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Digging deeper into the intronic sequences of the SPINK1 gene
  1. Wen-Bin Zou1,2,3,4,
  2. Emmanuelle Masson2,5,
  3. Arnaud Boulling2,3,
  4. David N Cooper6,
  5. Zhao-Shen Li1,4,
  6. Zhuan Liao1,4,
  7. Claude Férec2,3,5,7,
  8. Jian-Min Chen2,3,7
  1. 1Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, Shanghai, China
  2. 2Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France
  3. 3Etablissement Français du Sang (EFS)—Bretagne, Brest, France
  4. 4Shanghai Institute of Pancreatic Diseases, Shanghai, China
  5. 5Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, Brest, France
  6. 6Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
  7. 7Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), Brest, France
  1. Correspondence to Dr Jian-Min Chen, INSERM U1078 and EFS—Bretagne, 46 rue Félix Le Dantec, Brest 29218, France; Jian-Min.Chen{at} Dr Claude Férec, INSERM U1078, 46 rue Félix Le Dantec, Brest 29218, France; claude.ferec{at} Dr Zhuan Liao, Department of Gastroenterology, Changhai Hospital, the Second Military Medical University, 168 Changhai Road, Shanghai 200433, China; liaozhuan{at}

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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 …

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