LAMA4

Inheritance Pattern: AD

Disease ID:MONDO:0014095

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0006573

Submitter: LiferaOmics

Genetic evidence – Published db25-338-OR (Karusheva et al., Diabetes 2025 Supplement; DOI: 10.2337/db25-338-OR) – Reports one consanguineous family with lipodystrophy and metabolic dysfunction characterized by severe hypertriglyceridemia and recurrent pancreatitis, harboring a homozygous nonsense variant in LAMA4 (NM_002290.3:c.133C>T; p.Gln45Ter). Two affected siblings were reported, both homozygous for the variant. The family was consanguineous. Phenotype is consistent with autosomal recessive lipodystrophy. Case-level (biallelic predicted null in AR model; homozygous scored once per family; consanguineous so −0.5 applied) = (1.5 − 0.5) = 1.0; segregation (one additional affected sibling; conservative) = 0.5; case-control = 0; db25-338-OR total = 1.5. Published genetic evidence total = 1.5/12 Genetic evidence – Our cases Family 1 – One proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; segregation = 0 (affected siblings reported but not genotyped); case-control = 0; Family 1 total = 1.0. Our cases total = 1.0/12 Total genetic evidence (published + our cases) 1.5 + 1.0 = 2.5/12 Experimental evidence – Published db25-338-OR references prior biological studies demonstrating that loss of LAMA4 affects adipose tissue biology, and mouse models deficient in Lama4 show reduced adipose mass in specific depots, supporting biological plausibility for lipodystrophy. Gene function / biological plausibility = 0.5; experimental total = 0.5. Experimental evidence total = 0.5/6 Overall score Overall score = 2.5 + 0.5 = 3.0

Inheritance Pattern: AD

Disease ID:MONDO:0014095

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014095

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014095

Submitter: Illumina

The LAMA4 gene is located on chromosome 6 at 6q21 and encodes laminin subunit alpha 4. Laminins are a major component of basement membranes, and laminins containing α4 subunits are highly expressed in the microvasculature, cardiomyocyte sarcolemma, and cardiac and skeletal muscle. Laminins serve both structural and signaling roles and have been implicated in a diverse array of cellular functions such as cell adhesion and differentiation. LAMA4 was first reported in relation to an autosomal dominant dilated cardiomyopathy in 2007 (17646580: Knöll et al. 2007). At this time, evidence supporting this gene-disease relationship is limited to experimental data. Heterozygous variants in the LAMA4 gene have been reported in a small number of individuals with dilated cardiomyopathy (17646580: Knöll et al. 2007; 26406308: Marston et al. 2015), but none of these variants had sufficient evidence for disease causality. More recently, heterozygous LAMA4 variants have been reported in cases with possible alternative molecular bases for disease (25979592: Waldmüller et al. 2015; 29253866: Klauke et al. 2017; 30165862: Lu et al. 2018; 30764827: Refaat et al. 2019; 30650640: Abdallah et al. 2019; 29415625: Laenens et al. 2019). Homozygous LAMA4 knockout mice show microvascular anomalies and develop cardiomyopathy, neurological dysfunction, and kidney disease, while heterozygous mice do not show a phenotype (11809810: Thyboll et al. 2002; 11369940: Patton et al. 2001; 15814800: Wallquist et al. 2005; 16204254: Wang et al. 2006; 20035058: Abrass et al. 2010). Approximately one-third of zebrafish treated with morpholinos against LAMA4 show cardiovascular dysfunction and hemorrhage, but fish injected with a lower dose show no phenotype (17646580: Knöll et al. 2007). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Inheritance Pattern: AD

Disease ID:MONDO:0014095

Submitter: ClinGen

LAMA4 was originally evaluated for DCM by the ClinGen DCM GCEP on 10/11/2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 11/15/2024. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. Sylvius et al. (2001, PMID: 11085912) were the first to identify LAMA4 within the genetic locus associated with dilated cardiomyopathy (DCM). Human genetic evidence supporting the relationship between LAMA4 and autosomal dominant DCM includes case-level reports. Marston et al. (2015, PMID: 26406308) identified a missense variant in LAMA4 classified as Likely Benign in a patient with DCM, no segregation data were available, and it was not scored. Additionally, Abdallah and colleagues (2019, PMID: 30650640) described a pediatric case of infantile DCM that carried two variants: one in LAMA4 (inherited from the father, who had a normal heart evaluation) and one in MYH7 (inherited from the mother, who exhibited mild DCM). Consequently, there was insufficient evidence to conclude that the LAMA4 variant caused the DCM phenotype; it was more likely that the MYH7 variant was the contributing factor. Knoll and colleagues (2007, PMID: 17646580) identified three variants in LAMA4, which included two missense variants of unknown significance and one stop codon variant, in 3 DCM patients. Immunohistochemical analysis of myocardial biopsies revealed a significant loss of endothelial cells carrying the stop codon variant (p.R1073X). Findings from animal models also support this gene-disease association. Wang and colleagues (2006, PMID: 16204254) demonstrated that adult LAMA4 knockout mice exhibited a higher frequency of sudden death during noninvasive procedures, such as anesthesia induction. At 36–40 weeks of age, these mice showed a significant increase in left ventricular end-diastolic diameter and left ventricular end-systolic diameter. Over time, the mutant hearts displayed widening of the extravascular space, cardiomyocyte degeneration, and fibrosis. More recently, Barati and colleagues (2021, PMID: 36317039) described a case of DCM in a 42-year-old woman and evaluated variants in different genes coding crucial proteins in cardiac muscle structure i.e LAMA4. However, no variants were reported to be scored. Finally, Shen and colleagues (2022, PMID: 35284542) investigated genetic variants in Chinese patients with sporadic dilated cardiomyopathy. However, most of variants were VUS, Likely Benign, Benign and Authors did not include high impact genes for DCM i.e. TTN and FLNC. Since, the presence of LP o P variants in these genes cannot be excluded, this study was not scored. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of LAMA4 and AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 11/15/2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P