G+/P- individuals were recruited from the relatives of patients with HCM managed at a tertiary cardiovascular center from 2008 to 2025. Informed consent was obtained from all participants, permitting the use of anonymized data for research purposes. The study protocol adhered to the ethical guidelines of the Declaration of Helsinki (2000, Fifth revision) and was approved by the institutional ethical committee on March 22, 2023, No. EK 323/23.

Each participant underwent a comprehensive screening protocol for HCM, including medical history, physical examination, electrocardiography (ECG), and transthoracic echocardiography (TTE). Follow-up visits were scheduled every 1 to 3 years, depending on the age at which the affected relative was diagnosed and the participant’s preference.

Medical history was obtained from all individuals, including common cardiovascular risk factors such as arterial hypertension, diabetes mellitus, and coronary syndromes. Clinical examination included measurements of height, weight, blood pressure, and resting heart rate, followed by a cardiovascular assessment focused on signs of heart failure and/or arrhythmias.

An ECG was considered normal if no deviations from physiological values were observed; any abnormalities resulted in classification as an abnormal ECG. To assess LVH, the voltage of the QRS (Q, R and S waves of the electrocardiogram) complex was measured in leads aVL, V1 or V2, V3, and V5 or V6. The Sokolow–Lyon index was calculated as the sum of the depth of the S wave in V1 or V2 (whichever was greater) and the height of the R wave in V5 or V6 (whichever was greater). The Sokolow–Lyon index was considered positive for LVH if exceeding 34 millimetres (mm). The Cornell voltage criterion was calculated as the sum of the R-wave amplitude in lead aVL and the S-wave amplitude in lead V3. The Cornell criterion was considered positive for LVH when exceeding 20 mm in women and 28 mm in men.

A comprehensive TTE protocol was performed and evaluated by physicians experienced in the management of HCM. Measurements of all cardiac chamber dimensions were obtained, including assessment of left ventricular wall thickness. The left ventricular end-diastolic diameter (LVEDD) was measured in the parasternal long-axis (PLAX) view at end-diastole. Left atrial diameter was measured in the PLAX view during systole. Maximum left ventricular wall thickness (MLVWT) and interventricular septal (IVS) thickness were measured during diastole in both PLAX and parasternal short-axis views at multiple levels to ensure accurate assessment. Left ventricular ejection fraction (LVEF) was assessed by visual estimation by experienced physicians, with an estimated accuracy of 5%. All cardiac valves were evaluated morphologically and functionally to exclude significant valvular disease. The presence of left ventricular outflow tract obstruction (LVOTO) at rest and provoked (using Valsalva maneuver) was assessed visually in PLAX, apical five-chamber, and three-chamber views, and, when present, quantified using Doppler measurements in apical views. Significant LVOTO was defined as a maximum gradient >30 mm Hg obtained during rest or provoked. Coarctation of the aorta was excluded using the suprasternal view by visual assessment of the aortic arch and Doppler interrogation to exclude a significant pressure gradient in the descending aorta. Participants were classified as phenotype-negative (P-) if MLVWT was <13 mm. During follow-up, HCM was diagnosed when MLVWT ≥13 mm was observed on TTE, in the absence of uncontrolled arterial hypertension or other hemodynamic contributors, such as aortic stenosis or coarctation.

Targeted genetic testing was offered to relatives of genotype-positive (G+) patients with HCM. HCM patients, serving as probands, underwent targeted next-generation sequencing using a custom-designed candidate gene panel including sarcomeric and selected nonsarcomeric genes on the MiSeq platform (Illumina, USA). Molecular genetic testing of relatives of G + probands carrying P or LP variants was performed by targeted Sanger sequencing. Variant interpretation was performed by experienced clinical geneticists, and classifications were periodically re-evaluated in accordance with updates in public databases and emerging literature. Classification was based on integration of multiple lines of evidence, including population allele frequencies (gnomAD), computational prediction tools, published functional studies, previously reported pathogenic variants in public databases (ClinVar, HGMD), and segregation data when available. For sarcomeric genes associated with HCM, gene- and disease-specific ACMG/AMP modifications proposed by the ClinGen Cardiomyopathy Expert Panel were applied where applicable. ^, Non-Finnish European population allele frequencies from gnomAD were used as a reference population. Variants were classified as P, LP, variant of uncertain significance (VUS), likely benign (LB), or benign (B). VUS were not considered diagnostic and were not used for predictive testing of relatives. Individuals were defined as G+ if a P or LP variant was identified. Genotype-negativity (G-) was defined as the presence of a VUS, LB, or B variant.

Individuals were eligible for inclusion if they were aged ≥18 years, were relatives of G+ HCM patients, and had undergone targeted molecular genetic testing demonstrating a P or LP variant. In addition, individuals were required to have no evidence of LVH or LVOTO on TTE, with an MLVWT <13 mm.

Exclusion criteria included negative molecular genetic testing; evidence of LVH or LVOTO on TTE as defined above; the presence of aortic coarctation, clinically significant valvular heart disease, infiltrative or storage disorders; and syndromic forms of cardiomyopathy.

G+/P- individuals were defined as carriers of a P or LP HCM-associated variant without echocardiographic or cardiac magnetic resonance evidence of LVH (MLVWT <13 mm) and without clinical manifestations of HCM at the time of evaluation.

Data are presented as mean ± standard deviation (SD) for continuous variables and as proportions for categorical variables. Statistical analyses were performed using the Kolmogorov–Smirnov test, Student’s t test, Wilcoxon signed-rank test, Mann–Whitney U test, McNemar’s test, Fisher’s exact test, and the Chi-square test, as appropriate. Specifically, the Kolmogorov–Smirnov test was used to assess the normality of the distribution of continuous variables. Changes in normally distributed continuous variables during follow-up were analyzed using the paired Student’s t test, whereas changes in non-normally distributed continuous variables were analyzed using the Wilcoxon signed-rank test. Comparisons between independent non-normally distributed continuous variables were performed using the Mann–Whitney U test. McNemar’s test was used for paired categorical variables. Fisher’s exact test or the Chi-square test was used for independent categorical variables, depending on expected cell frequencies. Statistical analyses were performed using Prism version 8.1.1 (GraphPad Software Inc., San Diego, CA) and publicly available software (socscistatistics.com).

According to the above-mentioned criteria, the cohort included 34 individuals classified as G+/P-. The mean age at initial clinical evaluation was 31.7 ± 14.8 years, and the majority were females (73%). Arterial hypertension had been previously diagnosed in three individuals (9 %), while none had coronary disease or diabetes mellitus. Most participants were asymptomatic (85%); however, 9% reported exertional dyspnea corresponding to NYHA Class II, and one individual experienced palpitation ( Table 1 ).

Sequencing of a set of candidate genes revealed LP/P mutations in the following genes: MYBPC3 in 26 individuals (76 %), MYH7 in 8 individuals (24%), and MYL2 in 1 individual (3%). One patient had two LP mutations simultaneously detected in MYBPC3 and MYL2 .

The mean follow-up duration was 6.6 ± 3.7 years. Complete ECG and TTE data were available for 88% of individuals throughout the follow-up for both modalities ( Table 2 ). Vital status was verified in all individuals. The mean MLVWT increased from 9.6 ± 1.6 mm to 10.7 ± 3.3 mm (p = 0.01), and IVS thickness rose from 9.6 ± 1.7 mm to 10.4 ± 3.0 mm (p = 0.01). There were no significant changes in LVEDD (43.1 ± 4.9 mm vs 43.0 ± 5.5 mm, p = 0.74), left atrial diameter (33.7 ± 4.9 mm vs 33.4 ± 6.4 mm, p = 0.87), or LVEF (65.6 ± 4.7% vs 64.8 ± 1.7%, p = 0.21). The proportion of individuals with normal ECG findings remained unchanged (71% at baseline vs 67 % at follow-up, p = 0.23).

LVH, defined as an MLVWT ≥13 mm, developed in 9 of 34 individuals (26%) after a mean interval of 5.1 ± 4.1 years from the initial evaluation. The mean age at LVH onset was 37.0 ± 14.3 years. Five of these individuals carried a variant in the MYBPC3 gene, three in MYH7 , and one harbored variants in both MYBPC3 and MYL2 .

Individuals who developed HCM had higher baseline MLVWT and IVS thickness (11.0 ± 1.2 mm vs 9.1 ± 1.5 mm; p = 0.001 and 11.0 ± 1.2 mm vs 9.0 ± 1.6 mm; p = 0.001, respectively) and larger left atrial diameter (36.8 ± 5.0 vs 32.4 ± 4.6; p = 0.01) compared with those who did not. No significant differences were observed in LVEF and LVEDD.

Electrocardiographic voltages were higher in individuals who developed HCM, both for the Sokolow–Lyon index (31.1 ± 9.3 mm vs 24.5 ± 6.6 mm, p = 0.02) and the Cornell voltage criterion (20.6 ± 10.4 mm vs 11.1 ± 5.2 mm; p = 0.002). The proportion of individuals meeting the voltage criteria for LVH did not differ significantly for the Sokolow–Lyon index (11% vs 5%; p = 0.57), but significantly more individuals met the Cornell criterion for LVH in the group that developed HCM (33% vs 5%, p = 0.047).

The cohort included two families in which variable penetrance of the disease was demonstrated. (1) two brothers with the same MYBPC3 variant, where the younger sibling developed HCM at age 24, while the older brother remained phenotype-negative at the last follow-up, aged 27; (2) father and daughter with the same MYBPC3 variant, where the father developed HCM at the last follow-up, aged 54 years, after 4 years of follow-up, and his daughter remained P- until the last follow-up, aged 26.

No deaths occurred during the follow-up period, and there were no cases of sudden cardiac death (SCD) or aborted SCD. No events of heart failure, stroke, or atrial fibrillation were observed. There was one patient with an implantable cardioverter-defibrillator (ICD) implanted during follow-up ( Table 3 and Fig. 1 ). The patient was female, aged 23 at first evaluation, with a baseline MLVWT of 10 mm. Her notable family history included HCM (mother and aunt) and multiple SCD events (in aunt, aged 50 years, linked to HCM and carrying the same MYBPC3 variant, and both her grandfather and great-grandfather in their 50s). The ICD was implanted before the development of significant LVH, following comprehensive risk stratification and shared decision-making with the patient. Within the follow-up, four asymptomatic episodes of nonsustained ventricular tachycardia (nsVT) were documented. At the last follow-up, the patient was aged 32, with MLVWT 23 mm, no LVOTO, and no ICD therapy (antitachycardia pacing or shock).

Table 3

End points during follow-up

End point
Death from any cause	0 (0%)
Sudden cardiac death (SCD)/aborted SCD	0 (0%)
Left ventricular hypertrophy (LVH) development	9 (26%)
Age at hypertrophy development (years)	37.0 ± 14.3
Time from first evaluation to LVH development (years)	5.1 ± 4.1
Heart failure	0 (0%)
Atrial fibrillation	0 (0%)
Stroke	0 (0%)
Nonsustained VT	1 (3%)

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