A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1–17p13.3

• Published in: Human genetics Vol. 123; no. 6; pp. 625 - 631
• Main Authors: Lezirovitz, Karina, Maestrelli, Sylvia Regina Pedrosa, Cotrim, Nelson Henderson, Otto, Paulo A., Pearson, Peter L., Mingroni-Netto, Regina Celia
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2008; Springer; Springer Nature B.V
• Subjects: Analysis; Biomedical and Life Sciences; Biomedicine; Chromosomes, Human, Pair 17; Ectromelia - complications; Ectromelia - genetics; Female; Gene Function; Gene mutations; Genes; Genetic Linkage; Human Genetics; Humans; Limb Deformities, Congenital - complications; Limb Deformities, Congenital - genetics; Lod Score; Male; Metabolic Diseases; Molecular Medicine; Original Investigation; Pedigree; Syndrome; Tibia - abnormalities; Syndactyly; Tibial Defect; Autosomal Dominant Mode; Brachydactyly; Clubfoot
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-008-0515-7

Split-hand/foot malformation (SHFM) associated with aplasia of long bones, SHFLD syndrome or Tibial hemimelia-ectrodactyly syndrome is a rare condition with autosomal dominant inheritance, reduced penetrance and an incidence estimated to be about 1 in 1,000,000 liveborns. To date, three chromosomal regions have been reported as strong candidates for harboring SHFLD syndrome genes: 1q42.2–q43, 6q14.1 and 2q14.2. We characterized the phenotype of nine affected individuals from a large family with the aim of mapping the causative gene. Among the nine affected patients, four had only SHFM of the hands and no tibial defects, three had both defects and two had only unilateral tibial hemimelia. In keeping with previous publications of this and other families, there was clear evidence of both variable expression and incomplete penetrance, the latter bearing hallmarks of anticipation. Segregation analysis and multipoint Lod scores calculations (maximum Lod score of 5.03 using the LINKMAP software) using all potentially informative family members, both affected and unaffected, identified the chromosomal region 17p13.1–17p13.3 as the best and only candidate for harboring a novel mutated gene responsible for the syndrome in this family. The candidate gene CRK located within this region was sequenced but no pathogenic mutation was detected.