Fine Mapping of the Split-Hand/Split-Foot Locus ( SHFM3) at 10q24: Evidence for Anticipation and Segregation Distortion

• Published in: American journal of human genetics Vol. 64; no. 6; pp. 1646 - 1654
• Main Authors: Özen, Rýdvan S., Baysal, Bora E., Devlin, Bernie, Farr, Joan E., Gorry, Michael, Ehrlich, Garth D., Richard, Charles W.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-06-1999; University of Chicago Press
• Subjects: Anticipation; Biological and medical sciences; Chromosome 10q24; Chromosome Mapping; Chromosomes, Human, Pair 10; Diseases of the osteoarticular system; Ectrodactyly; Female; Fibroblast Growth Factor 8; Fibroblast Growth Factors - genetics; Foot Deformities, Congenital - genetics; Genetic linkage analysis; Hand Deformities, Congenital - genetics; Homeodomain Proteins - genetics; Humans; Karyotyping; Lod Score; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mutation; Oncogene Proteins - genetics; Pedigree; Phenotype; Proto-Oncogene Proteins; Segregation distortion; Split-hand/split-foot; Transmission distortion; Tropical medicine; Ectrodactyly; Split-hand/split-foot; Segregation distortion; Chromosome 10q24; Anticipation; Transmission distortion; Genetic linkage analysis; Genetic mapping; Human; Family study; Pathogenesis; Diseases of the osteoarticular system; Split-hand split-foot syndrome; Chromosome C10; Genetic determinism; Genetic disease; Allele; Gene; Disease of the hand; Malformation; Disease of the foot; Genetics; Molecular biology
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/302403

Split-hand/split-foot malformation (SHFM, ectrodactyly, or lobster-claw deformity) is a human limb malformation characterized by aberrant development of central digital rays with absence of fingers and toes, a deep median cleft, and fusion of remaining digits. SHFM is clinically heterogeneous, presenting both in an isolated form and in combination with additional abnormalities affecting the tibia and/or other organ systems, including the genitourinary, craniofacial, and ectodermal structures. Three SHFM disease loci have been genetically mapped to chromosomes 7q21 (
SHFM1), Xq26 (
SHFM2), and 10q24 (
SHFM3). We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the
SHFM3 region from 9 cM to an ∼2-cM critical interval between genetic markers D10S1147 and D10S1240. In several instances we found evidence for a more severe phenotype in offspring of a mildly affected parent, suggesting anticipation. Finally, data from this family, combined with those from six other pedigrees, mapped to 10q24, demonstrate biased transmission of
SHFM3 alleles from affected fathers to offspring. The degree of this segregation distortion is obvious in male offspring and is possibly of the same magnitude for female offspring.