The SMYD1 p.Asn101Ser is a partial loss-of-function variant that impairs mitochondrial function and leads to early-onset cardiomyopathy

A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization

The molecular and functional spectrum of SLC25A4-associated disease is expanded and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.

A loss-of-function mutation in the GTPase domain of MFN2, perverting mitochondrial dynamics, is associated with dilated cardiomyopathy

Rare Heterozygous Loss-of-Function Variants in MCOLN1 Identified in Two Sporadic Patients with α-Synucleinopathies.

It is demonstrated that both heterozygous MCOLN1 variants impair TRPML1 function in vitro, identifying MCOLN1 as a candidate gene for α-synucleinopathies that warrants further investigation in larger cohorts.

Expanding the Recessive Spectrum of Dilated Cardiomyopathy: RNA‐Level Validation of a Homozygous CTNNA3 Splice‐Site Variant

CTNNA3 encodes αT‐catenin, an intercalated disc (ICD) protein essential for cardiomyocyte coupling. Human omics studies have shown reduced CTNNA3 expression, ICD ultrastructural disruption, and dilated cardiomyopathy (DCM)–associated hyperphosphorylation of αT‐catenin. Direct RNA‐level evidence linking biallelic CTNNA3 variants to human cardiomyopathy has been lacking. Clinical exome sequencing was performed in a 21‐year‐old man with DCM, severe left ventricular systolic dysfunction (LVEF 20%), and atrial fibrillation (AF). The identified homozygous variant (NM_013266.4 : c.1733 − 1G > C) was assessed with multiple splicing prediction tools and functionally validated via a minigene hybrid assay in HEK293 cells. Splicing predictors indicated loss of the canonical acceptor site. The minigene assay confirmed three aberrant transcripts: out‐of‐frame exon 13 skipping with a premature stop codon, a 24‐nucleotide in‐frame deletion, and partial intron retention, resulting in a possibly nonfunctional protein. Under guideline‐directed medical therapy, LVEF normalized, but a persistent arrhythmic phenotype remained, with recurrent AF, frequent ventricular ectopic beats, and nonsustained ventricular tachycardia. We report a recessive form of DCM associated with a homozygous canonical splice‐site variant in CTNNA3, encoding the ICD protein αT‐catenin. Our results are consistent with human omics studies. Altogether, these data provide evidence that biallelic CTNNA3 splice‐disrupting variants can cause human cardiomyopathy driven by ICD dysfunction. The dissociation between ventricular recovery and persistent arrhythmia highlights the complex phenotypic spectrum of CTNNA3‐related disease.

The R120G Knock-in Mutation in αB-Crystallin is Insufficient to Induce Cardiomyopathy in Mice

Alpha B-crystallin (CryAB) is a small heat-shock protein highly expressed in cardiac tissue, where it functions as a molecular chaperone that helps prevent protein aggregation, particularly under stress conditions. A missense mutation in CryAB (R120G) causes autosomal dominant cardiomyopathy in humans and is characterized by extensive protein aggregation in cardiomyocytes. To better understand the pathogenic mechanisms underlying CryABR120G-associated cardiomyopathy, appropriate in vivo models are essential. Genetic mouse models are valuable tools for investigating disease pathogenesis and evaluating potential therapeutic strategies. In this study, we characterized a homozygous CryABR120G knock-in (KI) mouse model to assess the impact of this mutation on cardiac function. CryABR120G KI mice exhibited no overt changes in cardiac structure and function up to 12 months of age, with minimal changes in cardiac and proteotoxic stress markers, except for an increased atrial natriuretic peptide expression at 12 months. Protein quality control pathways remained largely unchanged. Although mitochondrial respiration was normal in young CryABR120G KI mice, it was reduced at 12 months of age. Despite the presence of insoluble protein aggregates, homozygous CryABR120G KI mice did not develop overt structural or functional cardiomyopathy through 12 months of age. These findings indicate that, within the age range examined, the CryABR120G KI model does not reproduce the overt cardiomyopathic phenotype associated with the CRYABR120G mutation in patients.

NFIX missense variants that disrupt the β-hairpin loop result in a severe form of Malan syndrome in adolescence with rapidly evolving scoliosis and muscle wasting

Purpose: Pathogenic variants in NFIX cause Marshall-Smith syndrome and Malan syndrome (MALNS). We identified a severe subtype of MALNS characterized by adolescent-onset musculoskeletal deterioration and investigated functional consequences of underlying variants. Methods: Clinical data were collected from seven individuals with pathogenic NFIX variants. Wild-type and mutated recombinant NFIX DNA-binding domains (DBDs) were evaluated using biochemical, structural, and DNA-binding assays. Results: Six individuals carrying R116W, R116P, K125E, or G147E NFIX substitutions developed progressive muscle wasting, markedly reduced body mass index, and rapidly progressive scoliosis after the typical childhood features of MALNS; two died from disease-related complications. A seventh individual with R116G did not develop this severe phenotype. Functional studies on recombinant NFIX DBDs showed complete or near-complete loss of DNA-binding activity for R116W, R116P, K125E, and G147E despite preserved protein folding, consistent with disrupted DNA recognition and a potential dominant-negative mechanism. In contrast, R116G exhibited a 7.7{degrees}C decrease in thermal stability, which may support haploinsufficiency mediated by protein degradation. Conclusion: Specific NFIX missense variants define a severe subtype of MALNS associated with progressive musculoskeletal deterioration. In vitro functional studies support variant-specific disruption of DNA binding, providing a mechanistic basis of genotype-phenotype correlations and informing prognosis, clinical surveillance, and therapy development.