perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”10.21508/1027-4065-2021-66-3-12-19perinatology-1400Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWSФенотипическая вариабельность и варианты-модификаторы у детей с наследственными заболеваниями сердцаPhenotypic variability and modifier variants in children with hereditary heart diseaseshttps://orcid.org/0000-0002-6672-4242ЩербаковаН. В.ShcherbakovaN. V.

Щербакова Наталья Владимировна – зав. лабораторией молекулярной и биохимической диагностики, врач-кардиолог консультативно-диагностического отделения

125412 Москва, ул. Талдомская, д. 2 

Moscow

shcherbakova.n@pedklin.ruЖиронкинаА. Б.ZhironkinaA. B.

Жиронкина Анна Борисовна – студентка VI курса педиатрического факультета 

117997 Москва, ул. Островитянова, д. 1 

Moscow

https://orcid.org/0000-0001-8491-0228ВоиноваВ. Ю.VoinovaV. Yu.

Воинова Виктория Юрьевна – д.м.н., зам. дир. по трансляционной медицине, глав. науч. сотр. отдела клинической генетики

125412 Москва, ул. Талдомская, д. 2 

Moscow

https://orcid.org/0000-0002-1780-3518ИльдароваР. А.IldarovaR. A.

Ильдарова Рукижат Абдул-Гафуровна – к.м.н., ст. науч. сотр. отдела детской аритмологии и кардиологии 

125412 Москва, ул. Талдомская, д. 2 

Moscow

https://orcid.org/0000-0001-7115-0186ШкольниковаМ. А.ShkolnikovaM. A.

Школьникова Мария Александровна – д.м.н., проф., науч. рук.

125412 Москва, ул. Талдомская, д. 2 

Moscow

ОСП «Научно-исследовательский клинический институт педиатрии им. академика Ю.Е. Вельтищева» ФГАОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияVeltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical UniversityRussian FederationФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава РоссииРоссияPirogov Russian National Research Medical UniversityRussian Federation2021290620216631219Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20212021Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/1400

Несмотря на достигнутые в последние десятилетия успехи в области поиска причин моногенных заболеваний человека, существует огромный пробел в понимании молекулярных причин фенотипической вариабельности. В настоящее время становится очевидным, что зачастую патогенный генетический вариант действует не в одиночку, а вместе с другими генетическими и негенетическими факторами, которые могут уменьшать или, наоборот, усугублять тяжесть заболевания. Таким образом, чтобы по-настоящему понять болезнь, необходимо учитывать всю совокупность механизмов, приводящих к результирующему фенотипу. В этой работе мы рассматриваем текущее состояние дел в области идентификации генетических и негенетических модификаторов фенотипа редких моногенных сердечно-сосудистых заболеваний.

Despite the recent achievements in searching for the causes of monogenic human diseases, there is still a massive gap in understanding the molecular causes of phenotypic variability. At the moment, it is evident that the pathogenic genetic variant often acts together with the other genetic and non-genetic factors that can reduce or, on the contrary, aggravate the severity of the disease. Thus, to completely understand the disease, we shall consider the entire set of mechanisms leading to the resulting phenotype. This paper reviews the current state of the art in identifying genetic and non-genetic phenotype modifiers for rare monogenic cardiovascular diseases.

детинаследственные заболеваниякардиологияфенотипическая вариабельностьнеполная пенетрантностьварианты-модификаторышкалы генетического рискаchildrenhereditary diseasescardiologyphenotypic variabilityincomplete penetrancemodifier variantsgenetic risk scalesReferencesWright C.F., FitzPatrick D.R., Firth H.V. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018; 19: 253–268. DOI: 10.1038/nrg.2017.116Wright C.F., FitzPatrick D.R., Firth H.V. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018; 19: 253–268. DOI: 10.1038/nrg.2017.116Boycott K.M., Rath A., Chong J.X., Hartley T., Alkuraya F.S., Baynam G. et al. International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases. Am J Hum Genet. 2017; 100: 695–705. DOI: 10.1016/j.ajhg.2017.04.003Boycott K.M., Rath A., Chong J.X., Hartley T., Alkuraya F.S., Baynam G. et al. International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases. Am J Hum Genet. 2017; 100: 695–705. DOI: 10.1016/j.ajhg.2017.04.003Chong J.X., Buckingham K.J., Jhangiani S.N., Boehm C., Sobreira N., Smith J.D. et al. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. Am J Hum Genet. 2015; 97: 199–215. DOI: 10.1016/j.ajhg.2015.06.009Chong J.X., Buckingham K.J., Jhangiani S.N., Boehm C., Sobreira N., Smith J.D. et al. The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities. Am J Hum Genet. 2015; 97: 199–215. DOI: 10.1016/j.ajhg.2015.06.009Щербакова Н.В., Воинова В.Ю., Школьникова М.А. Генетика и сердце: основания для внедрения генетического тестирования в клиническую практику. Педиатрия. 2020; 99 (3): 8–15. [Shcherbakova N.V., Voinova V.Yu., Shkolnikova M.A. Genetics and the heart: The basis for introducing genetic testing into clinical practice. Pediatriya Zhurnal Im GN Speranskogo. 2020; 99: 8–15. DOI: 10.24110/0031-403X-2020-99-3-8-15 (in Russ.)]Щербакова Н.В., Воинова В.Ю., Школьникова М.А. Генетика и сердце: основания для внедрения генетического тестирования в клиническую практику. Педиатрия. 2020; 99 (3): 8–15. [Shcherbakova N.V., Voinova V.Yu., Shkolnikova M.A. Genetics and the heart: The basis for introducing genetic testing into clinical practice. Pediatriya Zhurnal Im GN Speranskogo. 2020; 99: 8–15. DOI: 10.24110/0031-403X-2020-99-3-8-15 (in Russ.)]Walsh R., Tadros R., Bezzina C.R. When genetic burden reaches threshold. Eur Heart J. 2020; 41: 3849–55. DOI: 10.1093/eurheartj/ehaa269Walsh R., Tadros R., Bezzina C.R. When genetic burden reaches threshold. Eur Heart J. 2020; 41: 3849–55. DOI: 10.1093/eurheartj/ehaa269Oon Y.Y., Koh K.T., Khaw C.S., Mohd Amin N.H., Ong T.K. Phenotypic variation among siblings with arrhythmogenic right ventricular cardiomyopathy. Med J Malaysia. 2019; 74: 328–330Oon Y.Y., Koh K.T., Khaw C.S., Mohd Amin N.H., Ong T.K. Phenotypic variation among siblings with arrhythmogenic right ventricular cardiomyopathy. Med J Malaysia. 2019; 74: 328–330Kose M.D., Canda E., Kağnıcı M., Uçar S.K., Onay H., Yıldırım Sozmen E. et al. Coexistence of Gaucher Disease and severe congenital neutropenia. Blood Cells Mol Dis. 2019; 76: 1–6. DOI: 10.1016/j.bcmd.2018.07.001Kose M.D., Canda E., Kağnıcı M., Uçar S.K., Onay H., Yıldırım Sozmen E. et al. Coexistence of Gaucher Disease and severe congenital neutropenia. Blood Cells Mol Dis. 2019; 76: 1–6. DOI: 10.1016/j.bcmd.2018.07.001Davidson B.A., Hassan S., Garcia E.J., Tayebi N., Sidransky E. Exploring genetic modifiers of Gaucher disease: The next horizon. Hum Mutat. 2018; 39: 1739–1751. DOI: 10.1002/humu.23611Davidson B.A., Hassan S., Garcia E.J., Tayebi N., Sidransky E. Exploring genetic modifiers of Gaucher disease: The next horizon. Hum Mutat. 2018; 39: 1739–1751. DOI: 10.1002/humu.23611Rudnik-Schöneborn S., Barisić N., Eggermann K., Ortiz Brüchle N., Grđan P., Zerres K. Distally pronounced infantile spinal muscular atrophy with severe axonal and demyelinating neuropathy associated with the S230L mutation of SMN1. Neuromuscul Disord. 2016; 26: 132–135. DOI: 10.1016/j.nmd.2015.12.003Rudnik-Schöneborn S., Barisić N., Eggermann K., Ortiz Brüchle N., Grđan P., Zerres K. Distally pronounced infantile spinal muscular atrophy with severe axonal and demyelinating neuropathy associated with the S230L mutation of SMN1. Neuromuscul Disord. 2016; 26: 132–135. DOI: 10.1016/j.nmd.2015.12.003Missaglia S., Tasca E., Angelini C., Moro L., Tavian D. Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings. Mol Genet Metab. 2015; 115: 110–117. DOI: 10.1016/j.ymgme.2015.05.001Missaglia S., Tasca E., Angelini C., Moro L., Tavian D. Novel missense mutations in PNPLA2 causing late onset and clinical heterogeneity of neutral lipid storage disease with myopathy in three siblings. Mol Genet Metab. 2015; 115: 110–117. DOI: 10.1016/j.ymgme.2015.05.001Posey J.E., O’Donnell-Luria A.H., Chong J.X., Harel T., Jhangiani S.N., Coban Akdemir Z.H. et al. Insights into genetics, human biology and disease gleaned from family based genomic studies. Genet Med. 2019; 21: 798–812. DOI: 10.1038/s41436-018-0408-7Posey J.E., O’Donnell-Luria A.H., Chong J.X., Harel T., Jhangiani S.N., Coban Akdemir Z.H. et al. Insights into genetics, human biology and disease gleaned from family based genomic studies. Genet Med. 2019; 21: 798–812. DOI: 10.1038/s41436-018-0408-7Zareba W., Moss A.J., Locati E.H., Lehmann M.H., Peterson D.R., Hall W.J. et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003; 42: 103–109. DOI: 10.1016/s0735-1097(03)00554-0Zareba W., Moss A.J., Locati E.H., Lehmann M.H., Peterson D.R., Hall W.J. et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003; 42: 103–109. DOI: 10.1016/s0735-1097(03)00554-0Austin E.D., Loyd J.E., Phillips J.A. 3rd. Genetics of pulmonary arterial hypertension. Semin Respir Crit Care Med 2009; 30: 386–398. DOI: 10.1055/s-0029-1233308Austin E.D., Loyd J.E., Phillips J.A. 3rd. Genetics of pulmonary arterial hypertension. Semin Respir Crit Care Med 2009; 30: 386–398. DOI: 10.1055/s-0029-1233308van der Werf C., Nederend I., Hofman N., van Geloven N., Ebink C., Frohn-Mulder I.M.E. et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol. 2012; 5: 748–756. DOI: 10.1161/CIRCEP.112.970517van der Werf C., Nederend I., Hofman N., van Geloven N., Ebink C., Frohn-Mulder I.M.E. et al. Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives. Circ Arrhythm Electrophysiol. 2012; 5: 748–756. DOI: 10.1161/CIRCEP.112.970517Schwartz P.J., Crotti L., George A.L.J. Modifier genes for sudden cardiac death. Eur Heart J. 2018; 39: 3925–3931. DOI: 10.1093/eurheartj/ehy502Schwartz P.J., Crotti L., George A.L.J. Modifier genes for sudden cardiac death. Eur Heart J. 2018; 39: 3925–3931. DOI: 10.1093/eurheartj/ehy502Turner H., Jackson L. Evidence for penetrance in patients without a family history of disease: a systematic review. Eur J Hum Genet. 2020; 28: 539–550. DOI: 10.1038/s41431-019-0556-5Turner H., Jackson L. Evidence for penetrance in patients without a family history of disease: a systematic review. Eur J Hum Genet. 2020; 28: 539–550. DOI: 10.1038/s41431-019-0556-5Tuke M.A., Ruth K.S., Wood A.R., Beaumont R.N., Tyrrell J., Jones S.E. et al. Mosaic Turner syndrome shows reduced penetrance in an adult population study. Genet Med. 2019; 21: 877–886. DOI: 10.1038/s41436-018-0271-6Tuke M.A., Ruth K.S., Wood A.R., Beaumont R.N., Tyrrell J., Jones S.E. et al. Mosaic Turner syndrome shows reduced penetrance in an adult population study. Genet Med. 2019; 21: 877–886. DOI: 10.1038/s41436-018-0271-6Nollet E.E., Westenbrink B.D., de Boer R.A., Kuster D.W.D., van der Velden J. Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity-Related Cardiac Defects as a Major Disease Modifier. J Am Heart Assoc. 2020; 9: e018641. DOI: 10.1161/JAHA.120.018641Nollet E.E., Westenbrink B.D., de Boer R.A., Kuster D.W.D., van der Velden J. Unraveling the Genotype-Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity-Related Cardiac Defects as a Major Disease Modifier. J Am Heart Assoc. 2020; 9: e018641. DOI: 10.1161/JAHA.120.018641Weeke P.E., Kellemann J.S., Jespersen C.B., Theilade J., Kanters J.K., Hansen M.S. et al. Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality. Eur Heart J. 2019; 40: 3110–3117. DOI: 10.1093/eurheartj/ehz228Weeke P.E., Kellemann J.S., Jespersen C.B., Theilade J., Kanters J.K., Hansen M.S. et al. Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality. Eur Heart J. 2019; 40: 3110–3117. DOI: 10.1093/eurheartj/ehz228Lorenzini M., Norrish G., Field E., Ochoa J.P., Cicerchia M., Akhtar M.M. et al. Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers. J Am Coll Cardiol. 2020; 76: 550–559. DOI: 10.1016/j.jacc.2020.06.011Lorenzini M., Norrish G., Field E., Ochoa J.P., Cicerchia M., Akhtar M.M. et al. Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers. J Am Coll Cardiol. 2020; 76: 550–559. DOI: 10.1016/j.jacc.2020.06.011Hey T.M., Rasmussen T.B., Madsen T., Aagaard M.M., Harbo M., Mølgaard H. et al. Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy. Circ Heart Fail. 2019; 12: e005700. DOI: 10.1161/CIRCHEARTFAILURE.118.005700Hey T.M., Rasmussen T.B., Madsen T., Aagaard M.M., Harbo M., Mølgaard H. et al. Pathogenic RBM20-Variants Are Associated With a Severe Disease Expression in Male Patients With Dilated Cardiomyopathy. Circ Heart Fail. 2019; 12: e005700. DOI: 10.1161/CIRCHEARTFAILURE.118.005700Van Rijsingen I.A.W., Nannenberg E.A., Arbustini E., Elliott P.M., Mogensen J., Hermans-van Ast J.F. et al. Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. Eur J Heart Fail. 2013; 15: 376–384. DOI: 10.1093/eurjhf/hfs191Van Rijsingen I.A.W., Nannenberg E.A., Arbustini E., Elliott P.M., Mogensen J., Hermans-van Ast J.F. et al. Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. Eur J Heart Fail. 2013; 15: 376–384. DOI: 10.1093/eurjhf/hfs191Page S.P., Kounas S., Syrris P., Christiansen M., Frank-Hansen R., Andersen P.S. et al. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet. 2012; 5: 156–166. DOI: 10.1161/CIRCGENETICS.111.960831Page S.P., Kounas S., Syrris P., Christiansen M., Frank-Hansen R., Andersen P.S. et al. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet. 2012; 5: 156–166. DOI: 10.1161/CIRCGENETICS.111.960831Coll M., Pérez-Serra A., Mates J., Del Olmo B., Puigmulé M., Fernandez-Falgueras A. et al. Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death. Biology (Basel). 2017; 7: 3. DOI: 10.3390/biology7010003Coll M., Pérez-Serra A., Mates J., Del Olmo B., Puigmulé M., Fernandez-Falgueras A. et al. Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death. Biology (Basel). 2017; 7: 3. DOI: 10.3390/biology7010003Gifford C.A., Ranade S.S., Samarakoon R., Salunga H.T., de Soysa T.Y., Huang Y. et al. Oligogenic inheritance of a human heart disease involving a genetic modifier. Science. 2019; 364: 865–870. DOI: 10.1126/science.aat5056Gifford C.A., Ranade S.S., Samarakoon R., Salunga H.T., de Soysa T.Y., Huang Y. et al. Oligogenic inheritance of a human heart disease involving a genetic modifier. Science. 2019; 364: 865–870. DOI: 10.1126/science.aat5056Kuzmin E., VanderSluis B., Wang W., Tan G., Deshpande R., Chen Y. et al. Systematic analysis of complex genetic interactions. Science. 2018; 360: eaao1729. DOI: 10.1126/science.aao1729Kuzmin E., VanderSluis B., Wang W., Tan G., Deshpande R., Chen Y. et al. Systematic analysis of complex genetic interactions. Science. 2018; 360: eaao1729. DOI: 10.1126/science.aao1729Lee I., Lehner B., Vavouri T., Shin J., Fraser A.G., Marcotte E.M. Predicting genetic modifier loci using functional gene networks. Genome Res. 2010; 20: 1143–1153. DOI: 10.1101/gr.102749.109Lee I., Lehner B., Vavouri T., Shin J., Fraser A.G., Marcotte E.M. Predicting genetic modifier loci using functional gene networks. Genome Res. 2010; 20: 1143–1153. DOI: 10.1101/gr.102749.109Uppu S., Krishna A., Gopalan R.P. A Review on Methods for Detecting SNP Interactions in High-Dimensional Genomic Data. IEEE/ACM Trans Comput Biol Bioinforma. 2018; 15: 599–612. DOI: 10.1109/TCBB.2016.2635125Uppu S., Krishna A., Gopalan R.P. A Review on Methods for Detecting SNP Interactions in High-Dimensional Genomic Data. IEEE/ACM Trans Comput Biol Bioinforma. 2018; 15: 599–612. DOI: 10.1109/TCBB.2016.2635125Madhukar N.S., Elemento O., Pandey G. Prediction of Genetic Interactions Using Machine Learning and Network Properties. Front Bioeng Biotechnol. 2015; 3: 172. DOI: 10.3389/fbioe.2015.00172Madhukar N.S., Elemento O., Pandey G. Prediction of Genetic Interactions Using Machine Learning and Network Properties. Front Bioeng Biotechnol. 2015; 3: 172. DOI: 10.3389/fbioe.2015.00172Veitia R.A., Caburet S., Birchler J.A. Mechanisms of Mendelian dominance. Clin Genet. 2018; 93: 419–428. DOI: 10.1111/cge.13107Veitia R.A., Caburet S., Birchler J.A. Mechanisms of Mendelian dominance. Clin Genet. 2018; 93: 419–428. DOI: 10.1111/cge.13107Aubart M., Gazal S., Arnaud P., Benarroch L., Gross M-S., Buratti J. et al. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability. Eur J Hum Genet. 2018; 26: 1759–1772. DOI: 10.1038/s41431-018-0164-9Aubart M., Gazal S., Arnaud P., Benarroch L., Gross M-S., Buratti J. et al. Association of modifiers and other genetic factors explain Marfan syndrome clinical variability. Eur J Hum Genet. 2018; 26: 1759–1772. DOI: 10.1038/s41431-018-0164-9Maroilley T., Tarailo-Graovac M. Uncovering Missing Heritability in Rare Diseases. Genes (Basel). 2019; 10: 275. DOI: 10.3390/genes10040275Maroilley T., Tarailo-Graovac M. Uncovering Missing Heritability in Rare Diseases. Genes (Basel). 2019; 10: 275. DOI: 10.3390/genes10040275Senol-Cosar O., Schmidt R.J., Qian E., Hoskinson D., Mason-Suares H., Funke B. et al. Considerations for clinical curation, classification, and reporting of low-penetrance and low effect size variants associated with disease risk. Genet Med. 2019; 21: 2765–2773. DOI: 10.1038/s41436-019-0560-8Senol-Cosar O., Schmidt R.J., Qian E., Hoskinson D., Mason-Suares H., Funke B. et al. Considerations for clinical curation, classification, and reporting of low-penetrance and low effect size variants associated with disease risk. Genet Med. 2019; 21: 2765–2773. DOI: 10.1038/s41436-019-0560-8Arking D.E., Pulit S.L., Crotti L., van der Harst P., Munroe P.B., Koopmann T.T. et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet. 2014; 46: 826–836. DOI: 10.1038/ng.3014Arking D.E., Pulit S.L., Crotti L., van der Harst P., Munroe P.B., Koopmann T.T. et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet. 2014; 46: 826–836. DOI: 10.1038/ng.3014Lahtinen A.M., Marjamaa A., Swan H., Kontula K. KCNE1 D85N polymorphism--a sex-specific modifier in type 1 long QT syndrome? BMC Med Genet. 2011; 12: 11. DOI: 10.1186/1471-2350-12-11Lahtinen A.M., Marjamaa A., Swan H., Kontula K. KCNE1 D85N polymorphism--a sex-specific modifier in type 1 long QT syndrome? BMC Med Genet. 2011; 12: 11. DOI: 10.1186/1471-2350-12-11Nishio Y., Makiyama T., Itoh H., Sakaguchi T., Ohno S., Gong Y-Z. et al. D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome. J Am Coll Cardiol. 2009; 54: 812–819. DOI: 10.1016/j.jacc.2009.06.005Nishio Y., Makiyama T., Itoh H., Sakaguchi T., Ohno S., Gong Y-Z. et al. D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome. J Am Coll Cardiol. 2009; 54: 812–819. DOI: 10.1016/j.jacc.2009.06.005Lane C.M., Giudicessi J.R., Ye D., Tester D.J., Rohatgi R.K., Bos J.M. et al. Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant. Hear Rhythm. 2018; 15: 1223–1230. DOI: 10.1016/j.hrthm.2018.03.038Lane C.M., Giudicessi J.R., Ye D., Tester D.J., Rohatgi R.K., Bos J.M. et al. Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant. Hear Rhythm. 2018; 15: 1223–1230. DOI: 10.1016/j.hrthm.2018.03.038Amin A.S., Giudicessi J.R., Tijsen A.J., Spanjaart A.M., Reckman Y.J., Klemens C.A. et al. Variants in the 3’ untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J. 2012; 33: 714–723. DOI: 10.1093/eurheartj/ehr473Amin A.S., Giudicessi J.R., Tijsen A.J., Spanjaart A.M., Reckman Y.J., Klemens C.A. et al. Variants in the 3’ untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J. 2012; 33: 714–723. DOI: 10.1093/eurheartj/ehr473Rahit K.M.T.H., Tarailo-Graovac M. Genetic Modifiers and Rare Mendelian Disease. Genes (Basel). 2020; 11: 239. DOI: 10.3390/genes11030239Rahit K.M.T.H., Tarailo-Graovac M. Genetic Modifiers and Rare Mendelian Disease. Genes (Basel). 2020; 11: 239. DOI: 10.3390/genes11030239Lappalainen T., Scott A.J., Brandt M., Hall I.M. Genomic Analysis in the Age of Human Genome Sequencing. Cell. 2019; 177: 70–84. DOI: 10.1016/j.cell.2019.02.032Lappalainen T., Scott A.J., Brandt M., Hall I.M. Genomic Analysis in the Age of Human Genome Sequencing. Cell. 2019; 177: 70–84. DOI: 10.1016/j.cell.2019.02.032Scalco R.S., Morrow J.M., Booth S., Chatfield S., Godfrey R., Quinlivan R. Misdiagnosis is an important factor for diagnostic delay in McArdle disease. Neuromuscul Disord. 2017; 27: 852–865. DOI: 10.1016/j.nmd.2017.04.013Scalco R.S., Morrow J.M., Booth S., Chatfield S., Godfrey R., Quinlivan R. Misdiagnosis is an important factor for diagnostic delay in McArdle disease. Neuromuscul Disord. 2017; 27: 852–865. DOI: 10.1016/j.nmd.2017.04.013Graf J., Schwitalla J.C., Albrecht P., Veltkamp R., Berlit P., Hartung H-P. et al. Misdiagnoses and delay of diagnoses in Moyamoya angiopathy-a large Caucasian case series. J Neurol. 2019; 266: 1153–1159. DOI: 10.1007/s00415-019-09245-9Graf J., Schwitalla J.C., Albrecht P., Veltkamp R., Berlit P., Hartung H-P. et al. Misdiagnoses and delay of diagnoses in Moyamoya angiopathy-a large Caucasian case series. J Neurol. 2019; 266: 1153–1159. DOI: 10.1007/s00415-019-09245-9Van Leeuwen J., Pons C., Boone C., Andrews B.J. Mechanisms of suppression: The wiring of genetic resilience. Bioessays. 2017; 39: 10.1002/bies.201700042. DOI: 10.1002/bies.201700042Van Leeuwen J., Pons C., Boone C., Andrews B.J. Mechanisms of suppression: The wiring of genetic resilience. Bioessays. 2017; 39: 10.1002/bies.201700042. DOI: 10.1002/bies.201700042Visscher P.M., Wray N.R., Zhang Q., Sklar P., McCarthy M.I., Brown M.A. et al. 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet. 2017; 101: 5–22. DOI: 10.1016/j.ajhg.2017.06.005Visscher P.M., Wray N.R., Zhang Q., Sklar P., McCarthy M.I., Brown M.A. et al. 10 Years of GWAS Discovery: Biology, Function, and Translation. Am J Hum Genet. 2017; 101: 5–22. DOI: 10.1016/j.ajhg.2017.06.005Kolder I.C.R.M., Tanck M.W.T., Postema P.G., Barc J., Sinner M.F., Zumhagen S. et al. Analysis for Genetic Modifiers of Disease Severity in Patients With Long-QT Syndrome Type 2. Circ Cardiovasc Genet. 2015; 8: 447–456. DOI: 10.1161/CIRCGENETICS.114.000785Kolder I.C.R.M., Tanck M.W.T., Postema P.G., Barc J., Sinner M.F., Zumhagen S. et al. Analysis for Genetic Modifiers of Disease Severity in Patients With Long-QT Syndrome Type 2. Circ Cardiovasc Genet. 2015; 8: 447–456. DOI: 10.1161/CIRCGENETICS.114.000785Lahrouchi N., Tadros R., Crotti L., Mizusawa Y., Postema P.G., Beekman L. et al. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation 2020; 142: 324– 338. DOI: 10.1161/CIRCULATIONAHA.120.045956Lahrouchi N., Tadros R., Crotti L., Mizusawa Y., Postema P.G., Beekman L. et al. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation 2020; 142: 324– 338. DOI: 10.1161/CIRCULATIONAHA.120.045956Esslinger U., Garnier S., Korniat A., Proust C., Kararigas G., Müller-Nurasyid M. et al. Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS One. 2017; 12: e0172995. DOI: 10.1371/journal.pone.0172995Esslinger U., Garnier S., Korniat A., Proust C., Kararigas G., Müller-Nurasyid M. et al. Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS One. 2017; 12: e0172995. DOI: 10.1371/journal.pone.0172995Aung N., Vargas J.D., Yang C., Cabrera C.P., Warren H.R., Fung K. et al. Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development. Circulation. 2019; 140: 1318–1330. DOI: 10.1161/CIRCULATIONAHA.119.041161Aung N., Vargas J.D., Yang C., Cabrera C.P., Warren H.R., Fung K. et al. Genome-Wide Analysis of Left Ventricular Image-Derived Phenotypes Identifies Fourteen Loci Associated With Cardiac Morphogenesis and Heart Failure Development. Circulation. 2019; 140: 1318–1330. DOI: 10.1161/CIRCULATIONAHA.119.041161Tadros R., Francis C., Xu X., Vermeer A.M.C., Harper A.R., Huurman R. et al. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nat Genet. 2021; 53: 128–134. DOI: 10.1038/s41588-020-00762-2Tadros R., Francis C., Xu X., Vermeer A.M.C., Harper A.R., Huurman R. et al. Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nat Genet. 2021; 53: 128–134. DOI: 10.1038/s41588-020-00762-2Wijeyeratne Y.D., Tanck M.W., Mizusawa Y., Batchvarov V., Barc J., Crotti L. et al. SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families. Circ Genomic Precis Med. 2020; 13: e002911. DOI: 10.1161/CIRCGEN.120.002911Wijeyeratne Y.D., Tanck M.W., Mizusawa Y., Batchvarov V., Barc J., Crotti L. et al. SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families. Circ Genomic Precis Med. 2020; 13: e002911. DOI: 10.1161/CIRCGEN.120.002911Khera A.V., Chaffin M., Aragam K.G., Haas M.E., Roselli C., Choi S.H. et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018; 50: 1219–1224. DOI: 10.1038/s41588-018-0183-zKhera A.V., Chaffin M., Aragam K.G., Haas M.E., Roselli C., Choi S.H. et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018; 50: 1219–1224. DOI: 10.1038/s41588-018-0183-z

The authors declare that there are no conflicts of interest present.