A 40-year-old woman who developed severe heart failure shortly after a common cold has become the focus of a case report that highlights how genetically complicated familial dilated cardiomyopathy can be. Doctors at The Affiliated Hospital of Shandong University of Traditional Chinese Medicine found not one but two likely pathogenic variants in her heart muscle genes, and the case, published in Frontiers in Cardiovascular Medicine, illustrates why interpreting such dual findings demands caution rather than certainty.
The woman arrived at the hospital on March 31, 2026, after twenty days of episodic chest tightness and breathlessness that had worsened over five days following an upper respiratory tract infection. She was experiencing palpitations, cough, orthopnea, abdominal distension, fatigue, and exercise intolerance. She had no history of hypertension, diabetes, chronic kidney disease, or known cardiac disease. On examination, her temperature was 36.3 degrees Celsius, heart rate 103 beats per minute, and blood pressure 118/91 mmHg, with coarse breath sounds and mild bilateral leg edema.
Echocardiography told a stark story. Her left ventricular ejection fraction, a measure of how forcefully the heart pumps, was approximately 20 percent, far below the normal range. Imaging also revealed left atrial enlargement, mild-to-moderate mitral regurgitation, mild tricuspid and aortic regurgitation, and a small pericardial effusion. Chest computed tomography showed pulmonary edema, bilateral pleural effusions, cardiomegaly, and pericardial effusion. At the referring hospital, her NT-proBNP, a hormone released when the heart is under strain, had measured a striking 6990.23 pg/mL.
Yet some of the most diagnostically important results were the ones that stayed normal. Serial measurements of cardiac troponin I and myocardial enzymes, obtained on multiple occasions during hospitalization, remained within their reference ranges, showing no biochemical evidence of acute myocardial necrosis. Coronary angiography on April 2 demonstrated a left-dominant circulation without significant stenosis, ruling out obstructive coronary artery disease. An antinuclear antibody test was positive at 1:100 in a speckled pattern, but rheumatology consultation found insufficient evidence for systemic connective tissue disease.
Cardiovascular magnetic resonance imaging on April 9 demonstrated global left ventricular hypokinesis, left atrial enlargement, mild mitral regurgitation, a small pericardial effusion, and a clinically reported non-ischemic late-gadolinium-enhancement pattern at the papillary-muscle level involving the anterior and lateral walls. Critically, however, the examination did not include dedicated inflammatory sequences such as T2-weighted imaging, T2 mapping, or STIR. Combined with the repeatedly normal biomarkers, this meant active myocarditis could not be established. The team instead interpreted the episode as infection-associated acute decompensation in the setting of an inherited cardiomyopathy, a distinction the authors emphasize carries real weight: an infection that precedes heart failure is not proof of heart muscle inflammation.
Treatment followed guideline-directed medical therapy, including a loop diuretic, metoprolol succinate, spironolactone, and dapagliflozin. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, had to be stopped during hospitalization because of symptomatic hypotension, though it was later reintroduced at low dose under outpatient blood-pressure monitoring. The biomarker response was nonetheless encouraging: NT-proBNP fell from 4154 pg/mL on April 1 to 1094 pg/mL on April 6 and 828 pg/mL on April 12. A repeat echocardiogram on April 10 showed transient improvement to approximately 27 percent ejection fraction. But at two-month follow-up in late May, despite reduced chest tightness and tolerance of ordinary daily activities, ejection fraction remained at 25 percent, indicating persistent severe systolic dysfunction without meaningful reverse remodeling.
The rhythm picture added another layer of concern. Serial electrocardiograms showed sinus rhythm with poor R-wave progression and QS complexes in the anterior precordial leads, repolarization abnormalities, and ventricular premature complexes. QTc values measured 494, 463, and 479 milliseconds across the three recordings. Notably, standard 24-hour ambulatory Holter monitoring could not be arranged during the index hospitalization because of local medical insurance policies: simultaneous bedside telemetry and Holter monitoring would have resulted in complete non-reimbursement of all cardiac monitoring charges. Only ward bedside telemetry was therefore used, and the total 24-hour ventricular ectopy burden could not be quantified.
Genetic testing through enhanced whole-exome sequencing identified heterozygous likely pathogenic variants in two genes. The first, in BAG3, was a canonical splice-site variant, NM_004281.4:c.180 + 1G > T, absent from gnomAD and classified using PM2_P and PVS1 criteria. Loss-of-function BAG3 variants cause autosomal dominant dilated cardiomyopathy through haploinsufficiency and impaired cardiomyocyte proteostasis, and the gene carries a ClinGen haploinsufficiency score of 3. On reassessment of ClinVar, dbSNP, gnomAD, and the published literature, the authors found no prior report of this variant and describe it as previously unreported. The proband’s daughter carried the same variant; her son did not.
The second variant, in FLNC, was a frameshift deletion, NM_001458.5:c.761_779del, p.(Leu254Profs*14), also absent from gnomAD and predicted to cause loss of function, a recognized mechanism in FLNC-associated cardiomyopathy. Truncating FLNC variants are associated with dilated and arrhythmogenic cardiomyopathy, myocardial fibrosis, and ventricular arrhythmias, features that overlap with the patient’s non-ischemic late gadolinium enhancement and ventricular ectopy. Unlike the BAG3 variant, this FLNC variant had been previously reported in a Chinese cardiomyopathy cohort, so it is not novel. Both children were wild-type for FLNC, meaning segregation with disease could not be established. Additional findings included heteroplasmic MT-ND4 m.11778G > A at 34.4 percent heteroplasmy, classified as pathogenic but primarily associated with Leber hereditary optic neuropathy, and a 16p13.11 duplication classified as a variant of uncertain significance. Neither was considered an established explanation for the cardiac phenotype.
The family history deepened the puzzle. The proband reported heart-failure-related deaths in her father and younger brother during adulthood and in a nephew during childhood, a three-generation clustering compatible with probable autosomal dominant inheritance but marked by striking variability in age at onset and severity. Because the affected relatives were deceased and unavailable for testing, formal segregation analysis was impossible, and the relative contributions of BAG3 and FLNC cannot be definitively determined. The authors note that coexisting variants in robust cardiomyopathy genes appear uncommon: in one dilated cardiomyopathy cohort, only 2.3 percent of genotype-positive patients carried a second likely pathogenic or pathogenic variant in another robust DCM gene. A targeted search of PubMed, Web of Science, CNKI, Wanfang, and the Chinese Biomedical Literature Database through July 2026 did not identify a comparable Chinese case with both loss-of-function variants and family Sanger validation. The findings are therefore hypothesis-generating rather than proof of dual-gene causality.
The clinical implications extend beyond this single patient. Given persistent ejection fraction at or below 35 percent, non-ischemic late gadolinium enhancement, ventricular ectopy, a truncating FLNC variant, and an adverse family history, the authors argue that early multidisciplinary evaluation for primary-prevention implantable cardioverter-defibrillator therapy is appropriate rather than relying solely on a routine waiting period for recovery. ICD implantation was discussed with the patient after individualized assessment of arrhythmic risk and preventive benefit, but she did not proceed because of personal socioeconomic considerations. Continued optimization of tolerated therapy, ambulatory rhythm monitoring when feasible, correction of reversible factors behind the QTc prolongation, avoidance of QT-prolonging drugs, electrolyte optimization, and repeated device-risk assessment remain necessary.
For the family, cascade screening has already produced actionable information. The genotype-positive daughter requires developmentally appropriate genetic counseling and periodic clinical assessment, electrocardiography, and echocardiography, with cardiac magnetic resonance or ambulatory monitoring if symptoms or abnormalities develop. The son’s negative results for both BAG3 and FLNC reduce, but do not eliminate, concern, since segregation in affected relatives was never available. Both children should also receive counseling about the MT-ND4 finding. The case’s broader lessons, the authors write, are that infection-associated heart failure presentations should not be equated with confirmed myocarditis when biomarkers and inflammatory imaging criteria are unsupportive, that coexisting cardiomyopathy variants demand cautious genotype-phenotype interpretation, and that the combination of truncating FLNC variants, fibrosis, ectopy, persistent severe dysfunction, and adverse family history should prompt structured arrhythmic risk assessment.
Subject of Research: A familial case of severe non-ischemic dilated cardiomyopathy with coexisting likely pathogenic BAG3 and FLNC variants
Article Title: Familial severe non-ischemic dilated cardiomyopathy with coexisting likely pathogenic BAG3 and FLNC variants: a case report
Article References: Lili, W., Youcao, W., Xiaodong, Y., & Zhen, W. (2026). Familial severe non-ischemic dilated cardiomyopathy with coexisting likely pathogenic BAG3 and FLNC variants: a case report. Frontiers in Cardiovascular Medicine, 13, 2000926. https://doi.org/10.3389/fcvm.2026.2000926
Image Credits: AI Generated
DOI: 10.3389/fcvm.2026.2000926
Keywords: dilated cardiomyopathy, BAG3, FLNC, genetic testing, heart failure, cascade screening, cardiovascular magnetic resonance, ventricular arrhythmias, myocarditis, whole-exome sequencing, family history, implantable cardioverter-defibrillator
News Source: Juliet Wilcox. (October 30, 2026). Two Heart Disease Genes in One Family: Case Report Reveals Genetic Complexity of Dilated Cardiomyopathy. Scienmag.
