Unexplained young onset end-stage renal disease - additional genes

Gene: ROBO2

Red List (low evidence)

Comment on list classification: While there are more than 3 cases reported in literature with ROBO2 variants and vesicoureteral reflux, the evidence for this gene-disease association is limited and sometimes conflicting. Hence, this gene should remain Red.

Created: 17 Aug 2026, 1:20 p.m. | Last Modified: 17 Aug 2026, 1:20 p.m.

Panel Version: 2.6

PMID: 34059960 Liu et al., 2021
Study of 379 unrelated Chinese patients with Primary vesicoureteral reflux.
Patient 372 - male, 7yo, no extra-renal phenotype; het for ROBO2: 2381C>T, p.Ala794Val (not in gnomAD 4.1.1)
Patient 373 - male, 7yo, no extra-renal phenotype; het for ROBO2: 3230C>G, p.Pro1077Arg (only 1 allele reported in gnomAD v4.1.1)
Both classified VUS in the paper according to ACMG criteria.

PMID: 32041992 Darlow et al., 2020
Irish vesicoureteric reflux patients - 251 families screened for ROBO2 variants.
Non-coding variant in CpG island of ROBO2a was present in the VUR cases in one family, that was not present in 592 healthy Irish controls. Potential disease mechanism could be altered methylation of ROBO2.

PMID: 29194579 Rasmussen et al., 2018
Fetus 43 - affected by bilateral kidney agenesis, hypertrophic heart. Het for ROBO2 NM_002942.4: c.2005C>G, p.Arg669Gly, as well as a SLIT2 variant c.1022C>T, p.Pro341Leu - variants not in gnomAD. SLIT2 variants have also been reported in association with CAKUT (e.g., PMID: 26026792 Hwang et al., 2015) - cannot decouple the effect.

PMID: 27002985 Mitsioni et al., 2016
103 Greek children with nonsyndromic VUR or VUR-RHD (+ 200 controls) were screened for ROBO2 variants. ROBO2 variants were not found to be associated with nonsyndromic VUR or VUR-RHD in this cohort.

PMID: 24429398 Hwang et al., 2014
Cohort of 749 individuals from 650 different families with CAKUT, mostly from Eastern Europe (63%). 4 families had variants in ROBO2 - 2 of Indian origin, and 2 Eastern European. 4 unique ROBO2 missense variants were detected. Specific diagnoses of the 4 probands included Multicystic dysplastic kidney, Posterior urethral valves, Vesicoureteral reflux, and Ureteropelvic junction obstruction.

PMID: 23536131 Dobson et al., 2013
'Heterozygous non-synonymous ROBO2 variants are unlikely to be sufficient to cause familial vesicoureteric reflux'. Sequenced 227 index cases with primary VUR in an Irish population and found ROBO2 55 variants, of which 20 were novel. Only p.Pro522Thr and p.Val799Ile segregated with the disorder. Authors pose ROBO2 variants are more likely to act as modifiers, causing VUR with digenic or oligogenic inheritance.

PMID: 17357069 - Lu et al., 2007
Report of a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2.

FUNCTIONAL EVIDENCE: Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage exhibit striking CAKUT-VUR phenotypes. Robo2del5/del5 homozygotes uniformly died shortly after birth with multiplex, dysplastic kidneys and short ureters. 4 (15%) of 26 Robo2del5/+ heterozygous newborns exhibited a unilateral CAKUT-VUR phenotype. With gene dosage reduced further, up to 40-70% of the heterozygous knock-down mice exhibited CAKUT-VUR.

ROBO2 is associated with AD Vesicoureteral reflux 2, OMIM:610878 (OMIM accessed 17th Aug 2026). ROBO2 is also Green on Congenital anomalies of the kidney and urinary tract (CAKUT) in PanelApp Australia (accessed 17th Aug 2026).

Created: 17 Aug 2026, 11:05 a.m. | Last Modified: 17 Aug 2026, 2:22 p.m.

Panel Version: 2.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Vesicoureteral reflux 2, OMIM:610878; vesicoureteral reflux 2, MONDO:0012573

Publications

• 17357069
• 23536131
• 26026792
• 27002985
• 29194579
• 32041992
• 34059960

Red List (low evidence)

This gene has been added to this panel with red rating as it was present in R257 Unexplained young onset end-stage renal disease panel (v5.1) with the same rating before it was made a super panel.

Created: 25 Sep 2024, 9:36 p.m. | Last Modified: 25 Sep 2024, 9:36 p.m.

Panel Version: 0.65

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

I don't know

Gene imported from the 'Renal and urinary tract disorders' panel v1.8 with a rating of Red

Created: 9 Apr 2019, 11:17 a.m.

Red List (low evidence)

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

Red List (low evidence)

Red List (low evidence)

Several papers show association of vesicoureteric reflux with heterozygous ROBO2 polymorphisms but other studies do not. On the other hand, good evidence that biallelic mutations cause major renal tract malformations in mice.

Created: 22 Apr 2016, 11:39 a.m.

Mode of inheritance
Unknown

Comment on list classification: Demoted from amber to red as two reviewers in agreement.

Created: 29 Mar 2016, 10:33 a.m.