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Deep intronic mutations and human disease

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Next-generation sequencing has revolutionized clinical diagnostic testing. Yet, for a substantial proportion of patients, sequence information restricted to exons and exon–intron boundaries fails to identify the genetic cause of the disease. Here we review evidence from mRNA analysis and entire genomic sequencing indicating that pathogenic mutations can occur deep within the introns of over 75 disease-associated genes. Deleterious DNA variants located more than 100 base pairs away from exon–intron junctions most commonly lead to pseudo-exon inclusion due to activation of non-canonical splice sites or changes in splicing regulatory elements. Additionally, deep intronic mutations can disrupt transcription regulatory motifs and non-coding RNA genes. This review aims to highlight the importance of studying variation in deep intronic sequence as a cause of monogenic disorders as well as hereditary cancer syndromes.

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We thank Joana Tavares and Isabel Vaz for critical reading of the manuscript. This work was supported by Fundação para a Ciência e a Tecnologia (Grant PTDC/BEX-BCM/5899/2014 and fellowship SFRH/BD/90231/2012 to R.V.D).

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Correspondence to Maria Carmo-Fonseca.

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Vaz-Drago, R., Custódio, N. & Carmo-Fonseca, M. Deep intronic mutations and human disease. Hum Genet 136, 1093–1111 (2017).

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