ABCB6 was first reported in relation to autosomal dominant dyschromatosis universalis hereditaria (DUH) in 2013 (Zhang et al., PMID: 23519333). DUH is characterized by the presence of hypo- and hyperpigmented skin macules on the trunk, limbs, and face. At least 9 missense variants have been reported in humans. Evidence supporting this gene disease relationship includes case-level data, segregation data, and experimental data.
Variants in ABCB6 have been reported in individuals with the following disease entities: Dyschromatosis universalis hereditaria, Isolated microphthalmia with coloboma, and Familial pseudohyperkalemia. Further, biallelic truncating variants affecting ABCB6 are responsible for the Lan(-) blood group (MIM#111600). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and no consistent mechanism of disease. Therefore, the following disease entities have been split and curated separately: Dyschromatosis universalis hereditaria (MIM#615402), Isolated microphthalmia with coloboma (MIM#614497). Familial pseudohyperkalemia (MIM#609153) has not been curated at this time as it is an asymptomatic condition apparent only in refrigerated blood samples due to temperature-dependent leak of potassium across the cell membrane of erythrocytes.
Nine missense variants in ABCB6 have been reported in association with DUH in ten probands across six publications (PMID: 23519333; 24224009; 24498303; 25288164; 35024399; 30430618). Co-segregation with disease was observed in five families (PMID: 23519333; 24224009; 24498303; 25288164). The mechanism of disease is currently unknown. This gene-disease relationship is supported by expression studies, in vitro functional assays, and animal models (PMID: 23519333; 24498303; 29940187; 35461746). In summary, there is moderate evidence to support this gene-disease relationship. While 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 General Inborn Errors of Metabolism GCEP on 22MAR2024 (SOP 10).
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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