A Novel Nonsense Mutation in TRIP4 Gene Causes Severe Muscular Weakness with Respiratory Failure and Cardiomyopathy but without Skin, Joint, and/or Bone Abnormalities

Mutations in TRIP4 gene were recently associated with two different phenotypes consisting of prenatal spinal muscular atrophy, arthrogryposis multiplex congenita, and congenital bone fractures in five individuals and with severe muscle weakness, joint hyperlaxity, and skin abnormalities in four additional patients. TRIP4 gene encodes for a subunit of a transcription coactivator (activating signal cointegrator-1 complex) that was found to play a role in gene transactivation and lately also in late myogenesis.

We report on a now 15-month-old boy with severe congenital weakness, respiratory failure with ventilator dependency, and cardiomyopathy combined with normal cognition. Joint, skin, and/or bone abnormalities were not associated apart from moderate pectus excavatum und mild joint hypermobility. Muscle biopsy showed myopathic features with fiber size variation, focal endomysial fibrosis, and core-like lesions. At the age of 10 months, trio whole exome sequencing (trio-WES) was performed and revealed a homozygous nonsense mutation, c.1267C>G (p.Glu423*) in TRIP4 gene.

In contrast to previous reports, the symptoms in our patient were comparable to those in other, genetically heterogeneous congenital myopathies. Muscle biopsy confirmed myopathy and was not compatible with neurogenic or motoneuron disease, for example, spinal muscular atrophy. Whole-exome sequencing leads to confirmation of the underlying cause followed by more precise family counseling.