title: Frequency of genomic rearrangements involving the SHFM3 locus at chromosome 10q24 in syndromic and non-syndromic split-hand/foot malformation.
abstract: Split-hand/foot malformation (SHFM), or ectrodactyly, is characterized by underdeveloped or absent central digital rays, clefts of the hands and feet, and variable syndactyly of the remaining digits. SHFM occurs as both an isolated finding and a component of many syndromes. SHFM is a heterogeneous condition caused by multiple loci, including SHFM1 (chromosome region 7q21-q22), SHFM2 (Xq26), SHFM3 (10q24), SHFM4 (3q27), and SHFM5 (2q31). Mutations in TP63 at the SHFM4 locus are known to underlie both syndromic and non-syndromic forms SHFM, but the causes of most non-syndromic SHFM cases remain unknown. The recent identification of submicroscopic tandem chromosome duplications affecting the SHFM3 locus in seven families with non-syndromic SHFM has helped to further unravel the molecular basis of this malformation. In our ongoing studies of the SHFM3 locus in 44 additional cases of syndromic and non-syndromic SHFM, we have identified similar chromosome rearrangements in eight additional cases (18%), using pulsed-field gel electrophoresis (PFGE). We have also utilized real-time quantitative PCR (qPCR) to test for the duplications. Seven of the cases with rearrangements were non-syndromic. The current findings bring the total of SHFM3-associated cases with chromosome rearrangements to 15, which constitute 29% (15 of 51) of the cases screened to date. This includes 9 of 9 cases (100%) with known linkage to the SHFM3 locus, all of whom have non-syndromic SHFM, and 6 of 42 additional cases (14%), four of whom have non-syndromic SHFM. Thus, SHFM3 abnormalities underlie a substantial proportion of SHFM cases and appear to be a more frequent cause of non-syndromic SHFM than mutations in TP63.
authors.affiliation: Center for Molecular Studies, J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, 113 Gregor Mendel Circle, Greenwood, SC 29646, USA. deverman@ggc.org
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.forename: Chad T
authors.initials: CT
authors.lastname: Morgan
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.forename: Mary E
authors.initials: ME
authors.lastname: Laughridge
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Katie B
authors.initials: KB
authors.lastname: Clarkson
authors.forename: Randall
authors.initials: R
authors.lastname: Colby
authors.forename: Fiorella
authors.initials: F
authors.lastname: Gurrieri
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Roberson
authors.forename: Connie
authors.initials: C
authors.lastname: Schrander-Stumpel
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D016521:Electrophoresis, Gel, Pulsed-Field; D044783:F-Box Proteins / Q000235:genetics*; D005532:Foot Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D020440:Gene Duplication; D005787:Gene Frequency; D015321:Gene Rearrangement; D008040:Genetic Linkage; D006228:Hand Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D016133:Polymerase Chain Reaction / Q000379:methods; D013577:Syndrome
chemical_list: D044783:F-Box Proteins; C120449:FBXW4 protein, human