Tubulointerstitial kidney disease

Gene: JAG1

Green List (high evidence)

Comment on list classification: There are at least 3 unrelated individuals with monoallelic variants in JAG1 and isolated tubulointerstitial kidney disease. Based on the available evidence, this gene should be rated Green for Tubulointerstitial kidney disease.

Created: 29 Oct 2025, 4:13 p.m. | Last Modified: 29 Oct 2025, 4:13 p.m.

Panel Version: 3.6

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).

Created: 29 Oct 2025, 2:40 p.m. | Last Modified: 29 Oct 2025, 4:10 p.m.

Panel Version: 3.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Autosomal dominant tubulointerstitial kidney disease

Publications

• 41061854

Green List (high evidence)

JAG1 causes Alagile syndrome but new evidence shows it can give renal limited phenotypes resembling ADTKD
Sources: Expert list

Created: 10 Oct 2025, 7:59 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
tubulointersitial kidney disease; kidney failure

Publications

• PMID: 41061854

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments