A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta

Wayne A. Cabral, Aileen M. Barnes, Adebowale Adeyemo, Kelly Cushing, David Chitayat, Forbes D. Porter, Susan R. Panny, Fizza Gulamali-Majid, Sarah A. Tishkoff, Timothy R. Rebbeck, Serigne M. Gueye, Joan E. Bailey-Wilson, Lawrence C. Brody, Charles N. Rotimi, Joan C. Marini

Research output: Contribution to journalArticle

Abstract

Purpose: Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (OI). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age. Methods: Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers. Results: Approximately 0.4% (95% confidence interval: 0.22-0.68%) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48% (95% confidence interval: 0.95-2.30%) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive OI, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63-770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100-1350 CE). Conclusion: We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5% of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501-1867 CE).

Original languageEnglish (US)
Pages (from-to)543-551
Number of pages9
JournalGenetics in Medicine
Volume14
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

Fingerprint

Osteogenesis Imperfecta
African Americans
Mutation
Slaves
Microsatellite Repeats
Alleles
Parturition
Confidence Intervals
Ghana
Western Africa
Linkage Disequilibrium
Mutation Rate
Nigeria
North America
Haplotypes
Single Nucleotide Polymorphism
Digestion
Polymerase Chain Reaction

Keywords

  • founder mutation
  • LEPRE1
  • osteogenesis imperfecta
  • West Africa

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Cabral, W. A., Barnes, A. M., Adeyemo, A., Cushing, K., Chitayat, D., Porter, F. D., ... Marini, J. C. (2012). A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genetics in Medicine, 14(5), 543-551. https://doi.org/10.1038/gim.2011.44

A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. / Cabral, Wayne A.; Barnes, Aileen M.; Adeyemo, Adebowale; Cushing, Kelly; Chitayat, David; Porter, Forbes D.; Panny, Susan R.; Gulamali-Majid, Fizza; Tishkoff, Sarah A.; Rebbeck, Timothy R.; Gueye, Serigne M.; Bailey-Wilson, Joan E.; Brody, Lawrence C.; Rotimi, Charles N.; Marini, Joan C.

In: Genetics in Medicine, Vol. 14, No. 5, 05.2012, p. 543-551.

Research output: Contribution to journalArticle

Cabral, WA, Barnes, AM, Adeyemo, A, Cushing, K, Chitayat, D, Porter, FD, Panny, SR, Gulamali-Majid, F, Tishkoff, SA, Rebbeck, TR, Gueye, SM, Bailey-Wilson, JE, Brody, LC, Rotimi, CN & Marini, JC 2012, 'A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta', Genetics in Medicine, vol. 14, no. 5, pp. 543-551. https://doi.org/10.1038/gim.2011.44
Cabral, Wayne A. ; Barnes, Aileen M. ; Adeyemo, Adebowale ; Cushing, Kelly ; Chitayat, David ; Porter, Forbes D. ; Panny, Susan R. ; Gulamali-Majid, Fizza ; Tishkoff, Sarah A. ; Rebbeck, Timothy R. ; Gueye, Serigne M. ; Bailey-Wilson, Joan E. ; Brody, Lawrence C. ; Rotimi, Charles N. ; Marini, Joan C. / A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. In: Genetics in Medicine. 2012 ; Vol. 14, No. 5. pp. 543-551.
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abstract = "Purpose: Deficiency of prolyl 3-hydroxylase 1, encoded by LEPRE1, causes recessive osteogenesis imperfecta (OI). We previously identified a LEPRE1 mutation exclusively in African Americans and contemporary West Africans. We hypothesized that this allele originated in West Africa and was introduced to the Americas with the Atlantic slave trade. We aimed to determine the frequency of carriers for this mutation among African Americans and West Africans, and the mutation origin and age. Methods: Genomic DNA was screened for the mutation using PCR and restriction digestion, and a custom TaqMan genomic single-nucleotide polymorphism assay. The mutation age was estimated using microsatellites and short tandem repeats spanning 4.2 Mb surrounding LEPRE1 in probands and carriers. Results: Approximately 0.4{\%} (95{\%} confidence interval: 0.22-0.68{\%}) of Mid-Atlantic African Americans carry this mutation, estimating recessive OI in 1/260,000 births in this population. In Nigeria and Ghana, 1.48{\%} (95{\%} confidence interval: 0.95-2.30{\%}) of unrelated individuals are heterozygous carriers, predicting that 1/18,260 births will be affected with recessive OI, equal to the incidence of de novo dominant OI. The mutation was not detected in Africans from surrounding countries. All carriers shared a haplotype of 63-770 Kb, consistent with a single founder for this mutation. Using linkage disequilibrium analysis, the mutation was estimated to have originated between 650 and 900 years before present (1100-1350 CE). Conclusion: We identified a West African founder mutation for recessive OI in LEPRE1. Nearly 1.5{\%} of Ghanians and Nigerians are carriers. The estimated age of this allele is consistent with introduction to North America via the Atlantic slave trade (1501-1867 CE).",
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AU - Barnes, Aileen M.

AU - Adeyemo, Adebowale

AU - Cushing, Kelly

AU - Chitayat, David

AU - Porter, Forbes D.

AU - Panny, Susan R.

AU - Gulamali-Majid, Fizza

AU - Tishkoff, Sarah A.

AU - Rebbeck, Timothy R.

AU - Gueye, Serigne M.

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KW - founder mutation

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