As a continuation to Blueprint Genetics recent collaborative study on genetics of dilated cardiomyopathy (Eur Heart J 2015), we were enthusiastic to further evaluate variation of titin gene in large reference populations. This is an important step towards a better understanding of the titin truncations in cardiomyopathies.
Earlier studies have shown that truncating titin (TTN) mutations, especially in A-band region, represent the most common cause of dilated cardiomyopathy (DCM). Clinical interpretation of these variants is known to be challenging, as these variants are also present in reference populations. Therefore, we carried out systematic analyses of TTN truncating variants (TTNtv) in publicly available reference populations, including, for the first time, data from Exome Aggregation Consortium (ExAC). The goal was to establish more accurate estimate of prevalence of different TTNtv to allow better clinical interpretation of these findings.
The conclusions presented in the publication are that A-band TTNtv are more rare in the general population than previously reported. Based on this analysis, one in 500 carries a truncation in TTN A-band suggesting the penetrance of these potentially harmful variants is still poorly understood, and some of these variants do not manifest as autosomal dominant DCM. This calls for caution when interpreting TTNtv in individuals and families with no history of DCM. Considering the size of TTN, expertise in DNA library preparation, high coverage NGS strategies, validated bioinformatics approach, accurate variant assessment strategy, and confirmatory sequencing are prerequisites for reliable evaluation of TTN in clinical settings. Importantly, meaningful interpretation of these variants require systematic approach based on experience both from research and clinics.
Read more about the methods used as well as the results in the article published in PLOS One on December 23rd 2015. Link