Sub-Exome Target Sequencing in a Family With Syndactyly Type IV Due to a Novel Partial Duplication of the LMBR1 Gene: First Case Report in Fujian Province of China

Abstract

Syndactyly is one of the most frequent hereditary limb malformations with clinical and genetical complexity. Autosomal dominant syndactyly type IV (SD4) is a rare form of syndactyly, caused by heterozygous mutations in a sonic hedgehog (SHH) regulatory element (ZRS) which resides in intron 5 of the LMBR1 gene on chromosome 7q36.3. SD4 is characterized by complete cutaneous syndactyly of the fingers, accompanied by cup-shaped hands due to flexion of the fingers and polydactyly. Here, for the first time, we reported a large Chinese family from Fujian province, manifesting cup-shaped hands consistent with SD4 and intrafamilial heterogeneity in clinical phenotype of tibial and fibulal shortening, triphalangeal thumb-polysyndactyly syndrome (TPTPS). We identified a novel duplication of ∼222 kb covering exons 2-17 of the LMBR1 gene in this family by sub-exome target sequencing. This case expands our new clinical understanding of SD4 phenotype and again confirms the feasibility to detect copy number variation by sub-exome target sequencing.

Keywords: LMBR1; sub-exome target sequencing; syndactyly type IV; tibial and fibulal shortening; triphalangeal thumb-polysyndactyly syndrome.

Figure 1

Pedigree of the family with syndactyly and limb features of patients. (A) Pedigree of the three-generation family with syndactyly. (B) Images of limb features in the family. (C) X- ray images of hands and feet PA in II-2 and the proband (II-6). a) Hands PA of II2, postoperation: An extra metacarpal and two phalanges are observed at the lateral part of the first metacarpal on the left and right hand, and the soft tissue of the extra metacarpal and that of thumb is fused. The two hands of the distal phalangeal flexion overlap. b) Feet PA of II2: Both feet are varus, and the tarsal bones are markedly shortened. Extra tarsal and phalanx bones are found on feet. d) Bilateral tibial and fibular PA and LAT of II2: The left side of the tibia is markedly shortened; there is a bony eminence in the local cortex. c) Hands PA of II-6: The middle and the distal phalanx overlap, and the soft tissue of the distal part of both hands is fused. e) Feet PA of II-6: A polydactylism is observed at the lateral part of the hallux on left foot, which contains two sections of short phalange with the formation of the joint between phalanges, proximal phalanx bones, and the first tarsal joint; the size and morphology of the first tarsal bone is normal. The distal phalanx of the fifth toe on left foot enlarges and deforms.

Figure 2

Location distribution of reported duplication variants of LMBR1 gene in patients. The genomic positions of two genes (SHH, LMBR1) were shown above the black horizontal line (representing 7q36.3). The distributions of 17 known duplication variations and the one new found in the study were listed below. Arabic numerals indicated the number of the reported cases in Supplementary Table 1. Blue bars represented our case. Red vertical line indicated the position of the ZRS in all different duplication regions.