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We read with great interest the recent paper by Beer and Sahin-Tóth1 addressing the ‘missing heritability’ observed in approximately 60% of German cases of chronic pancreatitis.2 These authors opined that ‘discovery studies tend to focus on exons and exon–intron boundaries and may thus miss many intronic variants’.1 This premise seems eminently reasonable, given the generally much larger size of intronic sequences as compared with the coding sequences of protein-coding genes. However, there is a trade-off here. On the one hand, larger sequence size means larger target size for mutation, and hence the greater the number of mutations that could be missed if intronic sequences were not screened. On the other hand, to be of pathological significance, an intronic mutation must either create a new functional splicing donor or acceptor site or alternatively impact a functional sequence motif responsible for regulating splicing (eg, an intronic splicing enhancer), which depends upon many additional factors other than just sequence length. As yet, it is unclear what the ratio of pathological intronic:exonic variants will turn out to be, although intronic mutations are …
W-BZ and EM contributed equally.
Contributors ZSL, ZL, CF and JMC designed and directed the study. WBZ and AB performed in vitro functional analysis. EM performed targeted sequencing. All authors interpreted the data, revised the text and approved the final manuscript. JMC wrote the manuscript with contributions from WBZ and EM.
Funding WBZ is a joint PhD student between Changhai Hospital and INSERM U1078 and received a 1-year scholarship from the China Scholarship Council (No. 201403170271). Support for this study came from the National Natural Science Foundation of China (Grant Nos 81470884, 81422010 (ZL)), the Shanghai Rising-Star Program (Grant No. 13QA1404600 (ZL)), the Conseil Régional de Bretagne, the Association des Pancréatites Chroniques Héréditaires, the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun and the Institut National de la Santé et de la Recherche Médicale (INSERM).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethical Committee of the University of Brest.
Provenance and peer review Not commissioned; internally peer reviewed.
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