APOA4 was first reported in relation to autosomal dominant tubulointerstitial kidney disease in 2023 (Kmochová et al., PMID: 38096951). Affected individuals develop chronic kidney disease with variable progression to end-stage kidney disease, with a mean age of end-stage kidney disease of approximately 60 years (range 45 to > 85). Urinalysis reveals a bland urinary sediment. Deep kidney biopsies or tissue obtained from nephrectomy reveal the deposition of medullary amyloidosis composed of the mutated APOA4. Two missense variants that have been reported in two probands in this publication (PMID: 38096951) are included in the curation. The mechanism of pathogenicity appears related to medullary deposition of the abnormal apolipoprotein. This gene-disease relationship is also supported by expression studies (PMID: 38096951).
In summary, there is Limited evidence to support this gene-disease relationship. 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 Kidney Cystic and Ciliopathies Disorders GCEP on the meeting date February 28th, 2024 (SOP Version 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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