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Human Molecular Genetics Advance Access published online on May 30, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn164
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Homozygous WNT10b Mutation and Complex Inheritance in Split Hand Foot Malformation

Sibel Aylin Ugur1 and Aslihan Tolun1,*

1 Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, 34342, Turkey

* Aslihan Tolun, PhD Department of Molecular Biology and Genetics, KP 301 Bogazici University, Bebek 34342 Istanbul, Turkey Phone: 90 212 359 6472 (office) 90 212 257 2095 (home) 90 533 433 0377 (GSM) Fax: 90 212 287 2468 E-mail: tolun{at}boun.edu.tr

Received April 7, 2008; Revised May 7, 2008; Accepted May 28, 2008

Split Hand Foot Malformation (SHFM) is a complex limb malformation affecting the central rays of the autopod. We studied a large consanguineous kindred afflicted with autosomal recessive SHFM. Twelve affected members had central feet reductions with or without hand involvement while the remaining one had the mildest phenotype and atypical SHFM. We identified by homozygosity mapping a novel SHFM locus at 12q13.11-q13 with a maximum multipoint lod score of 5.47 and by subsequent candidate gene approach a homozygous missense WNT10b mutation (p.R332W) in all affected individuals but the atypical case plus in an asymptomatic female. We propose that either a second locus contributes to the manifestation of SHFM phenotype or a suppressor locus prevented trait manifestation in the non-penetrant female. We also investigated linkage to the five known SHFM loci. Four of the loci were excluded, while in TP63 (SHFM4), the only known gene responsible for SHFM, we detected in most affected subjects a rare insertion variant (rs34201045) at the alternate promoter used for transcription of the N-terminal-truncated p63 isotype. This is the first reported WNT10b mutation on the pathogenesis of limb development and recessive mutation in SHFM.

GenBank Accession Numbers: NM_003394 [GenBank] .2, NP_003385.2 [GenBank] , NM_003722 [GenBank] .3, NP_003713.3 [GenBank] and AF091627 [GenBank]

EMBL Accession Number. O00744


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