Abstract
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.
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Acknowledgments
The authors thank all family members for their enrollment in this study and laboratory fellows for their collaboration, especially Renata Soares Thiele de Aguiar for her invaluable help and Camila Juncansen, Katia Maria da Rocha, Maria Teresa Balester de Mello Auricchio and Martha Lima-Cozzo for technical support. We also thank Dr. Nina Amália Brancia Pagnan for her collaboration in the clinical evaluation of some patients; Dr. Diogo Meyer, Rodrigo Ramalho, Andrea R. Horimoto and Natale Cavaçana for helping with the Lod score calculations. This work was financially supported by FAPESP and PRONEX—Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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Contract grant sponsors: CEPID—Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and PRONEX—Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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Lezirovitz, K., Maestrelli, S.R.P., Cotrim, N.H. et al. A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1–17p13.3. Hum Genet 123, 625–631 (2008). https://doi.org/10.1007/s00439-008-0515-7
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DOI: https://doi.org/10.1007/s00439-008-0515-7