Highlights the utility of whole-genome sequencing and targeted gene review in diagnosing elusive congenital myopathies caused by digenic inheritance of TTN and SRPK3 variants.
The recently described skeletal myopathy from dual inheritance of TTN and SRPK3 genetic variants has demonstrated digenic inheritance constitutes an under-recognised burden amongst inherited neuromuscular disorders. Neuromuscular specialist input is essential to guide appropriate genetic testing for these elusive diagnoses. Here we present the first case since the initial discovery of this condition, of an adult age diagnosis of TTN/SRPK3 congenital myopathy. Our proband achieved an adult age diagnosis but had congenital symptoms previously diagnosed 'minimal change myopathy' from a childhood muscle biopsy. Their presentation was phenotypically consistent with the initial cohort. He exhibited congenital limb-girdle weakness/wasting, delayed motor developmental milestones, restrictive ventilatory deficit, Achilles tendon contractures and hyperCKaemia but no evidence of cardiomyopathy. Genetic diagnosis was achieved through research-based whole-genome sequencing and targeted SRPK3 gene review, after finding a TTN variant. Knowledge of these specific variants and inheritance pattern enabled diagnosis, where standard panel testing had missed it.
Spicer et al. (Tue,) studied this question.