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Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska changed review comment from: 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: 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 - 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).; to: 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 - 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).
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska changed review comment from: 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. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. 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.; to: 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. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. 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 Tubulointerstitial kidney disease.
Tubulointerstitial kidney disease v3.13 APOA4 Ida Ertmanska edited their review of gene: APOA4: Added comment: 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. ApoA4 deposits have also been reported in cases of systemic amyloidosis, with renal and cardiac involvement. 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.; Changed rating: GREEN; Changed publications to: 21900878, 27262366, 28449784, 33751222, 38096951, 39699959
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: 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. 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: 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 - 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).; to: 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: 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 - 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).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: 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. 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. 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: 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 - 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).; to: 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. 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: 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 - 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).
Tubulointerstitial kidney disease v3.10 APOA4 Ida Ertmanska changed review comment from: 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. 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. 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: 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: TFEB downregulation in aged mice leads to APOA4 amyloidosis - 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).; to: 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. 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. 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: 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 - 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).
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska changed review comment from: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies & ER stress analysis suggests that the tubulointerstitial renal disease was due to haploinsufficiency and loss of function. JAG1 is predicted to be dosage sensitive with pLI = 1.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025). ; to: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong. Confirmed exon skipping, abnormal transcripts constituted 44% in patient cells.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies & ER stress analysis in Families 2 & 3 suggests that the tubulointerstitial renal disease was due to haploinsufficiency and loss of function. While mRNA levels were comparable to WT, protein levels were reduced. JAG1 is predicted to be dosage sensitive with pLI = 1.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025).
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska changed review comment from: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies as well ER stress analysis suggests that the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025). ; to: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies & ER stress analysis suggests that the tubulointerstitial renal disease was due to haploinsufficiency and loss of function. JAG1 is predicted to be dosage sensitive with pLI = 1.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025).
Tubulointerstitial kidney disease v3.6 JAG1 Ida Ertmanska changed review comment from: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & unsolved kidney disease cases from the 100,000 Genomes project.
Variant in JAG1 was identified in three large families with unsolved ADTKD, and additional rare variants were identified in sporadic cases.
None of the 23 adult patients affected with isolated kidney failure (and tubulointerstitial nephritis in individuals with available kidney biopsy) had overt sign of liver, bile duct, heart, eye, or skeletal defect. JAG1 expression studies as well ER stress analysis suggests that the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function.; to: PMID: 41061854 Menguy et al., 2025 (in press)
Cohort of 203 families with Autosomal dominant tubulointerstitial kidney disease (ADTKD) & kidney disease cases with unknown aetiology from the 100,000 Genomes project - 1133 patients.
Variants in JAG1 were identified in three large families with unsolved ADTKD:
Family 1: c.864G>A, p.Trp288* - not in gnomAD v4.
Family 2: c.601C>T, p.Arg201Cys - MAF in gnomAD v4 = 0.000001695 (European); Revel score = 0.89.
Family 3: c.2372+3_2372+6del - not in gnomAD v4; SpliceAI score = 0.62 Splice-altering Strong.
Tubulointerstitial nephropathy was confirmed by kidney histology in 2 cases from 2 families. Variants shown to segregate with disease, with the exception of individual III-3 in Family 2, who was an asymptomatic carrier. Exome sequencing was used for families 1 & 3, and a targeted NGS panel for family 2.

Further 6 cases reported from the Necker hospital in Paris: individuals with chronic kidney disease, without proteinuria, hematuria, or uropathy. 6 rare missense variants in JAG1 were identified. Also, 2 cases from the 100,000 Genomes project were identified to harbour two different rare missense variants in JAG1. No access to supplementary material to retrieve the variant details at this time.

JAG1 expression studies as well ER stress analysis suggests that the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function.

JAG1 is associated with several autosomal dominant phenotypes in OMIM: Tetralogy of Fallot, 187500; Charcot-Marie-Tooth disease, axonal, type 2HH, 619574; Alagille syndrome 1, 118450, and a provisional association with Deafness, congenital heart defects, and posterior embryotoxon, 617992 (OMIM accessed 29th Oct 2025).
JAG1 is linked to Alagille syndrome in ClinGen, with a Definitive classification (April 2025).
Tubulointerstitial kidney disease v3.6 JAG1 John Sayer gene: JAG1 was added
gene: JAG1 was added to Tubulointerstitial kidney disease. Sources: Expert list
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to PMID: 41061854
Phenotypes for gene: JAG1 were set to tubulointersitial kidney disease; kidney failure
Penetrance for gene: JAG1 were set to Incomplete
Mode of pathogenicity for gene: JAG1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: JAG1 was set to GREEN
Added comment: JAG1 causes Alagile syndrome but new evidence shows it can give renal limited phenotypes resembling ADTKD
Sources: Expert list
Tubulointerstitial kidney disease v1.23 GATM Arina Puzriakova Phenotypes for gene: GATM were changed from Renal fanconi syndrome and kidney failure to Fanconi renotubular syndrome 1, OMIM:134600
Tubulointerstitial kidney disease v1.21 TTC21B Eleanor Williams Added comment: Comment on mode of inheritance: Leaving the mode of inheritance as Both mono and biallelic for now. It does appear that monoallelic variants are potential genetic modifiers and are found in combination with variants in other renal disease associated genes (see PMID: 26940125, PMID: 21258341) so seeking GMS review as to the best mode of inheritance.
Tubulointerstitial kidney disease v1.20 TTC21B Eleanor Williams edited their review of gene: TTC21B: Added comment: Looking at the mode of inheritance for this gene. It is reported as both AD and AR in OMIM for Nephronophthisis 12, OMIM:613820.

There are many biallelic cases reported e.g.

PMID: 21258341 - Davis et al 2011 - report 5 families with isolated nephronophthisis (NPHP). Patients in 3 families had compound heterozygous variants (P209L/C552X, c.2758-2A>G/P209L, W150R/c.3264-3C>G) in TTC21B and 2 families with a milder phenotype were homozygous for the P209L variant. They observed the same haplotype at coding regions spanning the locus in all P209L homozygotes. In all 5 families individuals heterozygous for the variants were unaffected. They also report one case with compound het variants (R411X/L795P) with a syndromic Jeune Asphyxiating Thoracic Dystrophy phenotype.

PMID: 26940125 - Bullich et al 2017 - TTC21B variants and nephrotic proteinuria with FSGS and tubulointerstitial lesions were identified in 2 families with homozygous (p.P209L) variants (both families from Morocco, high blood pressure noted in individuals from each), and in 1 family with compound het variants (p.P209L and p.H426D)(family from Spain).

PMID:34957165 - Gambino et al 2021 - patient from a North African family with severe hypertension and chronic kidney disease at age 20. Several cases of hypertension, myopia, and severe kidney disease were reported in the extended family. A homozygous p.P209L variant was identified in TTC21B.

PMID:34805047 - Bezdíčka et al 2021 - 2.5 yo patient presenting with brachydactyly, nephrotic-range proteinuria, and renal tubular acidosis, and a kidney biopsy revealed focal segmental glomerulosclerosis. She was hypertensive on admission. Compound het variants in TTC21B were identified p.Pro209Leu and p.Cys14Arg. The mother was a healthy carrier of the c.626C>T, p.Pro209Leu heterozygous variant.

PMID:35289079 - Olinger et al 2022 - 2 siblings with extreme early-onset HTN, proteinuria, and progressive CKD leading to kidney failure. Compound het variants in TTC21B were identified (p.(Gln834Ter) and p.(Pro209Leu)).

However, there are also reports of heterozygous variants in TTC21B in patients with kidney disease but it is thought that these may be modifier variants

PMID: 26940125 - Bullich et al 2017 - rare heterozygous variants in TTC21B were found in 5 patients, 4 with glomerular disease and 1 with cystic disease, but in addition to other likely pathogenic variants in other renal disease related genes (PKD1 , COL4A3, COL4A5 and NPHS2) suggesting a modifier role of TTC21B alleles. 2 patients presented a more severe phenotype than expected. A similar frequency for the total set of rare TTC21B variants predicted to be pathogenic was found between renal patients and controls

PMID: 21258341 - Davis et al 2011 - found an enrichment of pathogenic TTC21B alleles in ciliopathy patients (∼5%) and suggest that TTC21B might be a common contributor to the total mutational load in ciliopathies.; Changed publications to: 21258341, 26940125, 34957165, 34805047, 35289079
Tubulointerstitial kidney disease v1.16 DNAJB11 Eleanor Williams commented on gene: DNAJB11: The rating of this gene has been updated following NHS Genomic Medicine Service approval. The reviewers note a patient with likely pathogenic frameshift who had a later presentation of renal cysts on background of interstitial disease. 19 variants associated with DNAJB11 or AD PKD on HGMD. Recent collaborative paper by Huynh et al. (2020) reports a total of 77 patients (27 pedigrees) that have been described in the literature. The majority of these patients present with polycystic kidneys.
Tubulointerstitial kidney disease v1.4 DNAJB11 Eleanor Williams commented on gene: DNAJB11: Associated with Polycystic kidney disease 6 with or without polycystic liver disease #618061 (AD) in OMIM.

PMID: 29706351 - Cornec-Le Gall et al 2018 - Initially identified DNAJB11 variants by WES in two families presenting with Autosomal-dominant polycystic kidney disease (ADPKD)-like features. In family 1 a missense variant (p.Pro54Arg) was found in two family members presenting with non-enlarged polycystic kidneys. In family 2 a frameshifting change (c.166_167insTT) was found; they presented with small renal and liver cysts. Five additional multigenerational families carrying DNAJB11 mutations were identified by targeted analysis. From analysis of the phenotype and functional studies from DNAJB11-null cells they conclude that DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.

PMID: 29777155 - Allison 2018 - research highlight about the Cornec-Le Gall et al 2018 paper.
Tubulointerstitial kidney disease v1.0 SEC61A1 Zornitza Stark reviewed gene: SEC61A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30586318; Phenotypes: Familial juvenile Hyperuricemic nephropathy-4 MIM 617056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Tubulointerstitial kidney disease v1.0 DNAJB11 Zornitza Stark reviewed gene: DNAJB11: Rating: GREEN; Mode of pathogenicity: None; Publications: 29706351; Phenotypes: Tubulointerstitial disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Tubulointerstitial kidney disease v0.8 MT-TF Daniel Gale gene: MT-TF was added
gene: MT-TF was added to Tubulointerstitial kidney disease. Sources: Literature
Mode of inheritance for gene gene: MT-TF was set to MITOCHONDRIAL
Publications for gene: MT-TF were set to PMID: 28267784; 11231339; 20142618; 23135609
Phenotypes for gene: MT-TF were set to Tubulointerstitial kidney disease; tubulointerstitial nephritis; renal insufficiency; renal failure
Penetrance for gene: MT-TF were set to Complete
Review for gene: MT-TF was set to GREEN
gene: MT-TF was marked as current diagnostic
Added comment: Sources: Literature
Tubulointerstitial kidney disease v0.8 ZNF423 Eleanor Williams Added comment: Comment on list classification: Changing rating to Amber after discussion of 3 cases in NHS GMS renal specialist group call on 2019-02-04 - one case NPHP, one Joubert with PKD, one PKD/NPHP.
Tubulointerstitial kidney disease v0.7 REN Eleanor Williams Added comment: Comment on mode of inheritance: Updated MOI to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" after discussion in meeting with NHS GMS renal specialist group
Tubulointerstitial kidney disease v0.7 REN Eleanor Williams Mode of inheritance for gene: REN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Tubulointerstitial kidney disease v0.4 MUC1 Eleanor Williams commented on gene: MUC1: PMID: 23396133 (Kirby et al 2013) describe 6 families with an insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The insertion results in a frameshift which is predicted to produce a mutant protein that contains many copies of a novel repeat sequence but which lacks, owing to a novel stop codon shortly beyond the VNTR terminus, the downstream SEA self-cleavage module and both transmembrane and intracellular domains characteristic of the normal MUC1 precursor protein.
Tubulointerstitial kidney disease v0.3 GATM Eleanor Williams edited their review of gene: GATM: Added comment: PMID: 29654216 (Reichold et al 2018) reports 5 families with with a novel form of autosomal dominant
kidney disease characterized by renal tubular Fanconi syndrome early in life
followed by progression to renal glomerular failure in mid-adulthood. All patients show
monoallelic mutations in the gene GATM. 4 heterozygous missense mutations of evolutionary conserved amino
acid residues in GATM were found (c.958C>T, p.P320S; c.1006A>G, p.T336A; c.1007C>T, p.T336I;
c.1022C>T, p.P341L). In each family, one variant segregated with the disorder and was fully
penetrant. In silico analysis showed that the particular GATM mutations create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells.; Changed publications: 29654216
Tubulointerstitial kidney disease v0.3 GATM Eleanor Williams reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: ; Phenotypes: Renal fanconi syndrome and kidney failure; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tubulointerstitial kidney disease v0.3 NPHP3 Eleanor Williams reviewed gene: NPHP3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Nephronopthisis 3 MIM 604387, Meckel syndrome 7, MIM 267010, Renal-hepatic-pancreatic dysplasia 1, MIM 208540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Tubulointerstitial kidney disease v0.3 REN Eleanor Williams reviewed gene: REN: Rating: GREEN; Mode of pathogenicity: ; Publications: Zivna et al 2009 PMID: 19664745, Gribouval et al 2005 PMID: 16116425; Phenotypes: Familial juvenile Hyperuricemic nephropathy-2 MIM 613092, Renal tubular dysgenesis MIM 267430; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Tubulointerstitial kidney disease v0.3 HNF1B Eleanor Williams reviewed gene: HNF1B: Rating: GREEN; Mode of pathogenicity: ; Publications: Edghill et al 2006 PMID: 15930087; Phenotypes: Renal cysts and diabetes syndrome MIM 137920, NIDDM MIM 125853; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tubulointerstitial kidney disease v0.2 GATM Eleanor Williams gene: GATM was added
gene: GATM was added to Tubulointerstitial kidney disease. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: GATM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GATM were set to Renal fanconi syndrome and kidney failure
Mode of pathogenicity for gene: GATM was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments
Tubulointerstitial kidney disease v0.2 NPHP3 Eleanor Williams gene: NPHP3 was added
gene: NPHP3 was added to Tubulointerstitial kidney disease. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: NPHP3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NPHP3 were set to Renal-hepatic-pancreatic dysplasia 1, MIM 208540; Meckel syndrome 7, MIM 267010; Nephronopthisis 3 MIM 604387
Tubulointerstitial kidney disease v0.2 REN Eleanor Williams gene: REN was added
gene: REN was added to Tubulointerstitial kidney disease. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: REN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: REN were set to 16116425; 19664745
Phenotypes for gene: REN were set to Renal tubular dysgenesis MIM 267430; Familial juvenile Hyperuricemic nephropathy-2 MIM 613092
Tubulointerstitial kidney disease v0.2 HNF1B Eleanor Williams gene: HNF1B was added
gene: HNF1B was added to Tubulointerstitial kidney disease. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: HNF1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HNF1B were set to 15930087
Phenotypes for gene: HNF1B were set to Renal cysts and diabetes syndrome MIM 137920; NIDDM MIM 125853