The Effect of Inbreeding on the Distribution of Compound Heterozygotes: A Lesson from Lipase H Mutations in Autosomal Recessive Woolly Hair/Hypotrichosis

Abstract

Autozygosity mapping in consanguineous families has proven to be a powerful method for identifying recessive disease genes. Using this technique with whole genome SNP data generated from low density mapping arrays, we previously identified two genes that underlie autosomal recessive woolly hair (ARWH/hypotrichosis; OMIM278150), specifically P2RY5 and Lipase H (LIPH). In the current study, we sought to identify a novel disease locus for ARWH/hypotrichosis by analyzing two large consanguineous families from Pakistan who had initially been excluded for mutations at either of these disease loci by haplotype analysis with microsatellite markers. A genome-wide analysis of 10 members from each of the two families failed to identify significant regions of autozygosity or linkage. Upon genotyping an additional 10 family members in one of the families, parametric linkage analysis identified a region on chromosome 3q27 with evidence for linkage (Z = 2.5). Surprisingly, this region contains the LIPH gene. Microsatellite markers located within the LIPH gene were used for haplotype analysis and demonstrated that not one, but two haplotypes were segregating with the phenotype in each of these families. DNA sequencing identified two distinct LIPH mutations (280_369dup90 and 659_660delTA). Each affected individual (n = 38) was either homozygous for one mutation (n = 7 and 16 respectively), or compound heterozygous (n = 15). A review of the literature identified several reports of compound heterozygotes in consanguineous families. Prompted by this finding, we derived the probability that a patient affected with a recessive disease is carrying two mutations at the disease locus. We suggest that the validity of the IBD assumption may be challenged in large consanguineous families.

PrevalentLIPHfounder mutations lead to loss of P2Y5 activation ability of PA-PLA1α in autosomal recessive hypotrichosis

“…So far, 14 LIPH gene mutations have been reported, four of which are prevalent Horev et al, 2009;Jelani et al, 2008;Kamran-ul-Hassan Naqvi et al, 2009;Kazantseva et al, 2006;Nahum et al, 2009;Naz et al, 2009;Pasternack et al, 2009;Petukhova et al, 2009;Shimomura et al, 2009a,b,c]. One prevalent mutation, 985-bp deletion including exon 4 and the flanking introns, was detected in a large number of ARH patients from two ethnic groups, the Chuvash and Mari, in the Volga-Ural region of Russia [Kazantseva et al, 2006].…”

“…A deletion mutation exon7_8del has been identified in five consanguineous Pakistani families and 1 Guyanese family [Jelani et al, 2008;Petukhova et al, 2009;Shimomura et al, 2009bShimomura et al, , 2009c. A small deletion mutation 659_660delTA has been identified in several consanguineous Pakistani families and 1 Guyanese family [Jelani et al, 2008;Petukhova et al, 2009;Shimomura et al, 2009b,c].…”

“…A small deletion mutation 659_660delTA has been identified in several consanguineous Pakistani families and 1 Guyanese family [Jelani et al, 2008;Petukhova et al, 2009;Shimomura et al, 2009b,c]. Both mutations were defined as founder mutations shared in families from Pakistan and Guyana by haplotype analysis using microsatellite markers close to the LIPH gene [Jelani et al, 2008;Petukhova et al, 2009;Shimomura et al, 2009b,c]. In fact, these Guyanese families with ARH were descended from people who had come from India about 100 years ago, and it is plausible that both mutations originated from the Indian population [Shimomura et al, 2009c].…”

Identifying Genes Responsible for Intellectual Disability in Consanguineous Families

“…Although homozygous muta- tions are a common cause of disease in consanguineous families, it also happens regularly that consanguinity is unrelated to the disorder. Thus, compound heterozygosity can be causative for recessive genetic disorders and one should be aware of this, particularly when studying outbred families or families with affected individuals residing in a single sibship [84,85] .…”

The effect of population stratification on the frequency of compound heterozygosity

“…A recent study has explored the relationship between allele frequencies, the inbreeding coefficient, the number of mutations segregating and the probability that an individual affected with a recessive disorder is a compound heterozygote (Petukhova et al 2009). The authors concluded that compound heterozygosity underlies disease in A.…”