Nephrocalcinosis or nephrolithiasis

Gene: HNF4A

Comment on list classification: Changed rating to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update.

Created: 19 Oct 2020, 2:26 p.m. | Last Modified: 19 Oct 2020, 2:26 p.m.

Panel Version: 2.14

Green List (high evidence)

Multiple families reported; nephrocalcinosis is a feature.

Created: 16 Jan 2020, 5:07 a.m. | Last Modified: 16 Jan 2020, 5:07 a.m.

Panel Version: 2.0

Phenotypes
Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, OMIM #616026

Publications

• 31875549
• 24285859
• 22802087
• 30005691
• 28458902

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Only 1 specific mutation (R76W) is associated with FRTS, but that can be associated with NC

Created: 30 Oct 2019, 11:59 a.m. | Last Modified: 30 Oct 2019, 11:59 a.m.

Panel Version: 1.23

The rating of this gene has been updated following NHS Genomic Medicine Service approval. The reviewers note that nephrocalcinosis is a feature of Fanconi renotubular syndrome.

Created: 7 Mar 2022, 11:09 p.m. | Last Modified: 7 Mar 2022, 11:09 p.m.

Panel Version: 2.27

Comment on list classification: Although only one variant reported in all cases, there are now 7 cases in which the R76W/R63W (depending on reference transcript used) variant has been found in patients with Fanconi renotubular syndrome and nephrocalcinosis is a feature. Fly model also supports a pathogenic role for this variant.

Created: 24 Mar 2020, 3 p.m. | Last Modified: 24 Mar 2020, 3 p.m.

Panel Version: 2.4

Summary
4 publications (Hamilton et al 2014, Lui et al 2018, Walsh et al 2017, Anyiam et al 2019) report 7 cases of patients with R76W/R63W variants in which nephrocalcinosis is a feature. Fly model (Marchesin et al 2019) shows that the equivalent variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect.

Created: 24 Mar 2020, 2:37 p.m. | Last Modified: 24 Mar 2020, 2:47 p.m.

Panel Version: 2.3

Note the same codon is reported as R76W and R63W in different paper depending on whether NM_000457 or NM_175914 is used as the reference transcript.

Additional papers including those cited by Zornitza Stark:

PMID: 31875549 - Marchesin et al 2019 - Fly model which shows that the R85W variant in Drosophila nephrocytes works in a dominant-negative and cytotoxic effect. Expression of dHNF4 harboring the FRTS mutation affects the catabolism of lipid droplets in nephrocytes by interfering with mitochondrial function. They also showed that the FRTS mutation caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. The cytosolic aggregates have a cytotoxic affect. By contrast, the expression of another known close mutation in the DNA-binding domain, R89W (that leads to MODY1 but not to FRTS; Hamilton et al., 2014), did not cause any dominant-negative or cytotoxic effects.

PMID: 31949432 - Anyiam et al 2019 - described patient with Renal Fanconi syndrome and R63W mutation through 3rd pregnancy. She had a history of progressive renal insufficiency, persistent proteinuria, nephrocalcinosis, and recurrent nephrolithiasis.

PMID: 30005691 - Liu et al 2018 1 case of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Renal ultrasonography showed nephrocalcinosis. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia. (NOTE: no transcript identifier given but they refer to this as the same variant as R76W).

PMID: 28693455 - Walsh et al 2917 - 1 case of mother and son with heterozygous c.187C > T; p.Arg63Trp in HNF4A and Renal Fanconi syndrome. Mother is reported to have mild nephrocalcinosis

PMID: 22802087 - Stanescu et al 2012 - 1 case that presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Sequencing of HNF4A (MODY1) revealed a missense, de novo mutation (p.Arg76Trp, c.226C→T), (NM_000457) which is a known disease-causing MODY1 mutation in HNF4A. Nephrocalcinosis not specifically mentioned.

No nephrocalcinosis reported:
PMID: 28458902 - Clemente et al 2017 - 1 patient with congenital hyperinsulinaemic hypoglycaemia, rickets with craniotabes, wrist widening, genu varum and motor impairment. non-gap metabolic acidosis with acidified urine suggestive of proximal tubular acidosis, glycosuria with generalised aminoaciduria and tubular type proteinuria. Says this patient did NOT have the same ‘atypical’ Fanconi syndrome with hypercalciuria with relative hypocalcaemia, hypermagnesaemia, nephrocalcinosis and renal impairment as the patients reported by Hamilton et al 2014. A de novo variant p.Arg63Trp, c.187C > T (reference sequence: NM_175914.4) was found.

PMID: 27245055 - Improda et al 2016 - 2 infants with the p.R63W mutation HNF4A with macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia. No nephrocalcinosis reported but this may be due to young age.

Created: 23 Mar 2020, 1:35 p.m. | Last Modified: 24 Mar 2020, 2:53 p.m.

Panel Version: 2.3

Comment on list classification: Promoting from red to amber. Only one paper (PMID: 24285859) reporting variants in this gene associated with Fanconi syndrome and nephrocalcinosis and all patients have the same variant. Another paper reports that individuals with that variant have congenital hyperinsulinism and Fanconi syndrome but no nephrocalcinosis, however they are younger than the previously reported patients. Rating amber for now until another report confirms the association.

Created: 30 Oct 2019, 2:10 p.m. | Last Modified: 30 Oct 2019, 2:10 p.m.

Panel Version: 1.24

Associated with Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young #616026 (AD) in OMIM with nephrocalcinosis listed as a clinical feature.

PMID: 24285859 - Hamilton et al 2014 - report 6 patients from 4 families heterozygous for the p.R76W HNF4A mutation who have Fanconi syndrome and nephrocalcinosis in addition to neonatal hyperinsulinism and macrosomia. 1 family initially identified then 3 others identified with the same variant were identified. Nephrocalcinosis was present in all patients with the R76W mutation, but not in 20 patients with other mutations in the HNF4A gene. No haplotype analysis was done, and it is not stated if the patients were of the same ethnic origin.

PMID: 25819479 - Numakura et al 2015 - report two new cases of the p.R76W mutation, both of whom presented with congenital hyperinsulinism and Fanconi syndrome. Neither patient had nephrocalcinosis, however, they had increased levels of urinary calcium excretion and were younger than the patients described by Hamilton et al. [2]. They may have nephrocalcinosis in the future.

Created: 21 Oct 2019, 1 a.m. | Last Modified: 21 Oct 2019, 1 a.m.

Panel Version: 1.22