| Evidence type | Subject / finding | Core evidence | Genotype / frequency | Outcome or interpretation | Citation |
|---|---|---|---|---|---|
| Human—disease definition | CMD2J / dilated cardiomyopathy 2J | Autosomal-recessive, early-onset pediatric DCM caused by biallelic variants in **FLII** (flightless-I homolog); initially established in three unrelated families. This is **FLII**, not *FLNC*, *FLI1*, or an adjacent *LRRFIP* gene. | OMIM **620635** | Newly delineated ultra-rare Mendelian cardiomyopathy | (pqac-00000001, pqac-00000003) |
| Human—patient 1 | Family 1, Dutch, nonconsanguineous; individual II:2, female | Presented at **2 months** with tachyarrhythmia and DCM; reported cohort LVEF range was **23%–32%**, but the exact patient-specific value was not available in the extracted evidence | **NM_002018.3:** compound heterozygous c.1360C>T, p.(Gln454Ter) and c.3502C>T, p.(Arg1168Trp); gnomAD: truncating allele not reported in extracted table, p.Arg1168Trp MAF **0.000024** | Alive at **2 years**; cardiac function stable or improved; no reported extracardiac phenotype | (pqac-00000000, pqac-00000001) |
| Human—patient 2 | Family 2, Saudi Arabian, consanguineous; individual II:1, female | Presented at **5 months** with heart failure, DCM, and secundum atrial septal defect; cohort LVEF **23%–32%**, individual value unavailable | **NM_002018.3:** homozygous c.2020C>G, p.(Leu674Val); gnomAD **not reported/absent** in the study table | Alive at **6 years**; cardiac function stable or improved; ASD-II was the only additional reported structural feature | (pqac-00000000, pqac-00000001) |
| Human—patient 3 | Family 3, Saudi Arabian, consanguineous; individual II:1, male | Presented at **3 months** with heart failure and DCM; cohort LVEF **23%–32%**, individual value unavailable | **NM_002018.3:** homozygous c.3718C>T, p.(Arg1240Cys); gnomAD MAF **0.000057** | Alive at **9 years**; cardiac function stable or improved; no reported extracardiac phenotype | (pqac-00000000, pqac-00000001) |
| Human—inheritance and segregation | Three families | Recessive segregation: affected children carried biallelic variants, whereas heterozygous parents were reportedly unaffected by DCM | One protein-truncating and three conserved missense alleles; variants absent or extremely rare in gnomAD and predicted damaging | Supports autosomal-recessive causation; penetrance and expressivity cannot be estimated from three affected individuals | (pqac-00000001, pqac-00000005) |
| Model—direct disease evidence | CRISPR/Cas9 zebrafish carrying patient-mimicking *flii* alleles | Patient-specific alleles caused reduced ventricular fractional-area change/ejection fraction, abnormal trabeculation, myofibrillar disorganization, and altered cardiomyocyte adhesion; Flii localized to intercalated-disk and costamere-like adhesions | Modeled alleles included *flii* p.Arg1158Trp and p.Arg1230Cys plus a truncating allele; these are zebrafish equivalents, not human HGVS designations | Recapitulated key human cardiac abnormalities and supported hypomorphic pathogenic effects | (pqac-00000002, pqac-00000004) |
| Model—direct mechanistic branch | Zebrafish *flii* loss of function | Disrupted focal-adhesion/cell-junction organization: vinculin became diffuse and cadherin-2 lost punctate membrane localization; Notch reporter activity and nuclear Wwtr1/Taz were reduced, linking adhesion/myofibril defects to altered Notch and Hippo signaling | Null-like *flii* p.Asp110fs caused a more severe phenotype than patient-specific alleles | Severe trabeculation and ventricular-wall morphogenesis defects led to systolic failure and larval lethality; patient-specific alleles were milder | (pqac-00000002, pqac-00000004) |
| Model—complementary FLII mechanism | Cardiac-specific knockout and human-variant knock-in mice | Flii regulates sarcomeric actin thin-filament length through interaction/sequestration of tropomodulin-1; cardiac deletion shortened thin filaments and caused hypertrophy, impaired ventricular function, lung congestion, and early death. The syntenic p.Arg1245His knock-in also shortened thin filaments and increased cardiomyopathy susceptibility | Human low-frequency allele **rs8821, p.Arg1243His**; overall MAF **0.0175**, European MAF **0.0267**. This susceptibility allele is not one of the CMD2J family alleles | Independently establishes FLII as a cardiac sarcomere regulator; LMOD2 overexpression partially rescued knockout disease in mice, but this is not a validated human therapy | (pqac-00000006, pqac-00000007) |
| Evidence limitations | Current knowledge base | Only **three affected children from three families** were available in the defining report; no disease-specific prevalence, incidence, sex ratio, penetrance estimate, validated biomarker, histopathologic signature, quality-of-life measurement, or FLII-targeted treatment trial was identified | ACMG/AMP classifications and complete ancestry-stratified carrier frequencies were not available in the extracted primary evidence | Clinical management must presently follow general pediatric DCM/heart-failure guidance; zebrafish and mouse mechanisms should not be treated as demonstrated human myocardial pathology | (pqac-00000000, pqac-00000001, pqac-00000014) |


*Table: Compact audit table of the defining human cases, segregation evidence, direct zebrafish validation, complementary mouse mechanism, and principal evidence gaps for FLII-related CMD2J.*