Hereditary systemic amyloidosis

Gene: APOA4

Green List (high evidence)

Comment on list classification: There are 5 distantly related families reported in literature with with chronic kidney disease, harbouring 2 different monoallelic missense variants. The variants segregated with disease in an autosomal dominant manner (PMID: 38096951). Other reports found that ApoA4 protein is the main component of amyloid deposits found in renal biopsies of patients with medullary amyloidosis. Similarly, ApoA4 deposits have been reported in cases of cardiac amyloidosis. However, the affected individuals did not have pathogenic APOA4 mutations, suggesting variants in other genes may also lead to ApoA4 aggregation. Based on available evidence, this gene should be promoted to Green for Hereditary systemic amyloidosis.

Created: 19 Dec 2025, 8:43 a.m. | Last Modified: 19 Dec 2025, 8:43 a.m.

Panel Version: 1.27

PMID: 38096951 Kmochova et al., 2024
3 distantly related families with (NM_000482.4):c.196C>G, p.Leu66Val, 2 distantly related families with c.97G>A, p.Asp33Asn. Method: WGS. Affected individuals presented with chronic kidney disease, with mean age of kidney failure of 64.5 years. Kidney biopsies from affected individuals showed amyloid deposits in the medulla, with Apoa4 protein being the main constituent.
p.Leu66Val - 3 heterozygotes in gnomAD v4.1.0 (European), Revel score = 0.27
p.Asp33Asn - not in gnomAD v4, though p.Asp33Glu and p.Asp33Val have been reported; Revel score = 0.31

PMID: 33751222 Murakami et al., 2021
Report of a 68 yo Japanese man, with 4 variants in APOA4: 2 synonymous (p.Thr29Thr, p.Leu128Leu); '6981A>C',p.Asn248Thr; and c.743A>C, p.Asn248Thr - not in gnomAD v4. Only APOA4 was sequenced. Patient had history of renal cysts, diagnosed with HCM 2 years prior. Authors highlight that Apoa4 protein aggregation is causal, but the gene variant may not be.

PMID: 28449784 Bois et al., 2017
13 patients with AApoAIV cardiac amyloidosis, mean age 75 years. Patients had cardiac dysfunction. Of 9 patients evaluated in detail, 8/9 had chronic kidney disease (various stages). Autopsy of 4 cases showed small vessel involvement and prominent medullary renal deposits Genetic analysis was performed, but 'did not identify definitive pathological mutations.'

PMID: 27262366 Dasari et al. 2016
Reported 11 patients with Apolipoprotein A-IV associated amyloidosis (mean age at diagnosis 63.5yrs). Biopsies showed large amounts of eosinophilic Congo–red positive amyloid deposits restricted to the renal medulla. ApoA-IV protein was the most abundant peptide in the amyloid deposits. However, molecular analysis was performed in only 2/11 patients, and no APOA4 mutations were found.

PMID: 21900878 Sethi et al., 2012
52yo man with CKD and amyloid deposits in the medulla, harbouring 3 common, likely benign APOA4 variants: c.548G>A, p.(Thr29Thr); c.1678G>A, p.(Ser147Asn); c.2378G>T, p.(Gln380His). He also carried 2 APOA1 variants: c.60T>C, p.(His20His) - synonymous, not in gnomAD; c.209T>C, p.(Leu70Pro) - missense, not in gnomAD v4. APOA1 more likely to be causal? Only sequenced these 2 genes.

Conflicting functional evidence: PMID: 39699959 Nakamura et al., 2024: TFEB downregulation in aged mice leads to APOA4 amyloidosis, though only 26.7% of mice showed 'extensive' amyloid deposition. Variants in other genes may cause APOA4 to aggregate?

APOA4 is linked to Tubulointerstitial kidney disease, autosomal dominant 6, MIM: 621106 (OMIM accessed 18th Dec 2025).
Sources: Literature

Created: 18 Dec 2025, 12:13 p.m. | Last Modified: 19 Dec 2025, 8:48 a.m.

Panel Version: 1.27

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Tubulointerstitial kidney disease, autosomal dominant 6, OMIM: 621106; tubulointerstitial kidney disease, autosomal dominant 6, MONDO:0976234; AApoAIV amyloidosis, MONDO:0018589

Publications

• 21900878
• 27262366
• 28449784
• 33751222
• 38096951
• 39699959