Clinical and genetic characteristics of type 7 distal arthrogryposis caused by a pathogenic variant in the <i>MYH8</i> gene

Abstract

Distal arthrogryposis is a group of genetically heterogeneous congenital diseases characterized by non-progressive contractures predominantly distal joints of the upper and lower extremities. 11 genes have been identified as pathogenic variants causing the occurrence of autosomal dominant and autosomal recessive types of distal arthrogryposis. Almost all products of these genes are expressed in the structures of the neuromuscular system, which makes it possible to classify distal arthrogryposis as a neuromuscular disease. Type 7 distal arthrogryposis is a rare autosomal dominant disease characterized by two main symptoms: mandibular trismus and pseudocamptodactyly, a specific symptom of limited mobility of the interphalangeal joints during hand dorsiflexion with no restriction during palmar flexion. In all patients described in the literature from different populations with type 7 distal arthrogryposis, the same pathogenic variant c.2021G>A(p.Arg674Gln) was found in the MYH8 gene, the protein product of which is one of the myosin isoforms functioning in the embryonic period and providing the formation of muscle fiber structures.The aim of the work is to describe the clinical and genetic characteristics of the first family case of type 7 distal arthrogryposis in Russian patients. The patients underwent clinical examination and electromyography. Exome sequencing after DNA isolation from the proband’s blood according to the standard method was carried out on the NextSeq 500 platform (Illumina, USA) using the pairedend reading method (2 × 75 bp). Confirmation of the pathogenicity of the identified variants was carried out using automatic Sanger sequencing.As a result of molecular genetic analysis in a father and son with clinical manifestations of type 7 distal arthrogryposis, a heterozygous c.2021G>A variant in exon 18 of the MYH8 gene, which was previously described in all patients published in the literature, was detected, leading to the replacement of p.Arg674Gln(NM_002472.2) in a protein molecule. The examined patients did not reveal focal neurological symptoms, as well as minor developmental abnomalities, pathology of internal organs, ulnar deviations, equinovarus feet deformities, vertical orientation of the talus, contractures of the hip joints, which were found with varying frequency in previously described patients with variants in the MYH8 gene. Specific clinical signs of type 7 distal arthrogryposis, combined with the presence of a major nucleotide variant, make it possible to optimize the process of molecular genetic diagnosis of this type of hereditary arthrogryposis.