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

• Published in: Hernia : the journal of hernias and abdominal wall surgery Vol. 21; no. 1; pp. 95 - 100
• Main Authors: Mihailov, E., Nikopensius, T., Reigo, A., Nikkolo, C., Kals, M., Aruaas, K., Milani, L., Seepter, H., Metspalu, A.
• Format: Journal Article
• Language: English
• Published: Paris Springer Paris 01.02.2017; Springer Nature B.V
• Subjects: Abdominal Surgery; Adult; Aged; Aged, 80 and over; Connectin - genetics; Exome; Female; Genetic Linkage; Genome-Wide Association Study; Hernia, Inguinal - genetics; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation, Missense; Original; Original Article; Pedigree; Sequence Analysis, DNA; Genetics; Titin; Inguinal hernia; Whole-exome sequencing
• ISSN: 1265-4906; 1248-9204
• DOI: 10.1007/s10029-016-1491-9

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.