Titinopathy in a Canadian family sharing the British founder haplotype.

Hereditary myopathy with early respiratory failure (HMERF, OMIM 603689) is an autosomal dominant myopathy, often characterised by respiratory muscle weakness early in the disease course. This condition shares many similarities with myofibrillar myopathy (MFM) and it has been suggested that HMERF be considered within this disease category1,2. It is caused by mutations in TTN, which encodes the giant sarcomeric protein titin. The hotspot for mutations causing this disorder appears to be in the 119th fibronectin 3 (FN3) domain in the titin A-band, with the p.C30071R mutation3,4 being most common (using Genebank#: AJ277892 as the reference sequence), although other mutations have recently been described1,2,5,6. A mutation in the kinase domain of TTN (p.R32450W) was associated with this condition7, but this variant is also designated as a low-frequency polymorphism (rs140319117) in the European population. Two studies have now revealed that TTN mutations are responsible for about 5% of cases of undiagnosed MFM1,5, and the disease is now demonstrated to be internationally distributed2,5,6, beyond the British/Finnish founder effect which was initially described3,4. To date, only a single family with this disease has been reported from Canada5. We report the second Canadian family with this disease, caused by the common p.C30071R mutation in TTN, and demonstrate that this patient shares a founder haplotype with previously reported families from the North East of England.