ILK

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

Integrin-linked kinase (ILK) was evaluated for autosomal dominant dilated cardiomyopathy (DCM). ILK was originally evaluated for DCM by the ClinGen DCM GCEP on 09/27/2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 05/30/2025. The overall genetic evidence points decreased and experimental evidence points increased. With these updates at the time of recuration, the clinical validity classification did not change and remains Limited A summary of the information contributing to the classification of this gene at this time of re-evaluation is summarized herein. ILK is a serine/threonine protein kinase that plays important roles in cell matrix interactions and induction of biomechanical signals for cytoskeleton remodeling, angiogenesis, cell growth, proliferation, survival, and differentiation. Human genetic evidence supporting this gene-disease relationship includes case-level and segregation data. At least 5 missense variants were found in patients with DCM (Knoll et al, 2007, PMID: 17646580; Meder et al, 2011, PMID: 21252143; Haas et al, 2015, PMID: 25163546). Two of them were functionally analyzed and showed aberrations 2 or more of the following experiments: binding-, kinase-, cellular localization-assays and zebrafish rescue experiments (Brodehl et al, 2019, PMID: 30802431; Knoll et al, 2007, PMID: 17646580). Functional analysis of all tested ILK variants are in line with a loss of function mechanism. However, two of them showed high minimal allele frequencies (MAF) in general populations (gnomAD 4.1.0, Haas et al, 2015, PMID: 25163546). One variant was found with several other variants including TNNT2 (Meder et al., 2011, PMID: 21252143). One variant was found by targeted sequencing (LAMA4 and ILK, Knoll et al, 2007, PMID: 17646580). Thus, only one rare variant was found in a patient with DCM (Haas et al, 2015, PMID: 25163546). In addition, this gene-disease association is supported by expression studies and animal models. The gene is expressed in many tissues but especially high in heart (Hannigan et al, 1996, PMID: 8538749). ILK expression is increased in the hypertrophic ventricles from human patients with congenital and acquired outflow tract obstruction (Lu et al, 2006, PMID: 17088456). In addition, Several ILK animal models have been made that show cardiac phenotypes. Targeted ablation of ILK from the murine heart using different cardiac specific promoter (mck and αMHC) driven Cre expression results in DCM with spontaneous and inducible ventricular tachyarrhythmias (White et al, 2006, PMID: 16951252; Dai et al, 2014, PMID: 24319095; Quang et al, 2015, 26071395). Moreover, ectopic expression of wild-type ilk RNA from either zebrafish (zilkwt) or human (hilkwt) can rescue the cardiac contractile dysfunction induced by msq mutantation, whereas injection of msq mutant RNA (zilkL308P) has no effect. Although this gene-disease assertion is supported by expression evidence, animal models and rescue models, no reports have directly implicated the gene in humans. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of ILK and AD DCM. This classification was approved by the Dilated Cardiomyopathy Working Group on May 30, 2025 (SOP Version 10).