Discussion

Over 99% of pathogenic variants associated with hypertrophic cardiomyopathy are located within eight core sarcomeric genes: MYH7, MYBPC3, TNNT2, TPM1, MYL2, MYL3, TNNI3, and ACTC1. ^{Reference Walsh, Buchan and Wilk5} However, FHL1 has emerged as one of the three non-core sarcomeric genes with the strongest association with hypertrophic cardiomyopathy. ^{Reference Walsh, Buchan and Wilk5} Previously identified FHL1 variants include c.157-1G > A, c.134delA/K45Sfs, c.459C > A/C153X, and c.827G > C/C276S. ^{Reference Friedrich, Wilding and Reischmann3,Reference Giuca, Mitu and Popescu6} Beyond sarcomeric proteins, evidence implicating non-sarcomeric genes in HCM has been steadily expanding. For example, while ANK2 is more commonly associated with ankyrin-B syndrome and related arrhythmias, Lopes et al. identified ANK2 variants in 8.1% of HCM cases and reported that such variants were linked to greater maximum left ventricular wall thickness. ^{Reference Lopes, Syrris and Guttmann4} In our case, genetic testing revealed two novel heterozygous variants of uncertain significance: one in exon 7 of the FHL1 gene (c.755G > A), resulting in a missense mutation (p. Cys252Tyr), and another in exon 43 of the ANK2 gene (c.11454C > A), resulting in a missense mutation (p. Ser3818Arg). To our knowledge, these specific variants have not been previously reported. Documenting novel FHL1 variants is important, as a substantial proportion of phenotype-positive hypertrophic cardiomyopathy patients have no identifiable pathogenic mutation. ^{Reference Walsh, Buchan and Wilk5} This gap likely reflects limitations in current gene panels, which focus on well-established sarcomeric genes and may miss disease-causing variants in under-characterised or yet-to-be-identified genes. As more clinical and genomic data become available, some variants of unknown significance may be reassessed and reclassified. For example, the variant p.M659I (c.1977G > A) in the MYH7 gene, initially classified as a variant of unknown significance, was reclassified as pathogenic after cardiomyocytes with this mutation exhibited features consistent with hypertrophic cardiomyopathy. ^{Reference Pavlova, Shulgina, Zakian and Dementyeva7} These reclassifications can impact clinical decision-making and family screening.

Interestingly, the FHL1 gene is X-linked, and our patient was heterozygous for the identified variant. The strong paternal history of cardiomyopathy leads us to hypothesise that this variant was paternally inherited. However, complex family dynamics limited our ability to perform cascade genetic testing across generations, despite our strong recommendation. Nevertheless, in heterozygous females, disease expression may be influenced by X-inactivation, wherein one X chromosome is randomly silenced in each cell. We hypothesise that skewed lyonization favouring inactivation of the normal allele could have increased the proportion of cells expressing the variant allele, thereby potentially contributing to the hypertrophic cardiomyopathy phenotype in this case.

One of the primary goals in hypertrophic cardiomyopathy management is preventing sudden cardiac death. Risk stratification is essential to identify patients who may benefit from cardioverter-defibrillator placement for sudden cardiac death prophylaxis. According to the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guidelines, our patient had two conventional risk factors—positive family history of hypertrophic cardiomyopathy-related sudden cardiac death or arrest, and non-sustained ventricular tachycardia—qualifying her for a class IIa recommendation for cardioverter-defibrillator implantation. ^{Reference Writing Committee, Ommen and Ho8} However, many clinical practice guidelines rely heavily on adult-derived risk factors to predict sudden cardiac death risk in paediatric populations. Emerging evidence suggests that certain conventional risk markers in adults, such as a positive family history or LVOT obstruction, may not strongly correlate with sudden cardiac death risk in children. ^{Reference Miron, Lafreniere-Roula and Steve Fan9} Similarly, integrating genetic findings into risk assessment models remains an area of ongoing investigation. In paediatric patients, shared decision-making with families is crucial, given the higher rate of cardioverter-defibrillator-related complications and risk of overtreatment. The development of paediatric-specific risk models, such as HCM Risk-Kids (Norrish et al.) and PRIMaCY (Miron et al.), is a commendable step forward. ^{Reference Miron, Lafreniere-Roula and Steve Fan9,Reference Norrish, Ding and Field10} However, substantial discrepancies can exist between models. For example, our patient’s 5-year sudden cardiac death risk estimates varied considerably: 6% by HCM Risk-Kids, 21% by PRIMaCY without incorporating genetic data, and 29% when including a pathogenic genotype. Future research should focus on externally validating these models, comparing them directly, and evaluating the role of pathogenic or uncertain variants in sudden cardiac death prediction. ^{Reference Writing Committee, Ommen and Ho8}