title: Quantification of homozygosity in consanguineous individuals with autosomal recessive disease.
abstract: Individuals born of consanguineous union have segments of their genomes that are homozygous as a result of inheriting identical ancestral genomic segments through both parents. One consequence of this is an increased incidence of recessive disease within these sibships. Theoretical calculations predict that 6% (1/16) of the genome of a child of first cousins will be homozygous and that the average homozygous segment will be 20 cM in size. We assessed whether these predictions held true in populations that have preferred consanguineous marriage for many generations. We found that in individuals with a recessive disease whose parents were first cousins, on average, 11% of their genomes were homozygous (n = 38; range 5%-20%), with each individual bearing 20 homozygous segments exceeding 3 cM (n = 38; range of number of homozygous segments 7-32), and that the size of the homozygous segment associated with recessive disease was 26 cM (n = 100; range 5-70 cM). These data imply that prolonged parental inbreeding has led to a background level of homozygosity increased approximately 5% over and above that predicted by simple models of consanguinity. This has important clinical and research implications.
authors.affiliation: Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom. Electronic address: cw347@cam.ac.uk.
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.affiliation: Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Cox
authors.affiliation: Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
authors.forename: Kelly
authors.initials: K
authors.lastname: Springell
authors.affiliation: Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hampshire
authors.affiliation: Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
authors.forename: Moin D
authors.initials: MD
authors.lastname: Mohamed
authors.affiliation: Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.affiliation: Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Rowena
authors.initials: R
authors.lastname: Stern
authors.affiliation: Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.affiliation: Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Sandford
authors.affiliation: Department of Clinical Genetics, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Saghira
authors.initials: S
authors.lastname: Malik Sharif
authors.affiliation: Department of Clinical Genetics, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Gulshan
authors.initials: G
authors.lastname: Karbani
authors.affiliation: Department of Clinical Genetics, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Mustaq
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Bond
authors.affiliation: Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Clayton
authors.affiliation: Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
mesh_terms: D025063:Chromosome Disorders; D003241:Consanguinity; D005532:Foot Deformities, Congenital; D005808:Genes, Recessive; D030342:Genetic Diseases, Inborn; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide