Predicting functional effects of missense variants in voltage-gated sodium and calcium channels

doi:10.1126/scitranslmed.aay6848

. 2020 Aug 12;12(556):eaay6848.

doi: 10.1126/scitranslmed.aay6848.

Predicting functional effects of missense variants in voltage-gated sodium and calcium channels

Henrike O Heyne^{1

2

3

4}, David Baez-Nieto³, Sumaiya Iqbal^{5

2

3

6}, Duncan S Palmer^{5

2

3}, Andreas Brunklaus^{7

8}, Patrick May⁹; Epi25 Collaborative; Katrine M Johannesen^{10

11}, Stephan Lauxmann¹², Johannes R Lemke¹³, Rikke S Møller^{10

11}, Eduardo Pérez-Palma^{14

15}, Ute I Scholl^{16

17}, Steffen Syrbe¹⁸, Holger Lerche¹², Dennis Lal^{5

2

3

14

15

19}, Arthur J Campbell^{3

6}, Hao-Ran Wang³, Jen Pan³, Mark J Daly^{1

2

3

4}

Affiliations

¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. [email protected] [email protected].
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 5WR36M Helsinki, Finland.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Center for Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow G51 4TF, UK.
⁸ School of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
⁹ Luxembourg Centre for Systems Biomedicine, Belvaux, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg.
¹⁰ Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, 4293 Dianalund, Denmark.
¹¹ Department of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark.
¹² Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.
¹³ Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
¹⁴ Cologne Center for Genomics (CCG), University of Cologne, 50923, Germany.
¹⁵ Genomic Medicine Institute, Lemer Research Institute Cleveland Clinic, OH G92J47, USA.
¹⁶ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Nephrology and Medical Intensive Care and BIH Center for Regenerative Therapies, 10178 Berlin, Germany.
¹⁷ Berlin Institute of Health (BIH), 10178 Berlin, Germany.
¹⁸ Division of Pediatric Epileptology, Center for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
¹⁹ Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH G92J47, USA.

PMID: 32801145
DOI: 10.1126/scitranslmed.aay6848

Predicting functional effects of missense variants in voltage-gated sodium and calcium channels

Henrike O Heyne et al. Sci Transl Med. 2020.

. 2020 Aug 12;12(556):eaay6848.

doi: 10.1126/scitranslmed.aay6848.

Authors

Affiliations

¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. [email protected] [email protected].
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 5WR36M Helsinki, Finland.
⁵ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Center for Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Paediatric Neurosciences Research Group, Royal Hospital for Sick Children, Glasgow G51 4TF, UK.
⁸ School of Medicine, University of Glasgow, Glasgow G12 8QQ, UK.
⁹ Luxembourg Centre for Systems Biomedicine, Belvaux, University of Luxembourg, 4365 Esch-sur-Alzette, Luxembourg.
¹⁰ Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, 4293 Dianalund, Denmark.
¹¹ Department of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark.
¹² Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tuebingen, 72076 Tuebingen, Germany.
¹³ Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
¹⁴ Cologne Center for Genomics (CCG), University of Cologne, 50923, Germany.
¹⁵ Genomic Medicine Institute, Lemer Research Institute Cleveland Clinic, OH G92J47, USA.
¹⁶ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Nephrology and Medical Intensive Care and BIH Center for Regenerative Therapies, 10178 Berlin, Germany.
¹⁷ Berlin Institute of Health (BIH), 10178 Berlin, Germany.
¹⁸ Division of Pediatric Epileptology, Center for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
¹⁹ Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH G92J47, USA.

PMID: 32801145
DOI: 10.1126/scitranslmed.aay6848

Abstract

Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF (n = 518) and GOF (n = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCNxA/CACNA1x family genes.

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Predicting functional effects of missense variants in voltage-gated sodium and calcium channels

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Predicting functional effects of missense variants in voltage-gated sodium and calcium channels

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