ANKRD1

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

*ANKRD1* was first reported in relation to hypertrophic cardiomyopathy (HCM) in humans in 2009, where 2 unique missense variants were reported in probands with no family history of cardiomyopathy (Arimura T, et al., 2009, PMID: 19608031). *ANKRD1* has been associated with autosomal dominant HCM in 2 probands from 1 publication. Additional missense variants have been reported in humans, but either the frequency of the variants were too high, there were homozygotes present in gnomAD, the phenotypes more closely resembled DCM, or the probands had a variant in another HCM gene (Arimura T, et al., 2009, PMID: 1960803; Ng D, et al., 2013, PMID: 23861362; Cecconi M, et al., 2016, PMID: 27600940). This gene-disease relationship is supported by expression data, a cell culture model, and an animal model. High tissue specificity in the heart has been observed for this gene (Uhlén M, et al., 2015, PMID: 25613900). Expression studies in mature rat cardiomyocytes and the examination of contraction parameters using engineered heart tissues support the gene-disease association (Crocini C, et al., 2013, PMID: 23572067). Overexpression of ANKRD1 in mice with transverse aortic constriction was shown to exacerbate pathological cardiac remodeling through activation of the calcineurin/nuclear factor of activated T-cells pathway, a signaling pathway known to have an important role in cardiac hypertrophy (Chen C, et al., 2014, PMID: 25089522). This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on September 19th, 2017, with a classification of limited. It was reevaluated by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel on February 8th, 2023. As a result of this reevaluation, the classification was changed from limited to disputed.

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*ANKRD1* was first reported in relation to autosomal dominant congenital heart disease in 2022 (Yang et al., PMID: 30659708). One missense variant has been reported and is included in this curation (PMID: 30659708). This gene-disease relationship is also supported by evidence of *ANKRD1* expression in the human heart, protein interaction with NKX2.5, and a mouse model (overexpression of *ANKRD1*) that shows *ANKRD1* transgenic mice present with a sinus venosus defect. In summary, there is limited evidence supporting the relationship between ANKRD1 and autosomal dominant congenital heart disease. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date August 12th, 2024 (SOP Version 10)

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

ANKRD1 was originally evaluated for DXM by the ClinGen DCM GCEP on 08/12/2020. Evidence of the association of this gene with DCM was evaluated using SOP v10 on 02/07/2025. 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. ANKRD1 was first reported in relation to autosomal dominant DCM in 2009 (Duboscq-Bidot L et al, 2009, PMID: 19525294). Human genetic evidence supporting this gene-disease relationship includes case level data and segregation data. At least 16 unique variants (missense (n=13) and nonsense (n=3)) have been reported in humans, representing at least 23 probands from 7 publications (Duboscq-Bidot L et al, 2009, PMID: 19525294; Moulik et al, 2009, PMID: 19608030, Dalin et al, 2017, PMID: 27886618, Haas et al, 2015, PMID: 25163546, Marschall C et al, 2019, PMID: 31737537, Zhang XL et al, 2020, PMID: 32041989, van Lint et. al 2019, PMID: 30847666). Variants in this gene segregated with disease in 4 additional family members (Duboscq-Bidot L et al, 2009, PMID: 19525294). In addition, this gene-disease association is supported by evidence from expression studies (Duboscq-Bidot L et al, 2009, PMID: 19525294; Moulik et al, 2009, PMID: 19608030), in vitro functional assays (Moulik et al, 2009, PMID: 19608030), and non-human models (Zheng et al, 2021, PMID: 33734499). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of ANKRD1 with autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 02/07/2025 (SOP Version 10).