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.

Absent expression of the osteoblast-specific maternally imprinted genes,DLX5andDLX6,causes split hand/split foot malformation type I

“…Then we sought for pathogenic mutations in the 26 candidate genes in the 9 SHFM loci, including BHLHA9, BTRC, CHD3, DACTYLIN, DLX1, DLX2, DLX5, DLX6, EVX2, EPS15L1, FGF8, FGF13, HOXD2, HOXD5, HOXD6, HOXD7, HOXD9, HOXD10, HOXD11, HOXD12, HOXD13, LBX1, PBXW4, POLL, TP63 and WNT10B. 3 13…”

Lady with ‘lobster claw’ feet

“…Seven different chromosomal loci and point mutations in three signalling pathway genes have been identified, these being TP63, WNT10B and DLX5 4. Three cases of SHFM involving consanguineous families were due to mutations in the WNT10B gene 5.…”

Split Hand/Foot Malformation Associated with 7q21.3 Microdeletion: A Case Report

“…bilateral SHSF submucous cleft palate, deafness, ID, microcephaly, abnormal ears Scherer et al, 1994b 46,XYdel(7)(q21.12;q21.3) bilateral SHSF micrognathia, low-set ears Scherer et al, 1994b 46,XY,inv(7)(p22q21.3) bilateral SHSF NA Cobben et al, 1995 46,XY,inv(1)(q21q32),t(4;7)(q31.1;q21.3), inv(11) (p15.1q23) bilateral SHSF severe ID, microcephaly, triangular face, downward slanting palpebral fissures, small ears, prominent lower jaw with prognathism Ignatius et al, 1996 46,XX,der (7) Sowińska-Seidler et al, 2014]. The proband was also found to exhibit a larger deletion involving the bands 7q21.11q21.2, which localizes genes encoding the class-3 semaphorins SEMA3A, SEMA3D and SEMA3E.…”

“…Around 40% of individuals presenting with SHFM have associated non-limb congenital anomalies that include intellectual disability (ID), cleft palate and ectodermal dysplasia. The disorder is genetically heterogeneous involving several loci including 7q21.3, Xq26, 10q24, 3q27, 2q31, and 12q13 [Gurrieri and Everman, 2013;Sowińska-Seidler et al, 2014].…”