Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

Ito Kaoru; Patel Parth N.; Gorham Joshua M.McDonough BarbaraDePalma Steven R.Adler Emily E.Lam LienMacRae Calum A.Mohiuddin Syed M.Fatkin DianeSeidman Christine E.Seidman J. G.

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Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

机译：Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

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Genetic variants that cause haploinsufficiency account for many autosomal dominant (AD) disorders. Gene-based diagnosis classifies variants that alter canonical splice signals as pathogenic, but due to imperfect understanding of RNA splice signals other variants that may create or eliminate splice sites are often clinically classified as variants of unknown significance (VUS). To improve recognition of pathogenic splice-altering variants in AD disorders, we used computational tools to prioritize VUS and developed a cell-based minigene splicing assay to confirm aberrant splicing. Using this two-step procedure we evaluated all rare variants in two AD cardiomyopathy genes, lamin A/C (LMNA) and myosin binding protein C (MYBPC3). We demonstrate that 13 LMNA and 35 MYBPC3 variants identified in cardiomyopathy patients alter RNA splicing, representing a 50 increase in the numbers of established damaging splice variants in these genes. Over half of these variants are annotated as VUS by clinical diagnostic laboratories. Familial analyses of one variant, a synonymous LMNA VUS, demonstrated segregation with cardiomyopathy affection status and altered cardiac LMNA splicing. Application of this strategy should improve diagnostic accuracy and variant classification in other haploinsufficient AD disorders.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2017年第29期|7689-7694|共6页
作者
Ito Kaoru; Patel Parth N.; Gorham Joshua M.McDonough BarbaraDePalma Steven R.Adler Emily E.Lam LienMacRae Calum A.Mohiuddin Syed M.Fatkin DianeSeidman Christine E.Seidman J. G.;
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作者单位

Harvard Med Sch, Dept Genet, Boston, MA 02115 USA;

Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA;

Creighton Univ, Med Ctr, Dept Internal Med, Omaha, NE 68131 USAUniv New South Wales, Fac Med, Kensington, NSW 2052, Australia;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
VUS; splicing; cardiomyopathy; LMNA; MYBPC3;

Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing

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