De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes

Hum Mol Genet. 2019 Sep 1;28(17):2937-2951. doi: 10.1093/hmg/ddz117.

Lina Liang ¹, Xia Li ¹, Sébastien Moutton ² ³ ⁴, Samantha A Schrier Vergano ⁵, Benjamin Cogné ⁶, Anne Saint-Martin ⁷, Anna C E Hurst ⁸, Yushuang Hu ¹, Olaf Bodamer ⁹ ¹⁰, Julien Thevenon ² ³ ⁴, Christina Y Hung ⁹, Bertrand Isidor ⁶, Bénédicte Gerard ¹¹, Adelaide Rega ¹², Sophie Nambot ² ³ ⁴, Daphné Lehalle ² ³ ⁴, Yannis Duffourd ² ³ ⁴, Christel Thauvin-Robinet ² ³ ⁴, Laurence Faivre ² ³ ⁴, Stéphane Bézieau ⁶, Leon S Dure ¹³, Daniel C Helbling ¹⁴, David Bick ¹⁴, Chengqi Xu ¹, Qiuyun Chen ¹⁵, Grazia M S Mancini ¹⁶, Antonio Vitobello ⁴, Qing Kenneth Wang ¹ ¹⁵ ¹⁷

Affiliations

1 Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P. R. China.
2 Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Dijon 21079, France.
3 Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital d'Enfants, Dijon 21079, France.
4 Inserm UMR 1231 GAD team, Genetics of Developmental Disorders, Université de Bourgogne Franche-Comté, Dijon 21070, France.
5 Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
6 Service de Génétique Médicale, CHU de Nantes, Nantes 44093, France.
7 Neuropédiatrie, Centre de Référence des Epilepsies Rares, Hôpitaux Universitaires de Strasbourg, Strasbourg 67098, France.
8 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
9 Division of Genetics and Genomics, Boston Children's Hospital/Harvard Medical School, Boston, MA 02115, USA.
10 The Broad Institute of Harvard and MIT, Boston, MA 02115, USA.
11 Institut de Génétique Médicale d'Alsace, Laboratoires de Diagnostic Génétique, Unité de Génétique Moléculaire, Nouvel Hôpital Civil, Strasbourg 67000, Franc.
12 Pediatric Radiologist, Département de Radiologie et Imagerie Diagnostique et Thérapeutique, CHU, Dijon 21079, France.
13 Department of Pediatrics and Neurology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
14 Clinical Services Laboratory, HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
15 Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
16 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam 3015, The Netherlands.
17 Department of Genetics and Genome Science, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.

PMID: 31152168 DOI: 10.1093/hmg/ddz117

Abstract

KCNMA1 encodes the large-conductance Ca2+- and voltage-activated K+ (BK) Potassium Channel α-subunit, and pathogenic gain-of-function variants in this gene have been associated with a dominant form of generalized epilepsy and paroxysmal dyskinesia. Here, we genetically and functionally characterize eight novel loss-of-function (LoF) variants of KCNMA1. Genome or exome sequencing and the participation in the international Matchmaker Exchange effort allowed for the identification of novel KCNMA1 variants. Patch clamping was used to assess functionality of mutant BK channels. The KCNMA1 variants p.(Ser351Tyr), p.(Gly356Arg), p.(Gly375Arg), p.(Asn449fs) and p.(Ile663Val) abolished the BK current, whereas p.(Cys413Tyr) and p.(Pro805Leu) reduced the BK current amplitude and shifted the activation curves toward positive potentials. The p.(Asp984Asn) variant reduced the current amplitude without affecting kinetics. A phenotypic analysis of the patients carrying the recurrent p.(Gly375Arg) de novo missense LoF variant revealed a novel syndromic neurodevelopmental disorder associated with severe developmental delay, visceral and cardiac malformations, connective tissue presentations with arterial involvement, bone dysplasia and characteristic dysmorphic features. Patients with other LoF variants presented with neurological and developmental symptoms including developmental delay, intellectual disability, ataxia, axial hypotonia, cerebral atrophy and speech delay/apraxia/dysarthria. Therefore, LoF KCNMA1 variants are associated with a new syndrome characterized by a broad spectrum of neurological phenotypes and developmental disorders. LoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.

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