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Sudden infant death as the most severe phenotype caused by genetic modulation in a family with atrial fibrillation.
Forensic Sci Int Genet 2019; 43:102159FS

Abstract

AIMS

To assess the functional impact of two combined KCNH2 variants involved in atrial fibrillation, syncope and sudden infant death syndrome.

METHODS AND RESULTS

Genetic testing of a 4-month old SIDS victim identified a rare missense heterozygous in KCNH2 variant (V483I) and a missense homozygous polymorphism (K897T) which is often described as a genetic modifier. Electrophysiological characterisation of heterologous HERG channels representing two different KCNH2 genotypes within the family, showed significant differences in both voltage and time dependence of activation and inactivation with a global gain-of-function effect of mutant versus wild type channels and, also, differences between both types of recombinant channels.

CONCLUSIONS

The rare variant V483I in combination with K897T produces a gain-of-function effect that represents a pathological substrate for atrial fibrillation, syncope and sudden infant death syndrome events in this family. Ascertaining the genotype-phenotype correlation of genetic variants is imperative for the correct assessment of genetic testing and counselling.

TRANSLATIONAL PERSPECTIVE

According to the current guidelines for clinical interpretation of sequence variants, functional studies are an essential tool for the ascertainment of variant pathogenicity. They are especially relevant in the context of sudden infant death syndrome and sudden cardiac death, where individuals cannot be clinically evaluated. The patch-clamp technique is a gold-standard for analysis of the biophysical mechanisms of ion channels.

Authors+Show Affiliations

Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Spain. Electronic address: montserrat.santori@usc.es.Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Spain.Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Spain.Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Spain; Department of Medical Sciences, Medical School, Universitat de Girona, Spain.Servizo de Cardioloxía, Hospital de Pontevedra, Servizo Galego de Saúde, Pontevedra, Spain.Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Servizo de Pediatría, Hospital Clínico Universitario de Santiago de Compostela, Spain.Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Spain; Department of Medical Sciences, Medical School, Universitat de Girona, Spain; Red de Enfermedades Cardiovasculares (CIBERCV), Spain.Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Spain; Fundación Pública Galega de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Santiago de Compostela, Spain.Department of Medical Sciences, Medical School, Universitat de Girona, Spain; Red de Enfermedades Cardiovasculares (CIBERCV), Spain.Department of Medical Sciences, Medical School, Universitat de Girona, Spain; Red de Enfermedades Cardiovasculares (CIBERCV), Spain.Xenética Cardiovascular, Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Universidade de Santiago de Compostela, Spain; Red de Enfermedades Cardiovasculares (CIBERCV), Spain.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31522018

Citation

Santori, Montserrat, et al. "Sudden Infant Death as the Most Severe Phenotype Caused By Genetic Modulation in a Family With Atrial Fibrillation." Forensic Science International. Genetics, vol. 43, 2019, p. 102159.
Santori M, Gil R, Blanco-Verea A, et al. Sudden infant death as the most severe phenotype caused by genetic modulation in a family with atrial fibrillation. Forensic Sci Int Genet. 2019;43:102159.
Santori, M., Gil, R., Blanco-Verea, A., Riuró, H., Díaz-Castro, Ó., López-Abel, B., ... Brion, M. (2019). Sudden infant death as the most severe phenotype caused by genetic modulation in a family with atrial fibrillation. Forensic Science International. Genetics, 43, p. 102159. doi:10.1016/j.fsigen.2019.102159.
Santori M, et al. Sudden Infant Death as the Most Severe Phenotype Caused By Genetic Modulation in a Family With Atrial Fibrillation. Forensic Sci Int Genet. 2019 Aug 31;43:102159. PubMed PMID: 31522018.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sudden infant death as the most severe phenotype caused by genetic modulation in a family with atrial fibrillation. AU - Santori,Montserrat, AU - Gil,Rocío, AU - Blanco-Verea,Alejandro, AU - Riuró,Helena, AU - Díaz-Castro,Óscar, AU - López-Abel,Bernardo, AU - Brugada,Ramón, AU - Carracedo,Ángel, AU - Pérez,Guillermo J, AU - Scornik,Fabiana S, AU - Brion,María, Y1 - 2019/08/31/ PY - 2019/07/04/received PY - 2019/08/26/revised PY - 2019/08/29/accepted PY - 2019/9/16/pubmed PY - 2019/9/16/medline PY - 2019/9/16/entrez KW - Atrial fibrillation KW - Cardiac ion channel KW - Electrophysiology KW - Genetic variant KW - HERG KW - KCNH2 KW - Molecular autopsy KW - Patch-clamp KW - Polymorphism KW - Sudden infant death syndrome SP - 102159 EP - 102159 JF - Forensic science international. Genetics JO - Forensic Sci Int Genet VL - 43 N2 - AIMS: To assess the functional impact of two combined KCNH2 variants involved in atrial fibrillation, syncope and sudden infant death syndrome. METHODS AND RESULTS: Genetic testing of a 4-month old SIDS victim identified a rare missense heterozygous in KCNH2 variant (V483I) and a missense homozygous polymorphism (K897T) which is often described as a genetic modifier. Electrophysiological characterisation of heterologous HERG channels representing two different KCNH2 genotypes within the family, showed significant differences in both voltage and time dependence of activation and inactivation with a global gain-of-function effect of mutant versus wild type channels and, also, differences between both types of recombinant channels. CONCLUSIONS: The rare variant V483I in combination with K897T produces a gain-of-function effect that represents a pathological substrate for atrial fibrillation, syncope and sudden infant death syndrome events in this family. Ascertaining the genotype-phenotype correlation of genetic variants is imperative for the correct assessment of genetic testing and counselling. TRANSLATIONAL PERSPECTIVE: According to the current guidelines for clinical interpretation of sequence variants, functional studies are an essential tool for the ascertainment of variant pathogenicity. They are especially relevant in the context of sudden infant death syndrome and sudden cardiac death, where individuals cannot be clinically evaluated. The patch-clamp technique is a gold-standard for analysis of the biophysical mechanisms of ion channels. SN - 1878-0326 UR - https://www.unboundmedicine.com/medline/citation/31522018/Sudden_infant_death_as_the_most_severe_phenotype_caused_by_genetic_modulation_in_a_family_with_atrial_fibrillation L2 - https://linkinghub.elsevier.com/retrieve/pii/S1872-4973(19)30312-6 DB - PRIME DP - Unbound Medicine ER -