Dennis Dooijes

Lynch syndrome (LS) is associated with a high risk for colorectal cancer (CRC) and extracolonic malignancies, such as endometrial carcinoma (EC). The risk is dependent of the affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers. The studypopulation consisted out of 67 proven LS families. Clinical information including mutation status and tumour diagnosis was collected. Cumulative risks were calculated and compared using Kaplan Meier survival analysis. MSH6 mutation carriers, both males and females had the lowest risk for developing CRC at age 70 years, 54% and 30% respectively and the age of onset was delayed by 3-5 years in males. With respect to endometrial carcinoma, female MSH6 mutation carriers had the highest risk at age 70 years (61%) compared to MLH1 (25%) and MSH2 (49%). Also, the age of EC onset was delayed by 5-10 years in comparison with MLH1 and MSH2. Although the cumulative lifetime risk of LS related cancer is similar, MLH1, MSH2 and MSH6 mutations seem to cause distinguishable cancer risk profiles. Female MSH6 mutation carriers have a lower CRC risk and a higher risk for developing endometrial carcinoma. As a consequence, surveillance colonoscopy starting at age 30 years instead of 20-25 years is more suitable. Also, prophylactic hysterectomy may be more indicated in female MSH6 mutation carriers compared to MLH1 and MSH2 mutation carriers.

With great interest I read the letter by Germans et al., as a reaction to our manuscript titled ‘cardiac β-myosin heavy chain defects in two families with noncompaction cardiomyopathy: linking non-compaction to hypertrophic, restrictive and dilated cardiomyopathies’, describing two large non-compaction cardiomyopathy (NCCM) families with β-myosin heavy chain (MYH7) mutations.¹

Cardiomyopathies are classified according to distinct morphological characteristics. They occur relatively frequent and are an important cause of mortality and morbidity. Isolated ventricular non-compaction or non-compaction cardiomyopathy (NCCM) is characterized by an excessively thickened endocardial layer with deep intertrabecular recesses, reminiscent of the myocardium during early embryogenesis. Autosomal-dominant as well as X-linked inheritance for NCCM has been described and several loci have been associated with the disease. Nevertheless, a major genetic cause for familial NCCM remains to be identified. We describe, in two separate autosomal-dominant NCCM families, the identification of mutations in the sarcomeric cardiac β-myosin heavy chain gene (MYH7), known to be associated with hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). These results confirm the genetic heterogeneity of NCCM and suggest that the molecular classification of cardiomyopathies includes an MYH7-associated spectrum of NCCM with HCM, RCM, and DCM.

Alagille syndrome (AGS), also known as arteriohepatic dysplasia, is an autosomal dominant disorder with a prevalence of approximately one in 70,000 live births. AGS is characterised by intrahepatic bile duct paucity and other developmental abnormalities affecting the heart, liver, eyes, vertebrae and the craniofacial region. Mutations in the JAG1 gene have been demonstrated to cause Alagille syndrome. JAG1 encodes a cellular membrane-bound ligand for the Notch receptor and is expressed during the normal development of tissues affected in Alagille syndrome. JAG1 mutations are detected in approximately 70% of AGS patients and are mostly protein truncating mutations. JAG1 mutations have also been described in patients that do not demonstrate the complete AGS phenotype, suggesting that the phenotypic spectrum of JAG1 mutations is broader than thus far assumed.