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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 La Réunion Island Population

, MD and , PhD.

Author Information and Affiliations

Initial Posting: ; Last Revision: October 19, 2023.

Estimated reading time: 5 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 La Réunion 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 La Réunion Island Population

GeneDisorderMOIDNA Nucleotide Change
(Alias 1)		Predicted Protein Change% of Pathogenic Variants in Gene 2Carrier FrequencyEthnicity (Specific Region)Reference SequencesReferences
ARL6 Bardet-Biedl syndrome ARc.535G>A 3
(IVS9-1G>A)		--~100% 4UnknownLa Réunion Islanders NM_177976​.3 Gouronc et al [2020]
B4GALT7 Ehlers-Danlos syndrome, spondylodysplastic type (OMIM 130070)ARc.808C>Tp.Arg270Cys~100% 41/26La Réunion Islanders NM_007255​.3
NP_009186​.1 		Cartault et al [2015]
CAPN3 Calpainopathy ARc.946-1G>A
(IVS6-1G>A)		--~75%UnknownLa Réunion Islanders (Southern) NM_000070​.3 Fardeau et al [1996]
CFTR Cystic fibrosis ARc.1521_1523delCTTp.Phe508del44%UnknownLa Réunion Islanders NM_000492​.4
NP_000483​.3 		Chevalier-Porst et al [1992]
c.366T>Ap.Tyr122Ter27%
COL4A3 Alport syndrome ARc.4929-388G>T 5
(IVS51-388G>T)		--~100% 4UnknownLa Réunion Islanders (Southern) NM_000091​.5 Knebelmann et al [1995], Finielz et al [1998]
LEPR Leptin receptor deficiency (OMIM 614963)AR(del exons 6-8)p.Pro166CysfsTer7~92%UnknownLa Réunion Islanders NG_015831​.2 Huvenne et al [2015]
LHFPL5 Nonsyndromic deafness ARc.185delTp.Phe62SerfsTer23~89%1/53La Réunion Islanders NM_182548​.4
NP_872354​.1 		Lerat et al [2019]
LMNA Familial partial lipodystrophy type 2 (OMIM 151660)AD/ARc.1961dupGp.Thr655AsnfsTer49~93%NALa Réunion Islanders NM_170707​.4
NP_733821​.1 		Le Dour et al [2011], Treiber et al [2021]
MARS1 Interstitial lung & liver disease (OMIM 615486)ARc.1700C>T & c.1177G>A 6p.Ser567Leu & p.Ala393Thr 6~100% 41/100La Réunion Islanders NM_004990​.4
NP_004981​.2 		Hadchouel et al [2015]
PIGN Fryns syndrome ARc.329_549+1907del5064
(5064-bp del incl part of ex 5, ex 6, & ex 7)		p.Ser110ArgfsTer15~100% 4UnknownLa Réunion Islanders NM_176787​.5
NP_789744​.1 		Alessandri et al [2018]
SLC7A2 Infantile encephalopathy w/anorexiaARc.-23+3307A>G
(IVS1-1713A>G)		--~100% 41/50La Réunion Islanders NM_001008539​.4 Cartault et al [2012]
ST3GAL5 GM3 synthase deficiency ARc.740G>Ap.Gly247Asp~100% 4UnknownLa Réunion Islanders NM_003896​.4
NP_003887​.3 		Heide et al [2022]

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

AD = autosomal dominant; AR = autosomal recessive; ex = exon; LGMD = limb-girdle muscular dystrophy; MOI = mode of inheritance

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.

Nucleotide change affects donor splice site resulting in deletion of exon 8.

4.

To date, no additional pathogenic variants in this gene have been reported in individuals from La Réunion Island.

5.

G-to-T transversion activates a cryptic acceptor splice site located in an Alu element within intron 5, resulting in a 74-bp insertion into the mature transcript at the junction of exons 4 or 5 and exon 6.

6.

Affected individuals have been found to be homozygous for both variants listed.

Revision History

  • 19 October 2023 (sw) Revision: LEPR and SLC7A2 added; DNA nucleotide change aliases added
  • 20 July 2023 (sw) Revision: ST3GAL5 added
  • 8 December 2022 (sw) Initial posting

References

  • Alessandri JL, Gordon CT, Jacquemont ML, Gruchy N, Ajeawung NF, Benoist G, Oufadem M, Chebil A, Duffourd Y, Dumont C, Gérard M, Kuentz P, Jouan T, Filippini F, Nguyen TTM, Alibeu O, Bole-Feysot C, Nitschké P, Omarjee A, Ramful D, Randrianaivo H, Doray B, Faivre L, Amiel J, Campeau PM, Thevenon J. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Réunion Island, in patients with Fryns syndrome. Eur J Hum Genet. 2018;26:340-9. [PMC free article: PMC5839001] [PubMed: 29330547]
  • Cartault F, Munier P, Benko E, Desguerre I, Hanein S, Boddaert N, Bandiera S, Vellayoudom J, Krejbich-Trotot P, Bintner M, Hoarau JJ, Girard M, Génin E, de Lonlay P, Fourmaintraux A, Naville M, Rodriguez D, Feingold J, Renouil M, Munnich A, Westhof E, Fähling M, Lyonnet S, Henrion-Caude A. Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy. Proc Natl Acad Sci U S A. 2012;109:4980-5. [PMC free article: PMC3323976] [PubMed: 22411793]
  • Cartault F, Munier P, Jacquemont M-L, Vellayoudom J, Doray B, Payet C, Randrianaivo H, Laville J-M, Munnich A, Cormier-Daire V. Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome. Eur J Hum Genet. 2015;23:49-53. [PMC free article: PMC4266744] [PubMed: 24755949]
  • Chevalier-Porst F, Chomel JC, Hillaire D, Kitzis A, Kaplan JC, Goutaland R, Mathieu M, Bozon D. A nonsense mutation in exon 4 of the cystic fibrosis gene frequent among the population of the Reunion Island. Hum Mol Genet. 1992;1:647-8. [PubMed: 1284471]
  • Fardeau M, Eymard B, Mignard C, Tomé FM, Richard I, Beckmann JS. Chromosome 15-linked limb-girdle muscular dystrophy: clinical phenotypes in Reunion Island and French metropolitan communities. Neuromuscul Disord. 1996;6:447-53. [PubMed: 9027854]
  • Finielz P, Cartault F, Chuet C, Genin R. Alport syndrome in Reunion Island: phenotypic heterogeneity of the recessive-autosomal form. (Letter) Nephron. 1998;79:237. [PubMed: 9647515]
  • Gouronc A, Zilliox V, Jacquemont M-L, Darcel F, Leuvrey A-S, Nourisson E, Antin M, Alessandri J-L, Doray B, Gueguen P, Payet F, Randrianaivo H, Stoetzel C, Scheidecker S, Flodrops H, Dollfus H, Muller J. High prevalence of Bardet-Biedl syndrome in La Réunion Island is due to a founder variant in ARL6/BBS3. Clin Genet. 2020;98:166-71. [PubMed: 32361989]
  • Hadchouel A, Wieland T, Griese M, Baruffini E, Lorenz-Depiereux B, Enaud L, Graf E, Dubus JC, Halioui-Louhaichi S, Coulomb A, Delacourt C, Eckstein G, Zarbock R, Schwarzmayr T, Cartault, F, Meitinger T, Lodi T, de Blic J, Strom TM. Biallelic mutations of methionyl-tRNA synthetase cause a specific type of pulmonary alveolar proteinosis prevalent on Reunion Island. Am J Hum Genet. 2015;96:826-31. [PMC free article: PMC4570277] [PubMed: 25913036]
  • Heide S, Jacquemont ML, Cheillan D, Renouil M, Tallot M, Schwartz CE, Miquel J, Bintner M, Rodriguez D, Darcel F, Buratti J, Haye D, Passemard S, Gras D, Perrin L, Capri Y, Gérard B, Piton A, Keren B, Thauvin-Robinet C, Duffourd Y, Faivre L, Poe C, Pervillé A, Héron D, Thévenon J, Arnaud L, LeGuern E, La Selva L, Vetro A, Guerrini R, Nava C, Mignot C. GM3 synthase deficiency in non-Amish patients. Genet Med. 2022;24:492-8. [PubMed: 34906476]
  • Huvenne H, Le Beyec J, Pépin D, Alili R, Kherchiche PP, Jeannic E, Frelut ML, Lacorte JM, Nicolino M, Viard A, Laville M, Ledoux S, Tounian P, Poitou C, Dubern B, Clément K. Seven novel deleterious LEPR mutations found in early-onset obesity: a ΔExon6-8 shared by subjects from Reunion Island, France, suggests a founder effect. J Clin Endocrinol Metab. 2015;100:E757-66. [PubMed: 25751111]
  • Knebelmann B, Forestier L, Drouot L, Quinones S, Chuet C, Benessy F, Saus J, Antignac C. Splice-mediated insertion of an Alu sequence in the COL4A3 mRNA causing autosomal recessive Alport syndrome. Hum Mol Genet. 1995;4:675-9. [PubMed: 7633417]
  • Le Dour C, Schneebeli S, Bakiri F, Darcel F, Jacquemont ML, Maubert MA, Auclair M, Jeziorowska D, Reznik Y, Béréziat V, Capeau J, Lascols O, Vigouroux C. A homozygous mutation of prelamin-A preventing its farnesylation and maturation leads to a severe lipodystrophic phenotype: new insights into the pathogenicity of nonfarnesylated prelamin-A. J Clin Endocrinol Metab. 2011;96:E856-62. [PubMed: 21346069]
  • Lerat J, Bonnet C, Cartault F, Loundon N, Jacquemont ML, Darcel F, Rouillon I, Mezouaghi K, Guichet A, Litzler J, Gesny R, Gherbi S, Aissa IB, Digeon FSJ, Garabedian EN, Bonnefont JP, Genin E, Denoyelle F, Jonard L, Marlin S. High prevalence of congenital deafness on Reunion Island is due to a founder variant of LHFPL5. Clin Genet. 2019;95:177-81. [PubMed: 30298622]
  • Treiber G, Flaus Furmaniuk A, Guilleux A, Medjane S, Bonfanti O, Schneebeli S, Bernard C, Le-Moullec N, Bakiri F, Pholsena M, Rollot O, Vatier C, Jarlet E, Jéru I, Lascols O, Darcel F, Domun B, Venault A, Venault S, Jacquemont ML, Doray B, Maiza JC, Cogne M, Vigouroux C, Nobécourt E. A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies. Eur J Endocrinol. 2021;185:453-62. [PubMed: 34292171]
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