The *ABCC9 *gene (OMIM:601439) is located on chromosome 12 at 12p12.1 and encodes a subunit of ATP-sensitive potassium channels which coassembles with KCNJ11 to form cardiac and smooth muscle-type KATP channels . KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation. ABCC9 can also form a sulfonylurea-sensitive but ATP-insensitive potassium channel with KCNJ8. The ABCC9 gene was first reported in relation to autosomal dominant Cantu syndrome in 2012 (van Bon et al. 2012, PMID:22608503). Cantu syndrome (CS, MONDO ID: 0009406) is characterized by the following symptoms: cardiomegaly, hypertrichosis, and coarse facial features. In addition, some individuals with Cantu syndrome have hyperflexibility, edema, dilated aortic root, and mild intellectual disability. There is incomplete penetrance of CS-associated features, without clear correlation to genotype. Evidence supporting this gene-disease relationship includes case-level data and experimental data. There are at least 77 individuals with Cantu syndrome reported in literature, with 29 unique variants (10 cases confirmed to be de novo), 19 of which were scored in this curation (PMID: 31828977, PMID: 39031464). The curation includes heterozygous missense variants only, predominantly in the TMD2 region of the protein (transmembrane domain 2). The variants are predicted to result in membrane hyperpolarization, through a gain-of-function mechanism in KATP channels. Supporting experimental evidence includes functional alteration in patient cells (whole-cell voltage clamp experiment), and one mouse model. Studies of the knock-in mouse models showed increased vascular smooth muscle KATP channel activity, chronic vasodilation, and cardiomegaly. The phenotype was somewhat mild even in homozygous mice, due to an alternative splicing event that does not occur in human transcripts (PMID: 33529173 Zhang et al., 2021; PMID: 31821173, McClenaghan et al. 2020; PMID: 30089727, Huang et al. 2018). In summary, there is definitive evidence to support the relationship between ABCC9 and Cantu syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date February 21st, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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