Cystic kidney disease

Gene: CYP24A1

The OMIM entry for this gene disease association Hypercalcemia, infantile, 1, OMIM:143880 records an autosomal recessive mode of inheritance but no publications since 2011 have been assessed. There is now evidence that individuals may present with disease in adult hood, and some evidence that those with monoallelic variants present with milder disease.

Update on monoallelic cases where a phenotype is assessed:

PMID: 21675912 - Schlingmann et al 2011 - report 7 families with homozgyous or compound heterozgyous variants in CYP24A1 and infantile hypercalcaemia and 1 case with a heterozygous deletion affecting a splice site but the authors note that there may be another undetected variant outside of the coding region. Analysis was of a few candidate genes only. Renal cysts were not assessed.

PMID: 22337913 - Tebben et al 2012 - proband (aged 44 years) with hypercalcemia and hypercalciuria and elevated serum 1,25(OH)2D. Only CYP24A1 and CYP27B were sequenced. 2 splice mutations in CYP24A1 were identified. Seven family members from three generations showed chemical and clinical phenotypes with one or two CYP24A1 mutations, suggesting autosomal dominant transmission with partial penetrance of the trait. Renal cysts were noted in the proband and one heterozygous child of the proband.

PMID: 24235083 - Colussi et al 2014 - report 2 unrelated probands with homozgyous variants in CYP24A1 and recurrent nephrolithiasis, chronic hypercalcaemia with depressed parathyroid hormone (PTH) and increased 1,25(OH)(2)D levels; heterozygous carriers had nephrolithiasis (two of six), hypercalciuria (two of six) and high or normal-high 1,25(OH)(2)D (four of four).  The authors conclude that heterozygous carriers may also have subtle abnormalities of vitamin D metabolism that predispose them to events such as renal stones.                                                                                                                                      

PMID: 26214117 - Molin et al 2015 - report 25 patients out of a pool of 72 with hypercalcemia that had CYP24A1 variants. Only this gene was screened. 20 had biallelic variants, mostly with nephrocalincosis or renal stones. 5 neonates were heterozygous without renal disease. Further investigation of relatives found a further 21 heterozygotes who were found to have normal serum calcium and PTH levels. They note that while most heterozygous individuals remain asymptomatic, hypercalcemia may occur due to excessive vitamin D intake.

PMID: 27129455 - O'Keeffe et al 2016 - ABSTRACT ONLY ACCESSED - report a family with affected individuals with both biallelic and monallelic variants in CYP24A1. A gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations. However, they note that 2 subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia.

PMID: 34307984 - Hanna et al 2021 - report a high prevalance in of kidney cysts in patients with CYP24A1 deficiency. Looked at 16 patients from 12 pedigrees with confirmed pathogenic variants. Medullary and/or corticomedullary junction cysts were present in all cases. Heterozygous variants were reported in 2 families - patient 11, pedigree 7, and patients 1,2 and 3 in pedigree 1. Patient 10 was compound heterozygous. Family 1 is same family reported in Tebben et al 2012.

PMID: 38504242 - Wang et al 2024 - studied 6 patients with Idiopathic infantile hypercalcemia. 2 patients were found to have compound heterozygous mutations of CYP24A1, one patient had a monoallelic CYP24A1 variant (patient 1). Patient presented with hypercalcemia and had significant renal calcification.

PMID: 33249478 - Brancatella et al 2021 - ABSTRACT ONLY ACCESSED - a large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites. The 40 yo male proband proband, was homozygous for p.Arg223* pathogenic variant. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations, without any difference in the other biochemical parameters and in the rate of nephrolithiasis. The authors note that heterozygotes might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.

In conclusion, while the bulk of patients with Hypercalcemia have biallelic variants, those with monoallelic variants generally present with a milder phenotype or are asymptomatic, and therefore the mode of inheritance should be kept as biallelic until the association with disease is more clear.

Created: 25 Jan 2026, 11:55 p.m. | Last Modified: 27 Jan 2026, 5:33 p.m.

Panel Version: 8.2

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 21675912
• 22337913
• 24235083
• 26214117
• 2712945
• 34307984
• 38504242
• 33249478

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:54 p.m. | Last Modified: 24 Feb 2025, 5:54 p.m.

Panel Version: 7.12

CYP24A1 variants have been associated with Hypercalcemia, infantile, 1 (OMIM:143880). PMIDs: 34307984; 22337913; 27105398; 28324001 report numerous biallelic CYP24A1 variants in cases of OMIM:143880, with the occurrence of kidney cysts. PMID: 34307984 also reports a family, where three of the members are monoallelic for CYP24A1 variants, but present with OMIM:143880 and 2/3 of these cases also have kidney cysts. However, as this is the only report of monoallelic variants for this gene associated with OMIM:143880, the mode of inheritance for this gene should be BIALLELIC, autosomal or pseudoautosomal.

Created: 11 Nov 2024, 3:15 p.m. | Last Modified: 11 Nov 2024, 4:26 p.m.

Panel Version: 7.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Can give cystic kidney disease (mild, atypical) but useful to be added to R193 panel
Sources: Expert list

Created: 3 Nov 2024, 9:40 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
cystic kidney disease; nephrocalcinosis; hypercalcaemia

Publications

• 34307984
• 22337913
• 27105398
• 28324001