Genomewide linkage scan for split-hand/foot malformation with long-bone deficiency in a large Arab family identifies two novel susceptibility loci on chromosomes 1q42.2-q43 and 6q14.1.
Split-hand/foot malformation with long-bone deficiency (SHFLD) is a rare, severe limb deformity characterized by tibia aplasia with or without split-hand/split-foot deformity. Identification of genetic susceptibility loci for SHFLD has been unsuccessful because of its rare incidence, variable phenotypic expression and associated anomalies, and uncertain inheritance pattern. SHFLD is usually inherited as an autosomal dominant trait with reduced penetrance, although recessive inheritance has also been postulated. We conducted a genomewide linkage analysis, using a 10K SNP array in a large consanguineous family (UR078) from the United Arab Emirates (UAE) who had disease transmission consistent with an autosomal dominant inheritance pattern. The study identified two novel SHFLD susceptibility loci at 1q42.2-q43 (nonparametric linkage [NPL] 9.8, P=.000065) and 6q14.1 (NPL 7.12, P=.000897). These results were also supported by multipoint parametric linkage analysis. Maximum multipoint LOD scores of 3.20 and 3.78 were detected for genomic locations 1q42.2-43 and 6q14.1, respectively, with the use of an autosomal dominant mode of inheritance with reduced penetrance. Haplotype analysis with informative crossovers enabled mapping of the SHFLD loci to a region of approximately 18.38 cM (8.4 Mb) between single-nucleotide polymorphisms rs1124110 and rs535043 on 1q42.2-q43 and to a region of approximately 1.96 cM (4.1 Mb) between rs623155 and rs1547251 on 6q14.1. The study identified two novel loci for the SHFLD phenotype in this UAE family.
Naveed
Mohammed
M
Center for Arab Genomic Studies (CAGS), Dubai, United Arab Emirates.
Nath
Swapan K
SK
Gaines
Mathew
M
Al-Ali
Mahmoud T
MT
Al-Khaja
Najib
N
Hutchings
David
D
Golla
Jeffrey
J
Deutsch
Samuel
S
Bottani
Armand
A
Antonarakis
Stylianos E
SE
Ratnamala
Uppala
U
Radhakrishna
Uppala
U
D018912:Arabs; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D004198:Disease Susceptibility; D005260:Female; D005532:Foot Deformities, Congenital / Q000235:genetics*; D015894:Genome, Human; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D010375:Pedigree