Early Childhood-Onset Hypertrophic Cardiomyopathy in a Family with an In-Frame MYH7 Deletion

HomeCirculation: Genomic and Precision MedicineVol. 15, No. 4Early Childhood-Onset Hypertrophic Cardiomyopathy in a Family With an In-Frame MYH7 Deletion Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEarly Childhood-Onset Hypertrophic Cardiomyopathy in a Family With an In-Frame MYH7 Deletion Ella Field, MSc, Luis R. Lopes, MD, PhD, Kathleen Dady, MA, MSc, CGC and Juan Pablo Kaski, MD(Res) Ella FieldElla Field https://orcid.org/0000-0002-0808-2763 Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital (E.F., K.D., J.P.K.). Institute of Cardiovascular Science, University College London (E.F., L.R.L., K.D., J.P.K.). Search for more papers by this author , Luis R. LopesLuis R. Lopes https://orcid.org/0000-0002-6408-4667 Institute of Cardiovascular Science, University College London (E.F., L.R.L., K.D., J.P.K.). Barts Heart Centre, St Bartholomew’s Hospital, London, United Kingdom (L.R.L.). Search for more papers by this author , Kathleen DadyKathleen Dady Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital (E.F., K.D., J.P.K.). Institute of Cardiovascular Science, University College London (E.F., L.R.L., K.D., J.P.K.). Search for more papers by this author and Juan Pablo KaskiJuan Pablo Kaski Correspondence to: Juan Pablo Kaski, MD(Res), Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom. E-mail: E-mail Address: [email protected] https://orcid.org/0000-0002-0014-9927 Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital (E.F., K.D., J.P.K.). Institute of Cardiovascular Science, University College London (E.F., L.R.L., K.D., J.P.K.). Search for more papers by this author Originally published6 Jul 2022https://doi.org/10.1161/CIRCGEN.121.003667Circulation: Genomic and Precision Medicine. 2022;15Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 6, 2022: Ahead of Print Sarcomeric protein gene mutations are the commonest cause of hypertrophic cardiomyopathy (HCM) in all age groups. Pathogenic variants in the β myosin heavy chain (MYH7) gene are identified in around 20% of HCM cases. Here, we describe a family (Figure [A]) with early onset, severe HCM, segregating with a rare in-frame deletion in MYH7. Informed consent was sought from the family before publication.Download figureDownload PowerPointFigure. Phenotype characteristics in a family carrying a rare in-frame deletion in MYH7 A, Family pedigree, indicating individuals meeting diagnostic criteria for hypertrophic cardiomyopathy; (B) current PLAx and PSAx of III-2, aged 12 years; (C) PLAx and PSAx of III-6, at 6 months of age; (D) current ECG of III-1, aged 14 years.The female proband (II-1) was diagnosed aged 14 years, after presenting with syncope and documented supraventricular tachycardia. Her echocardiogram showed asymmetrical septal hypertrophy with left ventricular (LV) hypertrabeculation. She was treated for atrial arrhythmia during adulthood and underwent insertion of a primary prevention implantable cardioverter defibrillator due to nonsustained ventricular tachycardia on ambulatory monitoring and extensive late gadolinium enhancement on cardiac magnetic resonance. Her phenotype became restrictive, and she developed biventricular systolic dysfunction before unexpectedly dying aged 48 years, with no evidence of arrhythmia on implantable cardioverter defibrillator download.Her sister (II-2) was diagnosed with apical HCM during family screening aged 10 years and later required treatment for supraventricular tachycardia. She also underwent primary prevention implantable cardioverter defibrillator implantation during adulthood. Echocardiogram of the proband’s son (III-2) revealed asymmetrical septal hypertrophy at 7 weeks of age, with maximal LV wall thickness of 8 mm (Z-score +5.9). At 6 years, maximal LV wall thickness was 9 mm, with mildly impaired LV diastolic function and no resting LV outflow tract obstruction. ECG consistently demonstrated tall voltages and inferolateral Q waves. By 11 years, maximal LV wall thickness had increased to 18 mm (Figure [B]). At this time, the patient reported exertional breathlessness, palpitations and presyncope. Cardiac magnetic resonance showed LV mass of 148 g/m2 (an increase from 88 g/m2 2 years prior) and patchy late gadolinium enhancement in the intraventricular septum. He was considered at intermediate-to-high risk of ventricular arrhythmia (HCM-Risk Kids1 5-year estimated risk of 6.46%) and therefore underwent implantation of a primary prevention implantable cardioverter defibrillator. Antenatal echocardiography in the proband’s nephew (III-6) detected hyperechogenic foci without evidence of hypertrophy. He was diagnosed with HCM aged 4 months, with maximal LV wall thickness of 10 mm (Z-score +6.4; Figure [C]). This increased to 12 mm by his most recent review (aged 6 years), with hypertrabeculation of the apex and LV outflow tract obstruction. There has been no evidence of ventricular arrhythmia on ambulatory monitoring, and he remains asymptomatic.Following appropriate counselling, genetic testing was performed on a 21-gene HCM panel in III-6 aged 18 months and a likely pathogenic in-frame deletion in MYH7 (c.2791_2793delGAG; p.Glu931del) was detected. The variant is located in exon 23, corresponding to the neck region of the MYH7 protein, where disease-causing variants are frequently identified.2Cascade genetic testing identified the variant in all other diagnosed family members (II-1, II-2, and III-2). In addition, III-1 was found to carry the familial variant; although this 14-year-old individual does not meet diagnostic criteria for HCM, his ECG has shown voltage criteria for biventricular hypertrophy and pathological Q waves inferolaterally since early childhood (Figure [D]), with apical trabeculation on echocardiogram. Four family members (I-2, III-3, III-4, and III-5) with normal cardiac test results, including the proband’s mother, were found not to be carriers of the variant and were discharged from follow-up. The proband’s father (I-1) died of noncardiac causes before genetic testing was possible but had normal clinical investigations; the possibility of germline mosaicism can therefore not be excluded.The identified MYH7 variant was not previously described in control population databases but had been reported in individual HCM probands. Both III-2 and III-6 were reported elsewhere in the literature as members of a cohort previously described by Norrish et al.3 The variant was reported segregating with disease in one other family with severe HCM.4As observed across the genome, the majority of mutations identified in MYH7 HCM are missense,2 with other mutation mechanisms detected less frequently. Although in-frame deletions are rarely identified in MYH7 HCM, the phenotypes observed in this family suggest that such variants have potential to cause severe and early onset disease, with diagnosis made at initial cardiac screening in 3 individuals, in 2 of these during infancy. As the nucleotide deletion is not predicted to cause a frameshift/truncated protein, the functional consequences are likely similar to missense variants (ie, not through haploinsufficiency), but further mechanistic work is needed to confirm this.The in-frame MYH7 variant segregates with features of disease in 5 members of this family and is associated with ECG abnormalities and development of LV hypertrophy from early childhood. Such early disease penetrance as described here was not reported in previous descriptions of this variant. Application of MYH7-modified American College of Medical Genetics/Association for Molecular Pathology criteria supports the continued classification of this variant as likely pathogenic.5 While functional data relating to the variant are not currently available, this mechanistic insight might contribute toward its future reclassification. Our findings highlight the importance of clinical and genetic cascade screening for HCM in all age groups and provide further evidence for severe phenotypic expression of atypical mutation mechanisms.Article InformationSources of FundingE. Field and J.P. Kaski are supported by Max’s Foundation and Great Ormond Street Hospital Children’s Charity. J.P. Kaski (MR/T024062/1) and L.R. Lopes (MR/T005181/1) are supported by Medical Research Council Clinical Academic Research Partnership awards. This work is (partly) funded by the National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre.Disclosures None.FootnotesCorrespondence to: Juan Pablo Kaski, MD(Res), Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom. E-mail: j.[email protected]ac.ukReferences1. Norrish G, Ding T, Field E, Ziólkowska L, Olivotto I, Limongelli G, Anastasakis A, Weintraub R, Biagini E, Ragni L, et al. Development of a novel risk prediction model for sudden cardiac death in childhood hypertrophic cardiomyopathy (HCM Risk-Kids).JAMA Cardiol. 2019; 4:918–927. doi: 10.1001/jamacardio.2019.2861CrossrefMedlineGoogle Scholar2. Walsh R, Rutland C, Thomas R, Loughna S. Cardiomyopathy: a systematic review of disease-causing mutations in myosin heavy chain 7 and their phenotypic manifestations.Cardiology. 2010; 115:49–60. doi: 10.1159/000252808CrossrefMedlineGoogle Scholar3. Norrish G, Jager J, Field E, Quinn E, Fell H, Lord E, Cicerchia MN, Ochoa JP, Cervi E, Elliott PM, et al. Yield of clinical screening for hypertrophic cardiomyopathy in child first-degree relatives.Circulation. 2019; 140:184–192. doi: 10.1161/CIRCULATIONAHA.118.038846LinkGoogle Scholar4. Tesson F, Richard P, Charron P, Mathieu B, Cruaud C, Carrier L, Dubourg O, Lautié N, Desnos M, Millaire A, et al. Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy.Hum Mutat. 1998; 12:385–392. doi: 10.1002/(SICI)1098-1004(1998)12:6<385::AID-HUMU4>3.0.CO;2-ECrossrefMedlineGoogle Scholar5. Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, et al. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by clingen’s inherited cardiomyopathy expert panel.Genet Med. 2018; 20:351–359. doi: 10.1038/gim.2017.218CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails August 2022Vol 15, Issue 4 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.121.003667PMID: 35862010 Originally publishedJuly 6, 2022 Keywordsmutationhypertrophyprimary preventionphenotypeinformed consentPDF download Advertisement SubjectsCardiomyopathyGeneticsHypertrophy