KDSR is related to inherited disorders of keratinization associated with thrombocytopenia, it was first reported in relation to autosomal recessive erythrokeratodermia variabilis et progressiva 4 in 2017 (Boyden LM, et al., 2017, PMID: 28575652). At least 14 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, and complex rearrangement) have been reported in humans. Evidence supporting this gene-disease relationship included case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 30467204, 28575652, 31987885, 28774589). Variants in this gene segregated with disease in 1 additional family member. The gene-disease association is supported by its biochemical function as the KDS reductase in the sphingolipid metabolic pathway (PMID: 15328338), the rescue of aberrant size and proplatelet formation in patient megakaryocytes by the WT KDSR transcript in patient-derived induced-megakaryocytes (PMID: 30467204), and a zebrafish model with impaired thrombocyte formation (PMID: 30467204). In summary, KDSR is definitively associated with autosomal recessive erythrokeratodermia variabilis et progressiva 4.
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