Michelle M. Monasky
Emanuele Micaglio
Silvia Ignaccolo
Carlo Pappone- 1Arrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, Milan, Italy
- 2Vita-Salute San Raffaele University, Milan, Italy
Hypertrophic cardiomyopathy (HCM) is a condition in which the interventricular septum and the ventricles become enlarged, which could decrease the ability of the heart to effectively pump the blood, potentially leading to heart failure, arrhythmias, and sudden cardiac death (1, 2). The inheritance has been most often described as following an autosomal dominant pattern (3). However, other inherited causes of left ventricular hypertrophy may include Fabry disease (X-linked) and Friedreich's Ataxia (autosomal recessive) (3). Among recessive HCM, since at least 2017, ALPK3 mutations have been recognized as important causes (4).
HCM can be caused by variants in sarcomeric genes, non-sarcomeric protein-coding modifier genes, and regulatory non-coding RNA genes (5). Sarcomeric proteins are found in the thin or thick filaments or Z-disc. At least 30 genes can be responsible for HCM (6). Recent studies have used Whole Exome Sequencing to expand the HCM panel, resulting in possible new genes (7–9). Syndromic causes of HCM, such as VARS2 and FNIP1, are emerging genes for pediatric patients, identified by targeted clinical exome sequencing (10, 11). Such studies highlighted some new genotype-phenotype correlations and went beyond the simple task of genetics as “helpful for family planning.” In particular, VARS2 is additionally associated with pulmonary hypertension and hyperlactacidemia, while FNIP1 is additionally associated with B cell line immune deficiency and agammaglobulinemia.
We read with great interest a recently published report by Marston et al. (12) investigating the natural history of childhood-onset HCM, the impact of the genetic background, and comparing outcomes to adult-onset disease. HCM may present clinically during all phases of life, yet a higher risk of developing life-threatening ventricular arrhythmias or requiring a transplant or vascular assist device have been associated with earlier disease onset.
Marston et al. (12) performed genetic testing focusing on eight sarcomeric genes. Additionally, the genetic analysis of the genotyped cohort carried out by Marston et al. (12) still refers to HCM as a monogenic disease. Today, the traditional Mendelian fashion of inheritance has been replaced by the oligogenic inheritance model (13, 14), meaning that a mutational load can cause the HCM phenotype. Unfortunately, it is more difficult to provide constructive genetic counseling and help with family planning, understanding that HCM is an oligogenic disease with a complex multifactorial inheritance. Multiple pathogenic genetic variants may be distributed among the family members, which may result in an imperfect co-segregation with the phenotype (13). Modifier genes can play an important role in the expression of the phenotype (15). It is very important to see the family segregation analysis to understand the penetrance.
Moreover, in a nationwide study of Finnish patients (16), 49 variants of unknown significance (VUS) in 31 genes were detected in 20.4% of cases. Marston et al. (12) excluded patients with VUS. It would have been useful to know what VUS had been identified and which criteria had been employed to categorize them as such. VUS should not be interpreted as benign or not noteworthy, but rather as variants about which we do not yet have enough information to understand. Often, there is a wealth of knowledge to be gained from the study of VUS, and, in many cases, variants classified as VUS turn out to be pathogenic, affecting the recommendations made to a person/family (6). However, when it comes to clinical application, it is difficult to determine the combined effect of multiple “VUS,” considering that often only single patients or small pedigrees are examined, making segregation studies not feasible. Also, the ethnicity of the patients need to be considered when assessing the pathogenicity of rare VUS, as ethnicity is a factor in HCM (17). According to us, the HCM genetic panel should include only the established HCM genes for diagnostic purposes, especially in pre-symptomatic situations. We think that the OMIM (18) and Gene Reviews (19) websites can provide useful indications for clinicians. On the other hand, a too restrictive Next Generation Sequencing (NGS) panel might prevent the progress of scientific knowledge in the field of HCM. For this reason, we think that the Comprehensive Metabolic Panel, or an “enlarged” panel, encompassing both arrhythmia and metabolic genes, can be very important for research purposes. If both (diagnostic and research) NGS panels provided a negative result, exome studies would be a choice, with careful considerations about possible incidental results and variants of uncertain significance.
Regarding again the study by Marston et al. (12), it was unclear how “clinical significance” was defined when describing patients with “no clinically significant sarcomeric variants” who were classified as non-sarcomeric HCM. Furthermore, it would have been interesting to know what variants in non-sarcomeric proteins were excluded entirely from the study. Even minor genes identified might have shed more light on childhood-onset HCM, which is not well-characterized given the rarity of the phenotype—something which may correlate with the rarity of a particular genotype.
Finally, given the greater risk of developing life-threatening ventricular arrhythmias with childhood-onset HCM, it is important to consider the possibility of disease overlap in this subpopulation. Genes encoding channel and desmosomal proteins could be investigated. For example, the most commonly found mutated gene in Brugada syndrome is SCN5A, encoding for the sodium voltage-gated channel alpha subunit 5, and this gene's protein product is altered in HCM (20). Additionally, a transcriptional misregulation of SCN5A has been found in HCM patients even in the absence of SCN5A mutations (20). Moreover, heterozygous SCN5A variants with a putative negative effect on mRNA splicing have been found in a HCM case series (21). Thus, genes known to be altered in various channelopathies could be a subject of future research.
In conclusion, modifier genes and a possible oligogenic inheritance pattern should be considered when screening patients for HCM. Variants of unknown significance should be carefully evaluated for possible pathogenicity, and genes encoding channel and desmosomal proteins should be considered.
Author Contributions
MM and EM conceived, wrote, and revised the manuscript. SI provided useful comments. CP provided useful feedback and provided resources and funding. All authors contributed to the article and approved the submitted version.
Funding
This study was partially supported by Ricerca Corrente funding from Italian Ministry of Health to IRCCS Policlinico San Donato.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1. Jin H, Chemaly ER, Lee A, Kho C, Hadri L, Hajjar RJ, et al. Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy. FASEB J. (2010) 24:451–63. doi: 10.1096/fj.09-136622
2. American College of Cardiology Foundation/American Heart Association Task Force on Practice G American Association for Thoracic Surgery American Society of Echocardiography American Society of Nuclear Cardiology Heart Failure Society of America Heart Rhythm Society, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg. (2011) 142:1303–38. doi: 10.1016/j.jtcvs.2011.10.019
3. Basit H, Brito D, Sharma S. Hypertrophic Cardiomyopathy. Treasure Island, FL: StatPearls. (2021).
4. Caglayan AO, Sezer RG, Kaymakcalan H, Ulgen E, Yavuz T, Baranoski JF, et al. ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features. Cold Spring Harb Mol Case Stud. (2017) 3:a001859. doi: 10.1101/mcs.a001859
5. Baulina NM, Kiselev IS, Chumakova OS, Favorova OO. Hypertrophic cardiomyopathy as an oligogenic disease: transcriptomic arguments. Mol Biol (Mosk). (2020) 54:955–67. doi: 10.1134/S0026893320060023
6. Cirino AL, Ho C. Hypertrophic cardiomyopathy overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al. (editors). GeneReviews® Seattle, WA (1993-2021).
7. Hedberg-Oldfors C, Abramsson A, Osborn DPS, Danielsson O, Fazlinezhad A, Nilipour Y, et al. Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24. Hum Mol Genet. (2019) 28:1919–29. doi: 10.1093/hmg/ddz032
8. Huang S, Pu T, Wei W, Xu R, Wu Y. Exome sequencing identifies a FHOD3 p.S527del mutation in a Chinese family with hypertrophic cardiomyopathy. J Gene Med. (2020) 22:e3146. doi: 10.1002/jgm.3146
9. Ritter A, Berger JH, Deardorff M, Izumi K, Lin KY, Medne L, et al. Variants in NAA15 cause pediatric hypertrophic cardiomyopathy. Am J Med Genet A. (2021) 185:228–33. doi: 10.1002/ajmg.a.61928
10. Kusikova K, Feichtinger RG, Csillag B, Kalev OK, Weis S, Duba HC, et al. Case report and review of the literature: a new and a recurrent variant in the VARS2 gene are associated with isolated lethal hypertrophic cardiomyopathy, hyperlactatemia, and pulmonary hypertension in early infancy. Front Pediatr. (2021) 9:660076. doi: 10.3389/fped.2021.660076
11. Saettini F, Poli C, Vengoechea J, Bonanomi S, Orellana JC, Fazio G, et al. Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency. Blood. (2021) 137:493–9. doi: 10.1182/blood.2020006441
12. Marston NA, Han L, Olivotto I, Day SM, Ashley EA, Michels M, et al. Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy. Eur Heart J. (2021) 42:1988–96. doi: 10.1093/eurheartj/ehab148
13. Li L, Bainbridge MN, Tan Y, Willerson JT, Marian AJ. A potential oligogenic etiology of hypertrophic cardiomyopathy: a classic single-gene disorder. Circ Res. (2017) 120:1084–90. doi: 10.1161/CIRCRESAHA.116.310559
14. Castellana S, Mastroianno S, Palumbo P, Palumbo O, Biagini T, Leone MP, et al. Sudden death in mild hypertrophic cardiomyopathy with compound DSG2/DSC2/MYH6 mutations: revisiting phenotype after genetic assessment in a master runner athlete. J Electrocardiol. (2019) 53:95–9. doi: 10.1016/j.jelectrocard.2019.01.002
15. Daw EW, Chen SN, Czernuszewicz G, Lombardi R, Lu Y, Ma J, et al. Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. Hum Mol Genet. (2007) 16:2463–71. doi: 10.1093/hmg/ddm202
16. Jaaskelainen P, Vangipurapu J, Raivo J, Kuulasmaa T, Helio T, Aalto-Setala K, et al. Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy. ESC Heart Fail. (2019) 6:436–45. doi: 10.1002/ehf2.12420
17. Eberly LA, Day SM, Ashley EA, Jacoby DL, Jefferies JL, Colan SD, et al. Association of race with disease expression and clinical outcomes among patients with hypertrophic cardiomyopathy. JAMA Cardiol. (2020) 5:83–91. doi: 10.1001/jamacardio.2019.4638
18. Online Mendelian Inheritance in Man. (2021). Available online at: https://www.omim.org/ (accessed May 11, 2021).
19. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, et al. (editors). GeneReviews®. Seattle, WA (1993-2021).
20. Noyes AM, Zhou A, Gao G, Gu L, Day S, Andrew Wasserstrom J, et al. Abnormal sodium channel mRNA splicing in hypertrophic cardiomyopathy. Int J Cardiol. (2017) 249:282–6. doi: 10.1016/j.ijcard.2017.08.071
Keywords: hypertrophic cardiomyopathy, childhood-onset, genetic testing, monogenic, oligogenic, modifier genes, channel, desmosomal
Citation: Monasky MM, Micaglio E, Ignaccolo S and Pappone C (2021) Further Considerations in Childhood-Onset Hypertrophic Cardiomyopathy Genetic Testing. Front. Cardiovasc. Med. 8:698078. doi: 10.3389/fcvm.2021.698078
Received: 21 April 2021; Accepted: 31 May 2021;
Published: 21 June 2021.
Edited by:
Brenda Gerull, University Hospital Würzburg, GermanyReviewed by:
Anna Kostareva, Karolinska Institutet (KI), SwedenMichael Arad, Sheba Hospital, Israel
Juan Pablo Kaski, University College London, United Kingdom
Copyright © 2021 Monasky, Micaglio, Ignaccolo and Pappone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Carlo Pappone, Y2FybG8ucGFwcG9uZSYjeDAwMDQwO2FmLWFibGF0aW9uLm9yZw==
†These authors have contributed equally to this work