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Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

Patel, Kashyap A.; Kettunen, Jarno; Laakso, Markku; Stančáková, Alena; Laver, Thomas W.; Colclough, Kevin; Johnson, Matthew B.; Abramowicz, Marc; Groop, Leif LU and Miettinen, Païvi J., et al. (2017) In Nature Communications 8(1).
Abstract

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10-4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10-5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10-6) replication cohorts. RFX6... (More)

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10-4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10-5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10-6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

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Nature Communications
volume
8
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85031277419
  • wos:000412860000013
ISSN
2041-1723
DOI
10.1038/s41467-017-00895-9
language
English
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yes
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ec35b6f7-d15f-4166-bb1e-23bd49acbfa3
date added to LUP
2017-10-26 07:23:45
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2018-01-16 13:24:10
@article{ec35b6f7-d15f-4166-bb1e-23bd49acbfa3,
  abstract     = {<p>Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10<sup>-4</sup>). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10<sup>-5</sup>) and Finnish (n = 80, odds ratio = 22, P = 1 × 10<sup>-6</sup>) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.</p>},
  articleno    = {888},
  author       = {Patel, Kashyap A. and Kettunen, Jarno and Laakso, Markku and Stančáková, Alena and Laver, Thomas W. and Colclough, Kevin and Johnson, Matthew B. and Abramowicz, Marc and Groop, Leif and Miettinen, Païvi J. and Shepherd, Maggie H. and Flanagan, Sarah E and Ellard, Sian and Inagaki, Nobuya and Hattersley, Andrew T. and Tuomi, Tiinamaija and Cnop, Miriam and Weedon, Michael N.},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance},
  url          = {http://dx.doi.org/10.1038/s41467-017-00895-9},
  volume       = {8},
  year         = {2017},
}