Exome Sequencing Identifies a Dominant TNNT3 Mutation in a Large Family with Distal Arthrogryposis

Abstract

Distal arthrogryposis (DA) is a group of rare, clinically and genetically heterogeneous disorders primarily characterized by congenital contractures of the distal limb joints without a neuromuscular disease. Mutations in at least 8 different genes have been shown to cause DA. Here, we report a 4-generation Indian family with 18 affected members presenting variable features of camptodactyly, brachydactyly, syndactyly, decreased flexion palmar creases, ulnar deviation of the hands, sandal gaps and club feet. We undertook exome sequencing of 3 distantly related affected individuals. Bioinformatics filtering revealed a known pathogenic missense mutation c.188G>A (p.Arg63His) in TNNT3 in all 3 affected individuals that segregated with the phenotype. The affected individuals exhibit significant phenotypic variability. This study demonstrates the value of exome sequencing helping to define the causative variant in genetically heterogeneous disorders.

Keywords: Distal arthrogryposis; Sheldon-Hall syndrome; TNNT3.

Fig. 1

Pedigree of the family. The three individuals selected for exome sequencing are indicated by red arrows.

Fig. 2

Patient IV:21 has a triangular face (a) and mild cutaneous syndactyly (arrows) of F-2-4 (b). Feet are normal (c). Mild camptodactyly of the right middle finger, mild clinodactyly, and decreased flexion creases are also seen (d). Radiograph of the hips show bilateral dislocation of the hip joints (e).

Fig. 3

Patient IV:10 has proximally positioned thumbs, mild cutaneous syndactyly of F-2-5 (a), decreased palmar creases and tapering fingers (b). Feet had short big toes, wide sandal gaps and forefoot adduction (c). Radiographs of the patient's hands show contractures of thumbs at metacarpophalageal joints, partial cutaneous syndactyly (arrows) and clinodactyly (d), and radiographs of the feet show metatarsus varus (e).

Fig. 4

Patient IV:7 has a triangular face (a). The boy has surgical scars due to the correction of his club feet and small toes (b). Mild brachydactyly and mild cutaneous syndactyly with decreased palmar creases are shown (c, d). Radiographs of both feet (before surgery) show bilateral equinus and varus deformities (e, f).

Fig. 5

Clinical photographs of patient IV:3 show a triangular face (a) and surgical scars following correction of club feet and short toes (b). The girl's hands show mild brachydactyly and mild cutaneous syndactyly of F-2-5 (c, d). Ulnar deviation of the wrist and all fingers with camptodactyly and decreased flexion creases of the hands are also seen (d). Lateral radiographs of both feet (before surgery) revealed bilateral congenital vertical talus (e, f).

Fig. 6

Hands of patient II:3 reveal brachydactyly, camptodactyly and tapering fingers (a, b), with decreased palmar creases (b). Feet show brachydactyly and increased sandal gaps (c).

Fig. 7

Patient III:1 almost has normal hands and feet (a-c); however, she carries a mutation.

Fig. 8

Clinical photographs of patient III:8 show subtle brachydactyly in hands and feet (a-c).

Fig. 9

Patient III:16 has very mild brachydactyly and decreased palmar creases (a-c).

Fig. 10

Hands of patient IV:9 show brachydactyly, clinodactyly and tapering fingers with decreased palmar creases. Thumbs are short and proximally placed. Camptodactyly is more pronounced in the right little finger (a, b). Feet are normal (c).