UnknownCosta Rican NM_017882​.3
NP_060352​.1 		Gao et al [2002], Wheeler et al [2002], Sharp et al [2003]
GALK1 Galactokinase deficiency (OMIM 230200)ARc.1144C>Tp.Gln382Ter~92%1/190 2Costa Rican NM_000154​.2
NP_000145​.1 		Kolosha et al [2000]
PNKP Axonal Charcot-Marie-Tooth disease type 2B2 (OMIM 605589)ARc.1221_1223delCACp.Thr408del~100% 3UnknownCosta Rican NM_007254​.4
NP_009185​.2 		Leal et al [2018]
c.1549C>Tp.Gln517Ter
RPE65 Leber congenital amaurosis ARc.292_311del20p.Ile98HisfsTer2630%UnknownCosta Rican NM_000329​.3
NP_000320​.1 		Glen et al [2019]
c.1338G>Tp.Arg446Ser30%
c.242G>Tp.Arg81Ile25%
c.419G>Ap.Gly140Glu12.5%
SLC12A1 Bartter syndrome, type 1 (OMIM 601678)ARc.1875G>Ap.Trp625Ter57%~1/145 2Costa Rican NM_000338​.3
NP_000329​.2 		Kurtz et al [1997]
TCIRG1 Osteopetrosis (OMIM 259700)ARc.1213G>Ap.Gly405Arg~66%~1/86 2Costa Rican NM_006019​.4
NP_006010​.2 		Sobacchi et al [2001]
c.1331G>Tp.Arg444Leu~33%
UBR1 Johanson-Blizzard syndrome (OMIM 243800)ARc.1537C>Tp.Glu513Ter~100% 3UnknownCosta Rican NM_174916​.3
NP_777576​.1 		Sukalo et al [2014]

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

AR = autosomal recessive; MOI = mode of inheritance

1.

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

2.

Calculated carrier frequency based on the incidence of the disorder in individuals of Costa Rican ancestry; Estimated carrier frequency is not based on molecular testing of the population.

3.

To date, no additional pathogenic variants in this gene have been reported in individuals of Costa Rican descent.

References

  • Gao H, Boustany RM, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, Gillis T, Qin X, Liu S, Donahue LR, Bronson RT, Faust JR, Stout D, Haines JL, Lerner TJ, MacDonald ME. Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am J Hum Genet. 2002;70:324–35. [PMC free article: PMC384912] [PubMed: 11791207]
  • Glen WB Jr, Peterseim MMW, Badilla R, Znoyko I, Bourg A, Wilson R, Hardiman G, Wolff D, Martinez J. A high prevalence of biallelic RPE65 mutations in Costa Rican children with Leber congenital amaurosis and early-onset retinal dystrophy. Ophthalmic Genet. 2019;40:110–7. [PubMed: 30870047]
  • Kolosha V, Anoia E, de Cespedes C, Gitzelmann R, Shih L, Casco T, Saborio M, Trejos R, Buist N, Tedesco T, Skach W, Mitelmann O, Ledee D, Huang K, Stambolian D. Novel mutations in 13 probands with galactokinase deficiency. Hum Mutat. 2000;15:447–53. [PubMed: 10790206]
  • Kurtz CL, Karolyi L, Seyberth HW, Koch MC, Vargas R, Feldmann D, Vollmer M, Knoers NV, Madrigal G, Guay-Woodford LM. A common NKCC2 mutation in Costa Rican Bartter's syndrome patients: evidence for a founder effect. J Am Soc Nephrol. 1997;8:1706–11. [PubMed: 9355073]
  • Leal A, Bogantes-Ledezma S, Ekici AB, Uebe S, Thiel CT, Sticht H, Berghoff M, Berghoff C, Morera B, Meisterernst M, Reis A. The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics. 2018;19:215–25. [PMC free article: PMC6280876] [PubMed: 30039206]
  • Shah AB, Chernov I, Zhang HT, Ross BM, Das K, Lutsenko S, Parano E, Pavone L, Evgrafov O, Ivanova-Smolenskaya IA, Annerén G, Westermark K, Urrutia FH, Penchaszadeh GK, Sternlieb I, Scheinberg IH, Gilliam TC, Petrukhin K. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997;61:317–28. [PMC free article: PMC1715895] [PubMed: 9311736]
  • Sharp JD, Wheeler RB, Parker KA, Gardiner RM, Williams RE, Mole SE. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat. 2003;22:35–42. [PubMed: 12815591]
  • Sobacchi C, Frattini A, Orchard P, Porras O, Tezcan I, Andolina M, Babul-Hirji R, Baric I, Canham N, Chitayat D, Dupuis-Girod S, Ellis I, Etzioni A, Fasth A, Fisher A, Gerritsen B, Gulino V, Horwitz E, Klamroth V, Lanino E, Mirolo M, Musio A, Matthijs G, Nonomaya S, Notarangelo LD, Ochs HD, Superti Furga A, Valiaho J, van Hove JL, Vihinen M, Vujic D, Vezzoni P, Villa A. The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet. 2001;10:1767–73. [PubMed: 11532986]
  • Sukalo M, Fiedler A, Guzmán C, Spranger S, Addor MC, McHeik JN, Oltra Benavent M, Cobben JM, Gillis LA, Shealy AG, Deshpande C, Bozorgmehr B, Everman DB, Stattin EL, Liebelt J, Keller KM, Bertola DR, van Karnebeek CD, Bergmann C, Liu Z, Düker G, Rezaei N, Alkuraya FS, Oğur G, Alrajoudi A, Venegas-Vega CA, Verbeek NE, Richmond EJ, Kirbiyik O, Ranganath P, Singh A, Godbole K, Ali FA, Alves C, Mayerle J, Lerch MM, Witt H, Zenker M. Mutations in the human UBR1 gene and the associated phenotypic spectrum. Hum Mutat. 2014;2014;35:521–31. [PubMed: 24599544]
  • Telatar M, Wang S, Castellvi-Bel S, Tai LQ, Sheikhavandi S, Regueiro JR, Porras O, Gatti RA. A model for ATM heterozygote identification in a large population: four founder-effect ATM mutations identify most of Costa Rican patients with ataxia telangiectasia. Mol Genet Metab. 1998;64:36–43. [PubMed: 9682216]
  • Wheeler RB, Sharp JD, Schultz RA, Joslin JM, Williams RE, Mole SE. The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am J Hum Genet. 2002;70:537–42. [PMC free article: PMC384927] [PubMed: 11727201]

Revision History

  • 30 June 2022 (sw) Initial posting
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