ANK1 was first reported in relation to autosomal dominant Hereditary Spherocytosis (HS) in 1989 (Davies and Lux, PMID: 2675425). HS is characterized by the presence of spherical-shaped erythrocytes, termed spherocytes, on a peripheral blood smear. Spherocytes can accumulate in the spleen, causing anemia, jaundice, and splenomegaly. Complications include hyperbilirubinemia in neonates, cholelithiasis, hemolytic episodes, aplastic crises, and iron overload, although mild cases may go undetected without a blood smear. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern between autosomal dominant and autosomal recessive HS. Therefore, the following disease entities have been split by inheritance pattern into multiple disease entities with Spherocytosis, Type 1 (OMIM:182900) being the dominant form and the split curation for autosomal recessive HS will be curated separately. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Nine variants (missense, nonsense, frameshift, splicing) that have been reported in nine probands in three publications (PMIDs: 8640229, 31016877, 32436265) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. The mechanism of pathogenicity is known to be loss of function of ANK, leading to a loss of flexibility and shape of the erythrocyte membrane. This gene-disease association is also supported by multiple animal models, expression studies, in vitro functional assays, and biochemical function experiments (PMIDs: 2137557, 2139228, 1826225, 24688720, 31147440, 31016877). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) was reached. In summary, ANK1 is definitively associated with autosomal dominant Hereditary Spherocytosis. 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 General Gene Curation Expert Panel on the meeting date March 24, 2021 (SOP Version 8).
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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