Abstract
Background
Hepatocyte nuclear factor 1β (HNF1B) pathogenic variants constitute a major genetic contributor to congenital anomalies of the kidney and urinary tract (CAKUT), with patients simultaneously exhibiting distinct extrarenal features. Among these clinical manifestations, renal disease progression is crucial for long-term outcomes, needing comprehensive evaluation.
Methods
Using the Chinese Children Genetic Kidney Disease Database (2017–2024), we analyzed 26 pediatric HNF1B cases to characterize renal phenotypes and genotype correlations.
Results
All patients exhibited abnormal renal phenotypes at diagnosis: renal cysts (50%) and multicystic dysplastic kidney (MCDK) (37.5%). Genetic analysis revealed 16 patients (61.5%) had a 17q12 deletion including the HNF1B gene, while the remaining carried HNF1B intragenic pathogenic variants, including a novel c.1390-1405dup. Comparing phenotypic trajectories, 17q12 deletion cases showed earlier renal phenotype onset (median age: 0 vs. 1 year 11 months, p = 0.121), while HNF1B variants showed faster renal function deterioration (latest eGFR: 85 vs. 45.6 mL/min/1.73 m², p = 0.11). Three of five CKD 5 children underwent kidney transplantation before 15; one developed reversible tacrolimus-induced hyperglycemia.
Conclusion
Our results suggest a potential trend wherein the 17q12 deletion may be associated with a higher prevalence of developmental renal anomalies, while HNF1B pathogenic variants might correlate with an increased risk of tubular dysfunction, indicating possible distinct genotype-phenotype correlations. Based on these observations, we recommend that affected families receive tailored clinical management, including prenatal counseling, genotype-specific monitoring, and regular renal function assessment.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12882-025-04616-z.
Keywords: HNF1B, 17q12 deletion, CAKUT, Chronic kidney disease, Children
Introduction
The clinical evaluations of renal function progression, the assessment of extrarenal manifestations, and the identification of underlying genetic causes of renal cysts are all critical for the differential diagnosis of CAKUT, whether detected prenatally or postnatally, accounting for 20–30% of prenatal congenital malformations and affecting approximately 3–6 in 1000 live births [1]. Among monogenic CAKUT etiologies, HNF1B pathogenic variants constitute a predominant genetic cause, with this locus demonstrating particular susceptibility to pathogenic de novo variants [2]. As a pivotal transcription factor governing embryonic organogenesis, particularly in the kidney and pancreas, the HNF1B pathogenic variant is initially found to be responsible for Renal Cysts and Diabetes syndrome (RCAD; OMIM #137920) or Maturity-Onset Diabetes of the Young 5 (MODY5; OMIM #604284), following an autosomal dominant inheritance pattern [3, 4]. Of clinical significance, since glucose homeostasis abnormalities in HNF1B syndrome remain pharmacologically modifiable, kidney failure has emerged as the predominant prognostic determinant [5, 6]. Therefore, systematic characterization of HNF1B genotype-phenotype relationships, particularly focusing on renal manifestations, is crucial for both mechanistic understanding and clinical management.
As a member of the homeodomain-containing transcription factor superfamily, HNF1B comprises an amino-terminal dimerization domain, a bipartite POU-type DNA-binding domain, and a carboxy-terminal transactivation domain interacting with key coactivators and corepressors in organogenesis and homeostasis [7]. Specifically for kidney development, HNF1B plays critical roles in multiple morphogenetic processes, including ureteric bud branching, nephron patterning, and tubulogenesis. HNF1B absence prevents mesenchymal to epithelial transition, ultimately leading to renal hypoplasia [8]. When Hnf1b is deleted during the tubular elongation phase, a multicystic phenotype emerges, accompanied by downregulation of cystogenesis-related genes, such as Pkd2, Pkhd1, and Umod [9, 10]. For the postnatal kidney, HNF1B is involved in tissue maintenance and is responsible for metabolism and solute transport partially through regulating the expression of FXYD2, a key regulator for renal magnesium (Mg²⁺) reabsorption [11]. Consequently, HNF1B pathogenic variants can disrupt electrolyte homeostasis, another observable clinical phenotype. Notably, not all HNF1B abnormalities are associated with electrolyte disorders. In vitro studies have shown that specific pathogenic variants modify the expression networks of downstream target genes, suggesting a potential mechanism underlying phenotypic heterogeneity [12]. Thus, exploring the correlation between HNF1B pathogenic variant types and clinical phenotypes would facilitate the establishment of a precise diagnostic system for HNF1B-related disorders.
In this study, a pediatric cohort comprising 26 children with HNF1B-related disorders was established using the Chinese Children’s Genetic Kidney Disease Database (CCGKDD). After systematically analyzing their phenotypic and genotypic characteristics, we found that the 17q12 deletion cohort exhibited earlier onset of fetal renal phenotypic abnormalities(median age: 0 vs. 1 year 11 months, p = 0.121), whereas the HNF1B pathogenic variant group displayed more severe renal functional deterioration at final follow-up (latest estimated glomerular filtration rate (eGFR): 85 vs. 45.6 mL/min/1.73 m², p = 0.11). These phenotypic divergences likely stem from distinct genetic mechanisms, including transcription factor dominant-negative effects and haploinsufficiency-mediated pathways. Moreover, for HNF1B-mutated kidney transplant recipients developing tacrolimus-associated hyperglycemia, conversion to cyclosporine A or sirolimus may be considered.
Participants and methods
Subjects
A total of twenty-six Chinese pediatric patients with HNF1B pathogenic variants from CCGKDD were enrolled. The inclusion criteria required: (1) molecular diagnosis of HNF1B with pathogenic variants by sequencing, and (2) comprehensive clinical documentation. Specifically, genetic diagnosis is determined based on the following criteria: A definitive molecular diagnosis based on the identification of a heterozygous pathogenic variant or large genomic rearrangement affecting HNF1B, without pathogenic variants in other known genes associated with renal disease. This included: Sequence-level variants (e.g., nonsense, frameshift, splice-site, or missense variants) classified as pathogenic or likely pathogenic based on the ACMG/AMP guidelines [13] and confirmed by Sanger or next-generation sequencing; or large deletions encompassing all or a critical portion of the HNF1B gene, detected by MLPA or array CGH. Variants of uncertain significance (VUS) were excluded from the study. All classifications were reviewed by a clinical molecular geneticist. Detailed phenotypic data, including renal manifestations, diabetes status (in probands or family members), and other clinical features, were collected from institutional medical records. All the enrolled cases were distributed in four centers, scattered over thirteen provinces/municipalities (seventeen cities) in China.
Clinical diagnosis
All patients enrolled in this study were primarily diagnosed by pediatric nephrologists. CAKUT, pancreatic and hepatobiliary tract malformations were defined as structural abnormalities in the imaging tests, including ultrasonography, X-ray fluoroscopy, computed tomography, or magnetic resonance imaging. Hyperuricemia in children/adolescents was defined as serum uric acid levels ≥ 5.5 mg/dL [14]. Electrolyte abnormalities were diagnosed when abnormal levels persisted or necessitated intervention. Hypomagnesemia was defined as serum magnesium concentrations < 0.65 mmol/L. Diabetes was diagnosed as patients with chronic hyperglycemia meeting the following criteria repeatedly: (1) fasting plasma glucose level of ≥ 126 mg/dL; (2) 2-h post-load glucose ≥ 200 mg/dL during a 75 g oral glucose tolerance test; (3) random plasma glucose ≥ 200 mg/dL [15]. The estimated glomerular filtration rate (eGFR) was calculated from serum creatinine and body height according to the Schwartz formula [16]. Chronic kidney disease (CKD) stages I–V were defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group guidelines [17]. Genital abnormalities and neurological abnormalities were diagnosed by primary doctors.
Genetic analysis
Genetic studies for probands and available first-degree relatives included whole exome sequencing (WES), whole genome sequencing (WGS), gene copy number variation (CNV) analysis (e.g., by MLPA and array CGH), quantitative polymerase chain reaction (qPCR), or kidney panel examination. Peripheral venous blood (2–4 mL) was collected to extract genomic DNA using the Blood Genome Column Medium Extraction Kit following the manufacturer’s instructions (Kangweishiji, China). All sequencing was performed by the Beijing Chigene Translational Medicine Research Center Co., Ltd., Beijing, China. The paired-end reads were aligned to the Ensembl GRCh37/hg19 reference genome using Burrows-Wheeler Aligner (BWA). Single-nucleotide variants (SNVs) and small insertions/deletions (Indels) were called using the Genomic Analysis Toolkit (GATK) software (version 4.1.7). Copy number variants (CNVs) were detected using the Exon Depth algorithm. Sequence alterations were checked against published polymorphisms/mutations and evaluated for conservation across species. Pathogenicity analysis of variants was performed according to the ACMG [13] practice guidelines. Bidirectional Sanger sequencing was performed to validate the screened variants. Multiple computational software (Human Splicing Finder 3.1, PolyPhen-2, Mutation Taster, and VarCards) were used to evaluate the pathogenic effects of variants. In this study, genetic pathogenic variant analysis was performed using our independently developed platform, the Zhiyin Diagnostic Cloud (http://cloud.chigene.org).
Molecular modeling and structural analysis
The 3D modeled structures of the HNF1B protein for the wild-type and mutant types were prepared using homology modeling in SWISS-MODEL. Structural analysis was analyzed and visualized using the PyMOL software.
Statistical analysis
Continuous variables are presented as median (range). The Mann-Whitney test was used for comparison of non-normal distributed continuous variables between the two groups, while Fisher’s exact probability test was used for categorical variables. Kaplan-Meier survival curves were employed to compare the renal survival using end-stage kidney disease (ESKD) as an endpoint. A p value ≤ 0.05 was considered to be statistically significant. IBM SPSS Statistics 25 software (IBM Co., Armonk, NY, USA) was used for all calculations.
Results
Clinicopathological analysis of renal disorders
26 HNF1B-associated pediatric patients consisted of 10 males, 14 females, and 2 cases with unrecorded sex. The median age at disease onset was 0 years (range: 0-5.3 years), whereas the median age at genetic diagnosis was 5.8 years (range: 1.3–7.5 years), and the median age at the latest eGFR measurement of 21 patients with regular follow-up was 79 (IQR: 48.5–113) months. Reflecting the above median disease onset of 0 years, 15 cases (58%) exhibited abnormal renal findings on prenatal ultrasound. The spectrum included: hyperechoic kidneys (HE; 5/15), hydronephrosis (HN; 3/15), renal dysplasia (3/15), cysts (3/15), abnormal amniotic fluid volume (3/15), and solitary kidney (1/15) (Fig. 1). Notably, 3 cases presented with two concurrent abnormalities primarily involving amniotic fluid volume: P5 had prenatal oligohydramnios and bilateral kidney dysplasia; P9 had prenatal oligohydramnios, postnatal left MCDK, and bilateral HE; and P21 had prenatal hydramnios and bilateral HE. Transitioning to postnatal evaluation, all 24 cases that had undergone postnatal ultrasound demonstrated renal abnormalities. The remaining 2 cases, with abnormalities detected prenatally, were yet to be born at the close of the follow-up period. And the postnatal phenotype diverged from prenatal findings, with cysts emerging as the dominant feature (12/24), followed by MCDK (9/24) and renal dysplasia (5/24; defined sonographically by reduced kidney size and/or abnormal renal parenchymal architecture). Rare manifestations comprised ectopic kidney, duplex kidney, esicoureteral reflux (VUR), and nephrocalcinosis, each observed in one case. Based on current observations, we speculate that this observed phenotypic evolution may represent a progressive renal pathology from fetal to childhood stages in HNF1B-related nephropathy (Table 1).
Fig. 1.
Representative renal imaging alterations in HNF1B-associated kidney disease. (a) Ultrasound image of patient 11 shows multiple renal cysts. Red asterisks indicate the location of renal cysts. (b) CT image of patient 12 reveals a left renal stone. Red arrows indicate renal stones. (c) CT image of patient 14 demonstrates multiple cystic hypodense lesions in both kidneys. (d) Magnetic resonance urography (MRU) image of patient 11 depicts multiple cysts in the left kidney and cystic renal dysplasia in the right kidney. Red dashed lines outline the contours of the dysplastic kidney. Red asterisks indicate the location of renal cysts
Table 1.
Phenotypes and genotypes of the patients
| Case | Age | Sex | Family history | Prenatal renal assessment | Postnatal renal phenotype | Extral-renal phenotype | HNF1B gene mutation (accession no: NM_000458) or 17q12 deletion (assembly: GRCh37) | Mutation origin | |
|---|---|---|---|---|---|---|---|---|---|
| Onset | GD | ||||||||
| 1 | 0 | 4y | F | No | HE (B) | Cyst (B), CKD1 | No | 17q12 deletion; chr17: 34,815,551–36,249,430 (1.4 Mb) | NA |
| 2 | 0 | 1y1m | M | father: HN (R) and Cyst (B) | Dysplasia (L) | dysplasia (L), Cyst (R) | MD | 17q12 deletion; chr17: 34,536,497–36,388,301 (1.85 Mb) | Paternal |
| 3 | 0 | 5y9m | M | No | HE (B) | MCDK (B), HUA, CKD 2 | DD | 17q12 deletion; NA | NA |
| 4 | 8y5m | 8y5m | M | mother: Cyst and stones (B) | No | dysplasia (B), HE (B), HUA, proteinuria, CKD 3 | No | c.578 T > C (exon 3), p.M193T | Maternal |
| 5 | 0 | 2y8m | F | No | dysplasia (B), Oligohydramnios | MCDK (B), HN (B), HUA, CKD4 | DD | 17q12 deletion; chr17: 34,775,520–36,278,036 (1.5 Mb) | Maternal |
| 6 | 0 | 3 m | F | No | HN (L) | Cyst (B), HN (L), CKD 1 | No | 17q12 deletion; chr17: 34,765,237–36,276,584 (1.52 Mb) | De novo |
| 7 | 0 | 5 m | M | No | dysplasia(B) | dysplasia (B), HE (B), HUA, CKD 5 | No | c.441G>T (exon 2), p.Q147H | De novo |
| 8 | 11y9m | 11y10m | F | No | No | Cyst (L), MCDK (R), proteinuria, HUA, CKD 4 | No | c.1339 + 5 (IVS6) G > T | De novo |
| 9 | 1y3m | 1y4m | M | No | Oligohydramnios | MCDK (L), HE (B), HUA, CKD 2 | No | 17q12 deletion; chr17: 34,836,666–36,241,241 (1.4 Mb) | De novo |
| 10 | 7 m | 11 m | F | No | No | MCDK (B), HE (B), NC (B), HUA, CKD 3 | SP | c.493 C>G(exon 2), p.R165G | De novo |
| 11 | 7y9m | 7y9m | F | No | No | MCDK (R), HUA, CKD 5 | DD | 17q12 deletion; chr17: 34,495,987–36,293,050 (1.8 Mb) | Maternal |
| 12 | 0 | 1y6m | F | No | HN | MCDK (L), HUA, CKD 1 | EP | 17q12 deletion; chr17: 34,581,399–36,347,081 (1.77 Mb) | De novo |
| 13 | 7y6m | 7y6m | M | No | No | HN (L), dysplasia (R), VUR (B) | No | c.364G>T(exon 2), p.A122S | Paternal |
| 14 | 5y11m | 5y11m | F | No | No | Cyst (B), HE (B), CKD 2 | SP | 17q12 deletion; chr17: 34,493,374–36,104,875 (1.61 Mb) | NA |
| 15 | 2 m | 2 m | F | No | No | Cyst (B), proteinuria | elevated ALT/AST |
17q12 deletion; chr17: 34,842,526–36,104,883 (NA) |
NA |
| 16 | 3y6m | 13y10m | F | No | No |
HE (B), HUA, CKD 3 |
No | c.662 A>T(exon 3), p.D221V | Paternal |
| 17 | 0 | 6y3m | M | No | SK (R) | dysplasia (L), EK (L), CKD 2 | No |
17q12 deletion; chr17: 34,806,197–36,104,875 (1.3 Mb) |
De novo |
| 18 | 0 | 2y10m | M | father: Cyst (B); grandmother: CKD 5 | Cyst(B) | MCDK(B), HUA, CKD 2 | HypoMg | c.541 C>T(exon 2), p.R181X | Paternal |
| 19 | 0 | 0 | M | No | Cyst (R) | MCDK(L), Cyst (R), HUA, CKD 2 | No | c.544 + 3_544 + 6 (IVS2) delAAGT | Maternal |
| 20 | 0 | 0 | unknown | mother: Cyst (B) | HE (B), HN (R) | NA | No | c.1006del(exon 4), p.H336Tfs*40 | Maternal |
| 21 | 0 | 0 | unknown | No | HE (B), hydramnios | NA | No |
17q12 deletion; chr17: 34,434,562–36,252,160 (1.82 Mb) |
De novo |
| 22 | 8y5m | 8y5m | F | No | No | Cyst (B), CKD 5 | No | c.1390–1405 dup (exon 7), p.L469Rfs*87 | Maternal |
| 23 | 2y | 15y | F | father: Cyst (B); grandfather: DM | No | Cyst (B), HUA, CKD5 | DM, elevated ALT/AST |
17q12 deletion; chr17: 34,836,666–36,225,059 (1.26 Mb) |
Paternal |
| 24 | 6y10m | 6y10m | M | No | No |
Cyst (B); HUA, CKD 5 |
DM |
17q12 deletion; chr17: 34,497,248–36,104,875 (1.61 Mb) |
De novo |
| 25 | 0 | 6y9m | F | No | Cyst | Cyst (B); CKD 1 | PC |
17q12 deletion; chr17: 34,806,197–36,104,875 (1.3 Mb) |
De novo |
| 26 | 0 | 6y9m | F | No | HE (B) | Cyst (B), duplicate kidney (L); CKD 1 | No |
17q12 deletion; chr17: 34,842,543–36,104,875 (1.26 Mb) |
De novo |
Abbreviations: GD: genetic diagnosis; y: year, m: month. HE: renal parenchymal hyperechogenicity. B: bilateral. Cyst: multiple renal cysts. CKD: chronic kidney disease;
NA: not available. HN: hydronephrosis. L: left. R: right. MD: myelination dysplasia. MCDK: multicystic dysplastic kidney. HUA: hyperuricaemia. DD: developmental delay
NC: nephrocalcinosis. SP: small pancreas. EP: epilepsy. VUR: vesicoureteral reflux. ALT: alanine transaminase. AST: aspartate transaminase. SK: solitary kidney. EK: ectopic
kidney. DM: diabetes mellitus. PC: pancreatic cyst
Different from the cyst-dominant pathology observed on imaging, renal functional outcomes in HNF1B-related children demonstrated marked heterogeneity. Hyperuricemia was present in 58.3% (14/24) of patients, while microalbuminuria, a marker of early glomerular injury, was detected in 12.5% (3/24). Longitudinal follow-up (median: 15.5 months; range: 6–36 months) was conducted in 21 patients with available renal function records, revealing that nearly half of the cohort (10/21, 47.6%) progressed to advanced CKD (stages 3–5). The median follow-up of these 10 cases was 15 months (range: 6–31 months) from the onset of the renal phenotype to the end of the study (June 2024). Among the 5 patients who progressed to CKD 5, 3 underwent successful renal transplantation with stable graft function (Suppl. Tables 1 and Suppl. Figure 1). 1 developed post-transplant hyperglycemia managed by switching immunosuppression from tacrolimus to cyclosporine A, indicating cyclosporine A may offer superior glycemic control in pediatric HNF1B-associated nephropathy patients with post-transplant hyperglycemia. Meanwhile, two remained on regular peritoneal dialysis.
Extrarenal symptoms
Among our cohort, diabetes mellitus developed in 2 patients despite normal pancreatic morphology. Conversely, 3 patients maintained normal blood glucose levels with pancreatic developmental anomalies, including 2 hypoplastic pancreas and 1 multiple pancreatic cyst. Additionally, 2 showed elevated transaminases, 1 had hypomagnesemia, and 5 presented with neurological developmental abnormalities, including 1 epilepsy, 1 cerebral hypoplasia, and 3 psychomotor retardation.
Genotype
Genetic studies revealed total gene deletion of 17q12 in 16 patients (61.5%), 6 missense mutation (23.1%), 2 splice mutation (7.7%), and two other mutationss (a deletion and a duplicate), which together account for the remaining 7.7%, among which c.1390-1405dup in exon 7 was unreported (Fig. 2a). Notably, although c.1390-1405dup caused a frameshift translation due to a non-triplet 16 bp (bp) repeat, it did not lead to premature termination. Instead, it resulted significant changes of the last 89aa, corresponding to C-terminal transactivation domain (p.L469Rfs*87) and likely disrupting the interaction with coactivator/corepressor (Fig. 2b). Interestingly, 3D protein structure modeling suggested that beyond the local structural disruption after amino acid 469, spatial rearrangements also occur in regions with unchanged amino acid composition, indicating that the pathogenic variant may induce allosteric effects through long-range conformational propagation and further affecting overall protein stability or function (Fig. 2c). Moreover, the proband inherited the pathogenic variant maternally, with the mother showing no phenotypic abnormalities. In contrast, the proband exhibited rapid renal deterioration leading to CKD 5 and is currently managed with peritoneal dialysis.
Fig. 2.
Genetic characterization of patients with HNF1B mutations. (a) Schematic illustration of mutation sites in the HNF1B gene. Distinct terminal symbols of the lines represent various mutation types. Distinct colors of the lines denote the CKD stage at the last follow-up, while the gray dashed lines indicate that the CKD stage was unobtainable. (b) Deduced amino acid sequences were shown for wildtype (top) and unreported c.1390-1405dup (bottom) sequences. (c) Predicted 3D structural changes of HNF1B protein caused by C-terminal 89-amino acid frameshift translation (c.1390-1405dup; p.L469Rfs*87). Red arrows indicate 3D conformational changes; black text: wild-type amino acid residues with altered spatial configuration; red text: novel residues resulting from frameshift translation. The aa469, where frameshift translation initiates, is zoomed and shown in the right panel
Cascade screening of parental DNA in 22 patients identified HNF1B pathogenic variant transmission in 11 families, without significant parent-of-origin effect bias (6/11 showing maternal and 5/11 paternal inheritance). Five parents carrying pathogenic variants exhibited clinical symptoms of renal cysts, indicating HNF1B-related disorder is a highly penetrant genetic condition, with penetrance rates of 100% among the pediatric patients included in our study and 84% when incorporating parents carrying the same pathogenic variants, respectively. Among these inherited pathogenic variants, the molecular subtypes were whole gene deletion (4/11), missense pathogenic variant (3/11), splice site pathogenic variant (1/11), nonsense pathogenic variant (1/11), and indel pathogenic variant (2/11). The remaining 50% harbored de novo HNF1B pathogenic variants, highlighting the significant contribution of spontaneous genetic alterations in this cohort. Among these, 8/11 constituted complete gene deletions (17q12 deletion), 2/11 missense, and 1/11 splice pathogenic variant.
Overall, 17q12-related HNF1B whole gene deletions were the predominant type in our HNF1B pathogenic variant spectrum, with no significant difference in the proportion of inherited versus de novo pathogenic variants (p = 0.198). Additionally, our study also confirmed that HNF1B pathogenic variants remained highly clustered in the known hotspots of exon 2 and exon 3 [18].
Genotype-phenotype correlations
Based on the reported mutated genotype dichotomy of HNF1B, the study cohort was stratified into two groups based on genetic testing results: the 17q12 deletion group (16/26) and the HNF1B pathogenic variant group (10/26). Our findings indicated a higher prevalence, though not statistically significant (p = 0.300), of prenatal renal phenotypic abnormalities in the 17q12 deletion group (68%) compared to the HNF1B group (40%). During the follow-up period (median follow-up duration: 27.9 months in 16 pediatric patients developing renal dysfunction CKD stages 2–5), the 17q12 deletion group exhibited a faster eGFR decline per unit time compared to the HNF1B group (0.71 [-0.51, 3.83] vs. 0 [-0.95, 4.24] mL/min/1.73 m²/year, p = 0.227). The kidney survival rates at the 4-year and 12.5-year follow-up were 80% and 25%, respectively (Fig. 3a). At the latest follow-up assessment, the median eGFR in the 17q12 deletion group was numerically higher than that in the HNF1B group (85 [10–135] vs. 45.66 [10-87.7] mL/min/1.73m2, p = 0.110) (Fig. 3b), although this difference did not reach statistical significance. At the latest follow-up, a greater proportion of patients in the HNF1B group had progressed to CKD stages 3–5 than those in the 17q12 deletion group (p = 0.08), indicating more severe postnatal renal dysfunction in HNF1B variant carriers. All five cases with neurological abnormalities occurred in the 17q12 deletion group, while no neurodevelopmental disorders were observed in the HNF1B group (p = 0.116). This phenotypic distinction may reflect additional neurodevelopmental genes within the 17q12 deletion region, although statistical significance was not reached. No statistically significant differences were observed between the two genotypes in the distribution of secondary manifestations, including hyperuricemia, hypomagnesemia, diabetes mellitus, pancreatic abnormalities, hepatic dysfunction, or genitourinary malformations(Table 2).
Fig. 3.
Kaplan-Meier cumulative kidney survival rates in all patients (a) and according to the genotype (b). The endpoint of Kaplan-Meier was set as the progression to stage 3 chronic kidney disease (CKD) or above
Table 2.
Comparison of clinical phenotypes between patients with 17q12 deletions and HNF1B variants
| Characteristics | 17q12 deletion (16) |
HNF1B variant (10) |
p value |
|---|---|---|---|
| Age (months) at onset | 0 (0–93) | 23 (0-141) | 0.121 |
| Age (months) at GD | 69 (2-180) | 90 (5-166) | 0.325 |
| Prenatal ultrasound abnormalities | 11/16 | 4/10 | 0.300 |
| Latest eGFR | 85 (10–135) | 45.6 (10-87.7) | 0.110 |
| eGFR decline rate (mL/min/1.73 m²/year) | 0.71 (-0.51, 3.83) | 0 (-0.95, 4.24) | 0.277 |
| Latest CKD Stage | 0.080 | ||
| CKD stage 1–2 | 9/13 | 2/8 | |
| CKD stage 3–5 | 4/13 | 6/8 | |
| Hyperuricemia | 6/15 | 4/9 | 1.000 |
| Hypomagnesemia | 0/14 | 1/8 | 0.364 |
| Diabetes mellitus | 2/11 | 0/9 | 0.479 |
| Pancreatic abnormolities | 2/11 | 1/7 | 1.00 |
| Liver abnormalities | 2/14 | 0/8 | 0.515 |
| Genital abnormalities | 0/6 | 0/5 | NC |
| Neurological abnormality | 5/14 | 0/9 | 0.116 |
Data are presented as n/N, median (interquartile range). Abbreviations: GD: genetic diagnosis. eGFR: estimated glomerular filtration rate. CKD: chronic kidney disease. NC: not calculable. Statistical analyses were performed as follows: for non-normally distributed continuous variables, the Mann-Whitney U test was used; for between-group comparisons, Fisher’s exact test was applied for comparing rates
Discussion
Based on the transcription factor characteristics of the HNF1B, several cohorts have adopted a mutated genotype dichotomy (distinguishing between intragenic HNF1B pathogenic variants and 17q12 deletion spanning 15 genes including HNF1B) to investigate genotype-phenotype correlations. While convergent themes exist across studies, discrepancies in certain aspects also emerge, potentially reflecting variations in cohort characteristics and analytical approaches. Ulinski et al. found no difference in renal function or severity of renal morphologic lesions between patients with HNF1B deletions and point pathogenic variants [19]. Okorn et al. identified the presence of a maternal transmission bias, a positive correlation between renal cyst progression and declining renal function, as well as an association between early-onset ESKD (before 2 years of age) and bilateral dysplasia. Notably, both outcomes occurred independently of the mutant genotype [20].
In contrast, a recent study by Buffin-Meyer et al. demonstrated that patients with HNF1B variants exhibit significantly worse kidney survival than those with the 17q12 deletion, with the poorest renal outcomes observed in carriers of pathogenic variants located in the N-terminal POU-like domain [5]. Similarly, a cohort of adult patients with HNF1B-related disorders showed that, compared to patients with point mutations, those with 17q12 deletions had lower rates of CKD stage 3–4 or ESKD both at diagnosis and during long-term follow-up [21]. These findings are consistent with the trend observed in our cohort, in which patients with HNF1B pathogenic variants appeared to progress to CKD stage 3–5 earlier than those with 17q12 deletions. This phenotypic divergence may stem from dominant-negative effects exerted by mutant HNF1B proteins, with distinct molecular consequences based on mutation localization. Specifically, when mutations occur within the DNA-binding domain, the mutant protein retains dimerization capacity but impairs DNA recognition. For transactivation domain (TAD) -localized variants, mutant proteins maintain DNA binding capability but fail to recruit coactivators or coinhibitors due to disrupted interaction interfaces. In either case, these mutant proteins with compromised functions competitively occupy regulatory elements, progressively impairing wild-type protein function through a dominant-negative effect. Notably, the inhibitory effect may exhibit gradually intensified characteristics as the mutant protein proportion accumulates over time [18, 22]. In our cohort, no specific mutational loci within the HNF1B gene demonstrated preferential association with the progression to advanced kidney disease, likely due to the limited sample size.
Among the pathogenic variants, patient 22 harbored a novel HNF1B pathogenic variant (c.1390-1405dup, p.L469Rfs*87) in exon 7, different from the hotspot pathogenic variant (exon 2 and exon 3) and representing the first reported duplication affecting the C-terminal TAD [18]. Clinically, the patient exhibited a rapidly progressive renal phenotype, eventually developing CKD 5, requiring regular peritoneal dialysis and awaiting renal transplantation. On one hand, the pathogenic variant was maternally inherited, but the mother remained asymptomatic, possibly due to incomplete penetrance, consistent with previous observation that the phenotype can vary considerably among persons carrying the same HNF1B pathogenic variant, even among members of the same family [23]. Thus, prenatal screening for females from HNF1B-mutated families should integrate “genetic testing plus imaging assessment plus genetic counseling” to confirm pathogenic variant carriage, rather than absolutely predict phenotypes [22]. On the other hand, the impact of immunosuppressant selection on post-transplantation glycemic control requires heightened attention. In this study, three post-transplant children initially received tacrolimus for rejection prophylaxis, but one developed hyperglycemia, which resolved after switching from tacrolimus to cyclosporine A (CsA), both of which are cornerstone agents in post-transplant immunosuppression, although tacrolimus is often favored in pediatric renal transplantation due to its superior efficacy and a more favorable side-effect profile. Mechanistically, Tacrolimus impairs glucose metabolism by inhibiting the calcineurin-NFAT pathway, which disrupts β-cell insulin secretion, activates mTOR signaling, leads to peripheral insulin resistance, and reduces glucose uptake [24]. A Meta-analysis showed that tacrolimus use was associated with a higher incidence of new-onset diabetes than CsA after transplantation (NODAT) [25]. Therefore, based on these findings, the dual risk of HNF1B-related diabetes and CNI-induced hyperglycemia necessitates a proactive, individualized immunosuppressive strategy in transplant recipients.
Furthermore, in this study, we found that an additional trend of interest: the 17q12 deletion group showed a higher prevalence, though not statistically significant, of fetal renal abnormalities compared to the HNF1B pathogenic variant group (68% vs. 40%). This rate is consistent with the prevalence reported in a previous 17q12 del-associated cohort study (65%) [26]. Although further validation is required, this observation may suggest a potentially earlier onset of renal manifestations in deletion carriers. Mechanistically, the 17q12 deletion results in HNF1B haploinsufficiency, probably reducing its expression below the critical threshold required for normal nephrogenesis, a phenomenon consistent with the exquisite dosage sensitivity of transcription factors during embryonic cell fate determination [27]. In contrast, HNF1B missense/truncating pathogenic variants may retain partial protein activity, which could sustain early renal development through compensation by other proteins, such as HNF1A. Moreover, a recent study utilizing human induced pluripotent stem cells (hiPSCs) demonstrated that precisely timed attenuation of Wnt/β-catenin signaling was required to achieve optimal HNF1B activation, which was necessary for proper mesenchymal-epithelial transition (MET) during kidney tubule formation, highlighting the importance of HNF1B expression levels [8].
Although this study primarily focused on renal phenotypes associated with HNF1B mutations, it was important to recognize that HNF1B also serves as a critical transcriptional regulator in multi-organ development [18]. Emerging evidence suggests that extrarenal features in HNF1B-related disorders may also exhibit genotype-dependent patterns, much like the renal phenotypes [5]. Specifically, neurodevelopmental abnormalities appear more frequently associated with the 17q12 deletion, potentially due to the co-deletion of adjacent genes such as LHX1, whereas pancreatic hypoplasia shows no significant genotypic difference, likely reflecting the central role of HNF1B itself in pancreatic development and functional maintenance [5]. Notably, while pancreatic developmental anomalies are common, the clinical onset of associated diabetes occurs significantly later than renal manifestations. This temporal discrepancy suggests either differential organ sensitivity to HNF1B deficiency or, more likely, divergent developmental timing of HNF1B expression across organs.
In conclusion, our preliminary observations suggest that the 17q12 deletion group may exhibit earlier fetal renal phenotypes, while the HNF1B pathogenic variant group appeared to show worse renal function at follow-up, which was probably linked to genetic mechanisms including transcription factor haploinsufficiency and dominant-negative effects. The use of cyclosporine A, instead of tacrolimus, could be considered from the outset for patients with HNF1B-associated nephropathy to potentially prevent the development of post-transplant diabetes mellitus. The primary limitation of this study is the small sample size, coupled with incomplete assessment of extrarenal phenotypes in certain cases, which may have introduced bias in phenotype analysis. Future studies with larger sample sizes, comprehensive phenotypic profiling, and extended follow-up durations are essential to fully characterize the clinical landscape of HNF1B-related disorders. Such investigations will facilitate the development of evidence-based prognostic interventions, thereby enhancing our ability to inform clinical management and improve outcomes for affected individuals.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the [Ethics Committee of Wuhan Children’s Hospital] (Approval number: [2024R141-E01]). We thank all patients and their families for their participation in this study.
Abbreviations
- CAKUT
Congenital anomalies of the kidney and urinary tract
- CCGKDD
Chinese Children Genetic Kidney Disease Database
- MCDK
Multicystic dysplastic kidney
- eGFR
Estimated glomerular filtration rate
- ESKD
End-stage kidney disease
- TAD
Transactivation domain
- CsA
Cyclosporine A
- GD
Genetic diagnosis
- y
Year
- m
Month
- B
Bilateral
- L
Left
- R
Right
- HN
Hydronephrosis
- Cyst
Multiple renal cysts
- CKD
Chronic kidney disease
- DM
Diabetes mellitus
- MCDK
Multicystic dysplastic kidney
- HUA
Hyperuricaemia
- HE
Renal parenchymal hyperechogenicity
- NC
Nephrocalcinosis
- VUR
Vesicoureteral reflux
- SK
Solitary kidney
- EK
Ectopic kidney
- ALT
Alanine transaminase
- AST
Aspartate transaminase
- PC
Pancreatic cyst
- NA
Not available
- DD
Developmental delay
- MD
Myelination dysplasia
- EP
Epilepsy
- SP
Small pancreas
Author contributions
All authors contributed to the intellectual content of this manuscript and approved the final manuscript as submitted. HZ collected data and drafted the manuscript with the help of CW, XJ and XG; HY and PL and LH performed gene analysis and generated figures; XT, JL, RD and AZ interpreted the data; QS, XW and HX revised the article for important intellectual content. All authors have critically read and approved the manuscript.
Funding
This work was supported by Construction Project of Research Division of Children’s Kidney Disease of Wuhan Children’s Hospital (2022FEYJS003), Knowledge and Innovation Project of Wuhan Science and Technology Bureau (2023020201010197), Hubei Provincial Health Commission Joint Fund Project (WJ2023M149), Shanghai “Rising Stars of Medical Talents” Youth Development Program (SHWSRS(2023)_070), Shanghai Medical Health Clinical Research Youth Program (20244Y0024), National Natural Sciences Foundation of China for Young Scholars (81900602), and Shanghai Municipal Science and Technology Major Project (2023SHZDZX02C09).
Data availability
Sepuence data support the findings of this study have been deposited in the Clinvar database (https://www.ncbi.nlm.nih.gov/clinvar/) at the following URL (https://www.ncbi.nlm.nih.gov/clinvar/variation/4071464/, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000635616.9/?redir=vcv, https://www.ncbi.nlm.nih.gov/clinvar/variation/635666/, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000635668.11/?redir=vcv, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000372381.24/?redir=vcv, https://www.ncbi.nlm.nih.gov/clinvar/variation/4071465/, https://www.ncbi.nlm.nih.gov/clinvar/variation/4071463/, https://www.ncbi.nlm.nih.gov/clinvar/variation/4071466/, https://www.ncbi.nlm.nih.gov/clinvar/variation/805639/). And the corresponding accession number for the present HNF1B variants are VCV004071464.1, VCV000635616.9, VCV000635666.10, VCV000635668.11, VCV000372381.24, VCV004071465.1, VCV004071463.1, VCV004071466.1, and VCV000805639.10, respectively.
Declarations
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the [Ethics Committee of Wuhan Children’s Hospital] (Approval number: [2024R141-E01]).
Consent for publication
Written informed consent was obtained from all participants. In accordance with federal and institutional guidelines, informed consent was obtained from the legal guardians for pediatric patients younger than the age of 16, while informed consent was obtained directly from pediatric patients aged over 16 years themselves.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Hongying Zhang and Chunyan Wang have contributed equally to this work.
Contributor Information
Qian Shen, Email: shenqian@shmu.edu.cn.
Xiaowen Wang, Email: xiaowenwang331@163.com.
Hong Xu, Email: hxu@shmu.edu.cn.
References
- 1.Kolvenbach CM, Shril S, Hildebrandt F. The genetics and pathogenesis of CAKUT. Nat Rev Nephrol. 2023;19(11):709–20. [DOI] [PubMed] [Google Scholar]
- 2.Sawaf H, et al. Genetic susceptibility to chronic kidney disease: Links, risks and management. Int J Nephrol Renovasc Dis. 2023;16(11):1–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kolatsi-Joannou M, et al. Hepatocyte nuclear factor-1beta: a new kindred with renal cysts and diabetes and gene expression in normal human development. J Am Soc Nephrol. 2001;12(10):2175–80. [DOI] [PubMed] [Google Scholar]
- 4.Bellanné-Chantelot C, et al. Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes. 2005;54(11):3126–32. [DOI] [PubMed] [Google Scholar]
- 5.Buffin-Meyer B, et al. Renal and extrarenal phenotypes in patients with HNF1B variants and chromosome 17q12 microdeletions. Kidney Int Rep. 2024;9(8):2514–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Faguer S, et al. Calcineurin inhibitors downregulate HNF-1β and May affect the outcome of HNF1B patients after renal transplantation. Transplantation. 2016;100(9):1970–8. [DOI] [PubMed] [Google Scholar]
- 7.Barbacci E, et al. HNF1beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment. Hum Mol Genet. 2004;13(24):3139–49. [DOI] [PubMed] [Google Scholar]
- 8.Ng-Blichfeldt JP, et al. Identification of a core transcriptional program driving the human renal mesenchymal-to-epithelial transition. Dev Cell. 2024;59(5):595–e6128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bohn S, et al. Distinct molecular and morphogenetic properties of mutations in the human HNF1beta gene that lead to defective kidney development. J Am Soc Nephrol. 2003;14(8):2033–41. [DOI] [PubMed] [Google Scholar]
- 10.Gresh L, et al. A transcriptional network in polycystic kidney disease. Embo J. 2004;23(7):1657–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Adalat S, et al. HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol. 2009;20(5):1123–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Grand K, et al. HNF1B alters an evolutionarily conserved nephrogenic program of target genes. J Am Soc Nephrol. 2023;34(3):412–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Richards S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 2015;17(5):405–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gois PHF, Souza ERM. Pharmacotherapy for hyperuricemia in hypertensive patients. Cochrane Database Syst Rev. 2017;4(4):Cd008652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Seino Y, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Investig. 2010;1(5):212–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987;34(3):571–90. [DOI] [PubMed] [Google Scholar]
- 17.Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825–30. [DOI] [PubMed] [Google Scholar]
- 18.Clissold RL, et al. HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat Rev Nephrol. 2015;11(2):102–12. [DOI] [PubMed] [Google Scholar]
- 19.Ulinski T, et al. Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol. 2006;17(2):497–503. [DOI] [PubMed] [Google Scholar]
- 20.Okorn C, et al. HNF1B nephropathy has a slow-progressive phenotype in childhood-with the exception of very early onset cases: results of the German multicenter HNF1B childhood registry. Pediatr Nephrol. 2019;34(6):1065–75. [DOI] [PubMed] [Google Scholar]
- 21.Dubois-Laforgue D, Diabetes AC, Spectrum, et al. Long-term Prognosis, and Genotype/Phenotype correlations in 201 adult patients with hepatocyte nuclear factor 1B (HNF1B) molecular defects. Diabetes Care. 2017;40(11):1436–43. [DOI] [PubMed] [Google Scholar]
- 22.Hiesberger T, et al. Mutation of hepatocyte nuclear factor-1beta inhibits Pkhd1 gene expression and produces renal cysts in mice. J Clin Invest. 2004;113(6):814–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Madariaga L, et al. Variable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract. Clin Kidney J. 2019;12(3):373–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Rodriguez-Rodriguez AE, et al. Inhibition of the mTOR pathway: A new mechanism of β cell toxicity induced by tacrolimus. Am J Transpl. 2019;19(12):3240–9. [DOI] [PubMed] [Google Scholar]
- 25.Oliveras L, et al. Immunosuppressive drug combinations after kidney transplantation and post-transplant diabetes: A systematic review and meta-analysis. Transpl Rev (Orlando). 2024;38(3):100856. [DOI] [PubMed] [Google Scholar]
- 26.Verscaj CP, et al. Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions. Prenat Diagn. 2024;44(2):237–46. [DOI] [PubMed] [Google Scholar]
- 27.Rice AM, McLysaght A. Dosage sensitivity is a major determinant of human copy number variant pathogenicity. Nat Commun. 2017;8:14366. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Sepuence data support the findings of this study have been deposited in the Clinvar database (https://www.ncbi.nlm.nih.gov/clinvar/) at the following URL (https://www.ncbi.nlm.nih.gov/clinvar/variation/4071464/, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000635616.9/?redir=vcv, https://www.ncbi.nlm.nih.gov/clinvar/variation/635666/, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000635668.11/?redir=vcv, https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000372381.24/?redir=vcv, https://www.ncbi.nlm.nih.gov/clinvar/variation/4071465/, https://www.ncbi.nlm.nih.gov/clinvar/variation/4071463/, https://www.ncbi.nlm.nih.gov/clinvar/variation/4071466/, https://www.ncbi.nlm.nih.gov/clinvar/variation/805639/). And the corresponding accession number for the present HNF1B variants are VCV004071464.1, VCV000635616.9, VCV000635666.10, VCV000635668.11, VCV000372381.24, VCV004071465.1, VCV004071463.1, VCV004071466.1, and VCV000805639.10, respectively.