A HOX Gene Mutation in a Family with Isolated Congenital Vertical Talus and Charcot-Marie-Tooth Disease

Abstract

Congenital vertical talus (CVT), also known as "rocker-bottom foot" deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched "claw foot" appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six HOX genes and detection of a single missense mutation, M319K (956T-->A), in the HOXD10 gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; theta =0), and it very likely accounts for both CVT and CMT in heterozygotes.

Skeletal Muscle Abnormalities and Genetic Factors Related to Vertical Talus

“…Despite the relative frequency of vertical talus [19] and the strong evidence for a genetic basis of the disorder [8,9,12,23,26], it is not known for most cases whether abnormalities are primarily in the muscle, bone, nerve, or vasculature. An exception to this uncertainty is in the case of distal arthrogryposis, a limb contracture syndrome in which vertical talus is a common feature [15].…”

“…Specific gene mutations have been identified in a few patients. A mutation in the HOXD10 gene encoding, a homeobox transcription factor gene expressed early in limb development, was associated with vertical talus in two families with autosomal dominant inheritance [8,26]. Variable hand and foot anomalies, including isolated vertical talus, were associated with GDF5 (cartilage-derived morphogenetic protein-1) gene mutations in several large families [9,24].…”

Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden

“…The SNP arrays have proven a very useful tool for identifying disease genes associated to a variety of disorders [21][22][23][24]. The method is highly advantageous, since it offers rapid highthroughput genotyping demanding only small amounts of DNA and the SNP resolution results in a limited need for subsequent time-consuming fine mapping.…”

De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5′ end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations

“…41,42 A missense mutation in HOXD10 segregates in a family with rocker-bottom feet and Charcot-MarieTooth disease. 43 Polyalanine coding repeat expansions in exon 1 of HOXD13 cause synpolydactyly. 44,45 Intragenic frameshift deletions, 46 missense mutations in exon 2 47,48 and an acceptor splice site mutation 49 have been associated with novel hand and/or foot malformations.…”