In true digenic inheritance (DI), pathogenic variants at two independent loci must be inherited together to result in disease manifestation. While thousands of monogenic diseases have been identified, only a very small number of DI diseases are known. We had originally proposed SRPK3, an X-linked serine/arginine protein kinase, as a candidate gene for centronuclear myopathy with cores. However, further interrogation of the SRPK3 pedigrees suggested that variants in this gene were not sufficient to cause disease. Through whole exome sequencing analysis, we identified heterozygous, predominantly truncating, variants in a second locus, the TTN gene, in all patients of the initial cohort. Thanks to an extensive international collaboration, we have now gathered a cohort of 36 families where pathogenic variants in both genes must be present for the myopathy to manifest. The double heterozygosity was not seen amongst 125,000 control individuals interrogated, nor is it due to an overall high frequency of TTN truncating variants, as these were significantly more common in the SRPK3 patients than in other genetically diagnosed recessive LGMD cohorts, strongly suggesting our findings are not due to chance. Furthermore, double mutant zebrafish reproduce our findings, where the srpk3-/-;ttn1+/- embryos show a severe muscle phenotype not observed in the srpk3-/- or ttn1+/- embryos alone. We therefore propose that this novel congenital myopathy is caused by digenic inheritance of pathogenic variants in SRPK3 and TTN.
Professor Volker Straub, on behalf of the SRPK3 Study Group. John Walton Muscular Dystrophy Research Centre, Institute of Translational and Clinical Research, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Professor Straub’s interest in muscle diseases is in translational research. The overall goal of the Research Centre in Newcastle is to accelerate the development and delivery of treatments for patients with neuromuscular diseases. His current research involves the application of muscle imaging, the use of zebrafish and mouse models, next generation sequencing and other –omics technologies for the characterization of genetic neuromuscular disorders. He was the co-founder of the EU FP6 funded network of excellence for genetic neuromuscular diseases, TREAT-NMD. He is the CI/ PI for a number of natural history and interventional trials in Duchenne muscular dystrophy, limb girdle muscular dystrophy, Pompe disease, spinal muscular atrophy and other NMDs.
He is currently the president of the World Muscle Society and an author on >350 peer-reviewed publications.