Fine mapping of the X‐linked split‐hand/split‐foot malformation (SHFM2) locus to a 5.1‐Mb region on Xq26.3 and analysis of candidate genes

Abstract

Split-hand/split-foot malformation (SHFM) is a genetically heterogeneous disorder, with five known loci, that causes a lack of median digital rays, syndactyly, and aplasia or hypoplasia of the phalanges, metacarpals, and metatarsals. In the only known SHFM2 family, affected males and homozygous females exhibit monodactyly or bidactyly of the hands and lobster-claw feet. This family (1) was revisited to include additional subjects and genealogical data. All 39 affected males and three females fully expressed the SHFM, while 13 carrier females examined exhibited partial expression of SHFM. We narrowed the previously linked 22-Mb genetic interval on Xq24-q26 (2), by analyzing additional family members and typing additional markers. The results define a 5.1-Mb region with a new centromeric boundary at DXS1114 and a telomeric boundary at DXS1192. We did not identify mutations in the exons and exon/intron boundaries of 19 candidate genes. These data suggest that the mutation may lie in a regulatory region of one of these candidate genes or in another gene within the SHFM2 region with unclear role in limb development.

Clinical, genetic, and molecular aspects of split‐hand/foot malformation: An update

“…Milder and asymmetric clinical manifestations were noted in some carrier females, while other carrier females were unaffected. However, sequencing of 19 candidate genes showed no mutations, thus raising the possibility of an undiscovered mutation in another gene or a regulatory element in this region [Faiyaz-Ul-Haque et al, 2005]. To date, the cause of SHFM at this locus has not been identified.…”

“…The SHFM2 locus was identified in a sevengeneration consanguineous Pakistani kindred segregating isolated SHFM in an X-linked fashion [Ahmad et al, 1987] and in which linkage to chromosome Xq26 was subsequently established [Faiyaz ul Haque et al, 1993]. The description of this family was later updated with additional clinical information and fine mapping data that narrowed the critical region to a 5.1 Mb interval containing approximately 70 genes [Faiyaz-Ul-Haque et al, 2005]. The phenotype was severe with involvement of all four limbs in the affected hemizygous males and two homozygous affected females.…”

Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation

“…2,3 SHFM is highly heterogeneous. Linkage or cytogenetic analysis of the nonsyndromic forms in humans has revealed six different loci for SHFM1-6 types: chromosome 7q21.2-q21.3 (SHFM1, MIM 183600), 4,5 Xq26 (SHFM2, MIM 313350), 6 10q24 (SHFM3, MIM 600095), [7][8][9][10] 3q27 (SHFM4, MIM 605289), 1 2q31 (SHFM5, MIM 606708) 11,12 and 12q13 (SHFM6, MIM 225300). 13,14 SHFM1, 3, 4 and 5 exhibit autosomal-dominant inheritance; SHFM6 exhibits autosomal-recessive transmission; SHFM2 exhibits X-linked inheritance pattern.…”

“…13,14 SHFM1, 3, 4 and 5 exhibit autosomal-dominant inheritance; SHFM6 exhibits autosomal-recessive transmission; SHFM2 exhibits X-linked inheritance pattern. 6,15,16 TP63 (also called P63, MIM603273) 17 encodes a homolog of the tumor suppressor p53 18 and is associated with both isolated and syndromic SHFM4. Intragenic homozygous mutation of WNT10b (MIM 601906), identified by linkage analysis and positional cloning in 2008, produces the autosomal-recessive SHFM6 phenotype.…”

Epidemiology, etiology, and genetic aspects of reduction deficiencies of the lower limb

“…The affected male will have all carrier daughters because he can transmit only a mutant X. His sons will be unaffected [18].…”