Up to date, ten mutations in the TRIP4 gene were identified including missense and nonsense variants, frameshift mutations or homozygous deletion of exons predicting loss of functional domains. Transmission was autosomal recessive in all cases, with no de novo mutations. Mutations were distributed along the entire length of the gene (table 1).
Table 1: Summary of the mutations currently identified.
Patients might present compound heterozygosity for a missense and a truncating mutation or two different truncating mutations. The pathophysiological mechanism involves transcriptional and post-transcriptional regulation defects that are critical for the establishment of the myogenesis process including the proliferation of myoblastic precursor cells and muscle growth. In 2 out of 10 cases nonsense mutations generated an alternative splice isoform. In these patients, a motoneuron phenotype was reported associated with respiratory insufficiency and bone defects.