title: A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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).
authors.affiliation: Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.forename: Adebowale
authors.initials: A
authors.lastname: Adeyemo
authors.forename: Kelly
authors.initials: K
authors.lastname: Cushing
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Susan R
authors.initials: SR
authors.lastname: Panny
authors.forename: Fizza
authors.initials: F
authors.lastname: Gulamali-Majid
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tishkoff
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Rebbeck
authors.forename: Serigne M
authors.initials: SM
authors.lastname: Gueye
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.forename: Charles N
authors.initials: CN
authors.lastname: Rotimi
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
mesh_terms: D001741:Black or African American / Q000235:genetics; D044383:Black People / Q000235:genetics; D015331:Cohort Studies; D004247:DNA / Q000097:blood; D018703:Founder Effect; D006580:Genetic Carrier Screening; D060005:Genotyping Techniques; D005869:Ghana / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D015810:Linkage Disequilibrium / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D009549:Nigeria / Q000453:epidemiology; D009656:North America / Q000453:epidemiology; D010013:Osteogenesis Imperfecta / Q000453:epidemiology / Q000235:genetics*; D064828:Prolyl Hydroxylases; D011509:Proteoglycans / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D011509:Proteoglycans; D004247:DNA; D064828:Prolyl Hydroxylases; C485657:P3H1 protein, human