Split-hand/foot malformation - molecular cause and implications in genetic counseling

Abstract

Split-hand/foot malformation (SHFM) is a congenital limb defect affecting predominantly the central rays of the autopod and occurs either as an isolated trait or part of a multiple congenital anomaly syndrome. SHFM is usually sporadic, familial forms are uncommon. The condition is clinically and genetically heterogeneous and shows mostly autosomal dominant inheritance with variable expressivity and reduced penetrance. To date, seven chromosomal loci associated with isolated SHFM have been described, i.e., SHFM1 to 6 and SHFM/SHFLD. The autosomal dominant mode of inheritance is typical for SHFM1, SHFM3, SHFM4, SHFM5. Autosomal recessive and X-linked inheritance is very uncommon and have been noted only in a few families. Most of the known SHFM loci are associated with chromosomal rearrangements that involve small deletions or duplications of the human genome. In addition, three genes, i.e., TP63, WNT10B, and DLX5 are known to carry point mutations in patients affected by SHFM. In this review, we focus on the known molecular basis of isolated SHFM. We provide clinical and molecular information about each type of abnormality as well as discuss the underlying pathways and mechanism that contribute to their development. Recent progress in the understanding of SHFM pathogenesis currently allows for the identification of causative genetic changes in about 50 % of the patients affected by this condition. Therefore, we propose a diagnostic flow-chart helpful in the planning of molecular genetic tests aimed at identifying disease causing mutation. Finally, we address the issue of genetic counseling, which can be extremely difficult and challenging especially in sporadic SHFM cases.

Fig. 1

Schematic presentation of the different anatomical types of SHFM (a) classical cleft characterized by the aplasia of the central rays of the autopod; (b) monodactyly characterized by the aplasia of both central and preaxial rays of the autopod

Fig. 2

Limbs of the SHFM patients with different molecular origin of the defect (a) male proband with a classical cleft of the hands carrying a balanced chromosomal translocation t(7;12)(q21.2;q21.3) involving SHFM1 locus; (b, c) female proband carrying a typical 10q24 duplication of the SHFM3 locus showing ectrodactyly and preaxial polydactyly of the hands as well as ectrodactyly of the feet; (d) female proband with a classical cleft of the feet carrying a nonsense heterozygous point mutation c.G1974A(p.W658X) in the TP63 gene

Fig. 3

Diagnostic flow-chart useful in the planning of SHFM genetic diagnostics. Order of tests account for the relative frequencies of different SHFM causes as well as prices (in the case of karyotyping vs TP63 sequencing). CNV – copy number variation, AD – autosomal dominant, AR – autosomal recessive, WES – whole exome sequencing, WGS – whole genome sequencing