title: Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.
abstract: Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, P<0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, P<0.001) and LQT3 (57%, P=0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, P<0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.
authors.affiliation: INSERM, UMR S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France.|Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: INSERM, UMR S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France.|Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Berthet
authors.affiliation: INSERM, UMR S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France.|Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.|AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service de Biochimie Métabolique, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Fressart
authors.affiliation: INSERM, UMR S1166, Paris, France.|Cardiology Department, AP-HP, Hôpital Bichat, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.affiliation: INSERM, UMR S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France.|Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Maugenre
authors.affiliation: Hôpital Cardiologique de Lille, CHRU, Service de cardiologie A, Lille, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Klug
authors.affiliation: AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mizusawa
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nynke
authors.initials: N
authors.lastname: Hofman
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Stallmeyer
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Zumhagen
authors.affiliation: Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.|Division of Cardiology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.affiliation: AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Münster, Germany.|Interdisciplinary Centre for Clinical Research (IZKF) of the University of Münster, Münster, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.affiliation: Biostatistics Unit, AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France.
authors.forename: Sophie
authors.identifier: 0000-0002-2866-4330
authors.initials: S
authors.lastname: Tezenas du Montcel
authors.affiliation: INSERM, UMR S1166, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S1166, Paris, France.|Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
mesh_terms: D000328:Adult; D000483:Alleles; D002648:Child; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D000072740:Paternal Inheritance; D010375:Pedigree
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human