Whole-exome sequencing identifies a potential TTN mutation in a multiplex family with inguinal hernia.

PURPOSE: Inguinal hernia repair is one of the most common procedures in general surgery. Males are seven times more likely than females to develop a hernia and have a 27 % lifetime 'risk' of inguinal hernia repair. Several studies have demonstrated that a positive family history is an important risk factor for the development of primary inguinal hernia, which indicates that genetic factors may play important roles in the etiology of the disease. So far, the contribution of genetic factors and underlying mechanisms for inguinal hernia remain largely unknown. The aim of this study was to investigate a multiplex Estonian family with inguinal hernia across four generations. METHODS: The whole-exome sequencing was carried out in three affected family members and subsequent mutation screening using Sanger sequencing was performed in ten family members (six affected and four unaffected). RESULTS: Whole-exome sequencing in three affected family members revealed a heterozygous missense mutation c.88880A>C (p.Lys29627Thr; RefSeq NM_001256850.1) in the highly conserved myosin-binding A-band of the TTN gene. Sanger sequencing demonstrated that this mutation cosegregated with the disease in this family and was not present in ethnically matched control subjects. CONCLUSION: We report that missense variant in the A-band of TTN is the strongest candidate mutation for autosomal-dominant inguinal hernia with incomplete penetrance.

16p11.2 Locus modulates response to satiety before the onset of obesity.

BACKGROUND: The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown. OBJECTIVE: This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs. METHODS: We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia. RESULTS: Response to satiety is gene dosage-dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI. CONCLUSIONS: These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence.