A regional service for patients with inherited cardiac conditions was established in the west of Scotland (population 3 million) in 2007. Funding for molecular genetic analysis for abnormalities of the four common sarcomeric proteins is provided by the National Services Division of the Scottish government. We describe our experience with our first 100 families, 65 with hypertrophic cardiomyopathy (HCM) and 35 with definite familial dilated cardiomyopathy (DCM). In families with HCM a molecular genetic diagnosis was made in 41/65 (63%) with one family having two mutations. In those with a confirmed mutation, HCM was attributed to a mutation in myosin binding-protein C (MYBPc) in 28 (68%), to cardiac beta myosin heavy chain (MYH7) in 11 (27%) and troponin T in three (7%). In the 21 families with a positive family history of HCM but no history of sudden cardiac death, a molecular genetic diagnosis was made in 15 (71%, 11 MYBPc and four MYH7). In the 24 families with a positive family history of HCM and a history of sudden cardiac death a molecular genetic diagnosis was made in 21 (87%, 12 with MYBPc and five with MYH7, three with troponin T and one with double mutation in MYBPc and MYH7). In the 15 families with only a single index case (no antecedent case) a mutation was found in only four (two MYBPc, one MYH7 and one variant of uncertain significance). Clarification of results is awaited in the remaining four families. In contrast, in 35 families with definite familial DCM, mutation analysis has been abnormal in only four (11%), with two families with autosomal dominant mutation in lamin A/C and one MYH7 and one troponin I. In patients with HCM cascade screening has been performed in 44 clinically unaffected relatives, and 24 have been screened negative by molecular genetic analysis and discharged from follow-up.
Conclusion In patients with HCM, molecular genetic analysis of four common sarcomeric proteins detected a pathogenic mutation in 63% overall, with a high detection of 87% in those with a family history of sudden cardiac death but a low pick-up rate of only 11% in those with no antecent family history. Cascade screening in 44 unaffected family members has resulted in 24 being discharged from follow-up. The turnaround time for results from the index case is now down to approximately 3 months, making cascade screening cost effective, efficient and realistic in patients with HCM. This is not the case yet in DCM, and a reassessment of the genes to be screened is underway.