Biallelic PKD1 mutations causing neonatal death in an extremely preterm infant: a Korean case report of very early-onset ADPKD

Abstract

Background

Very early-onset autosomal dominant polycystic kidney disease (VEO-ADPKD) caused by biallelic PKD1 mutations is extremely rare and often phenocopies autosomal recessive PKD (ARPKD), complicating prenatal diagnosis and genetic counseling.

Case presentation

We report an extremely preterm Korean male infant (27 + 3 weeks, 1300 g) with fetal polycystic kidney disease and severe oligohydramnios from 24 + 6 weeks. The infant died on day 2 with refractory hypoxemia despite maximal support. Clinical exome sequencing revealed compound heterozygous PKD1 variants: a paternally inherited truncating variant (c.11343 C > A, p.Tyr3781Ter) and a maternally inherited non-truncating hypomorphic variant (c.3876 C > A, p.Phe1292Leu). Segregation analysis confirmed trans configuration and identified paternal somatic mosaicism (imbalanced heterozygous peaks on Sanger sequencing), accounting for the phenotypic discordance between the infant’s lethal presentation and the father’s mild disease at age 31. No pathogenic variants were identified in PKHD1, PKD2, or other cystic kidney disease genes.

Conclusions

This first Korean case demonstrates that biallelic PKD1 mutations cause neonatal-lethal disease that mimics ARPKD via gene-dosage effects, with parental mosaicism creating unpredictable recurrence risks. Genomic autopsy enabled an accurate diagnosis and strongly supports preimplantation genetic testing for this couple.

Background

Polycystic kidney disease (PKD) is traditionally classified as autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD). ADPKD, caused by PKD1 (~ 80%) or PKD2 (~ 15%) mutations, typically manifests in adulthood with hypertension and progressive kidney failure. ARPKD, caused by PKHD1 mutations, presents perinatally with severe symptoms and high mortality [1, 2]. A rare subset of ADPKD exhibits very early-onset (VEO) presentation in utero or neonatally. Due to severe renal involvement and pulmonary hypoplasia, VEO-ADPKD is often clinically indistinguishable from ARPKD, complicating diagnosis and counseling [3].

Recent genomic studies reveal VEO-ADPKD is driven by a “gene dosage effect,” where clinical severity depends on total functional polycystin-1 or polycystin-2 levels [4]. Biallelic PKD1 inheritance—particularly combining a null allele with a hypomorphic variant—reduces protein levels below the threshold for normal renal development, creating a “pseudo-recessive” pattern [5]. While heterozygous parents remain asymptomatic, affected children exhibit severe phenotypes mimicking ARPKD.

The clinical course of prenatally diagnosed ADPKD is highly variable; not all severe prenatal findings lead to neonatal death [6]. Despite significant clinical implications, detailed molecular reports of VEO-ADPKD from Korea remain limited. We report the first Korean case of neonatal-lethal VEO-ADPKD caused by compound heterozygous PKD1 mutations, emphasizing genomic autopsy’s critical role in diagnosis and reproductive planning.

Case presentation

A 31-year-old Korean woman, gravida 1 para 0, conceived via in vitro fertilization-embryo transfer. Prenatal ultrasonography at 20 + 6 weeks revealed bilaterally enlarged fetal kidneys with increased echogenicity. By 24 + 6 weeks, severe oligohydramnios (amniotic fluid index < 5) and cardiomegaly developed, raising suspicion for polycystic kidney disease (Fig. 1A-B).

Fig. 1.

Prenatal and postnatal ultrasonographic findings. Prenatal ultrasonography at 24 + 6 weeks of gestation demonstrated (A) bilaterally enlarged fetal kidneys with increased echogenicity (measurements from prenatal ultrasonography at 24 + 6 weeks: right kidney 5.90 × 3.11 cm, left kidney 5.60 × 2.80 cm, both markedly exceeding the 95th percentile for gestational age) and (B) cardiomegaly with severe oligohydramnios (amniotic fluid index < 5), raising suspicion for polycystic kidney disease. Postnatal renal ultrasonography at day of life 0 (gestational age 27 + 1 weeks) revealed (C) the right kidney with markedly increased echogenicity, numerous tiny cystic lesions throughout the parenchyma, and a larger cyst measuring approximately 1 cm, and (D) the left kidney showing similar changes with swelling and heterogeneous echotexture due to multiple small cysts. Complete loss of corticomedullary differentiation was observed bilaterally. These findings were consistent with severe polycystic kidney disease but were indistinguishable from autosomal recessive polycystic kidney disease (ARPKD) based on imaging alone, underscoring the critical importance of molecular genetic testing for accurate diagnosis

Family history revealed that the father (31 years old, carrying the p.Tyr3781Ter variant) had known renal cysts detected on routine ultrasonography at age 28, with a positive family history of ADPKD in his father (the infant’s paternal grandfather), who developed kidney failure requiring dialysis at age 55. The father demonstrated a clinical phenotype consistent with early-stage ADPKD for his age. At age 28, routine ultrasonography detected bilateral renal cysts (the largest cyst was 1.2 cm in the right kidney). At age 31 (time of the infant’s birth), he remained clinically asymptomatic without hypertension (blood pressure 118/76 mmHg), chronic kidney disease (serum creatinine 0.9 mg/dL, estimated glomerular filtration rate 98 mL/min/1.73 m²), or abdominal pain. The mother had no family history of kidney disease. The mother received betamethasone for fetal lung maturation and magnesium sulfate for neuroprotection. At 27 + 3 weeks, fetal distress prompted emergency cesarean section, delivering a male infant weighing 1300 g (appropriate for gestational age). Apgar scores were 3 at 1 min and 5 at 5 min.

The infant exhibited generalized edema, hypotonia, and severe respiratory distress requiring immediate endotracheal intubation. Initial physical examination revealed no dysmorphic features or extrarenal malformations. Mechanical ventilation was initiated with high-frequency oscillatory ventilation. Chest radiography showed diffuse ground-glass opacities consistent with respiratory distress syndrome (RDS) and pulmonary hypoplasia.

Postnatal renal ultrasonography revealed markedly enlarged bilateral kidneys (right 6.2 cm, left 5.8 cm; normal renal length for 27 weeks gestational age is approximately 2.6–2.9 cm [7]), representing approximately 2-fold enlargement compared to normal for gestational age with diffusely increased echogenicity, numerous small cystic lesions throughout the parenchyma, a larger cyst measuring 1.0 cm in the right kidney, and complete loss of corticomedullary differentiation. These findings were consistent with severe polycystic kidney disease but radiologically indistinguishable from ARPKD (Fig. 1C-D).

Despite maximal medical intervention, including surfactant administration, multiple inotropes (dopamine, dobutamine, epinephrine), inhaled nitric oxide for persistent pulmonary hypertension of the newborn (PPHN), and diuretics, the infant developed progressive oliguria progressing to anuria, refractory and persistent bradycardia. Echocardiography confirmed severe PPHN with right-to-left shunting. After comprehensive discussions with the parents regarding the extremely poor prognosis, a do-not-resuscitate (DNR) agreement was reached. The infant died on DOL 2. The final diagnosis was PPHN, RDS, extreme prematurity, and polycystic kidney disease.

Clinical exome sequencing was performed using the Illumina TruSight One panel, which provides comprehensive coverage of over 5,000 clinically relevant genes, including all known genes associated with cystic kidney diseases. This targeted panel was selected for its optimized coverage of disease-causing genes and cost-effectiveness in the clinical diagnostic setting. The panel comprehensively assessed cystic kidney disease-related genes, including PKHD1 (ARPKD), PKD2 (ADPKD type 2), HNF1B (renal cysts and diabetes syndrome), NPHP1-11 (nephronophthisis), IFT140, NEK8, PDIA6, and genes associated with ciliopathies and syndromic forms of cystic kidney disease.

Genetic analysis using next-generation sequencing (NGS) identified compound heterozygous PKD1 variants (NM_001009944.3) with balanced variant allele frequencies (c.11343 C > A: 49.2%, read depth 156×; c.3876 C > A: 50.1%, read depth 148×), consistent with constitutional compound heterozygosity. The paternally inherited variant, c.11343 C > A (p.Tyr3781Ter), is a truncating variant located in exon 39 that causes premature termination and complete loss of function (null allele, classified as pathogenic per American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria). The maternally inherited variant, c.3876 C > A (p.Phe1292Leu), is a non-truncating hypomorphic missense variant located in exon 11, affecting the PKD domain (amino acid residues 1289–1775), and classified as likely pathogenic. This classification follows the KDIGO 2025 nomenclature recommendations for PKD1 variants.

Targeted parental Sanger sequencing was performed for segregation analysis and mosaicism assessment. The father demonstrated somatic mosaicism for the c.11343 C > A variant, with Sanger chromatogram showing an imbalanced heterozygous pattern with reduced mutant allele peak height (approximately 30–40% of wild-type peak intensity), indicating that only a subset of peripheral blood leukocytes carry this variant. This mosaic pattern was reproducible across multiple independent polymerase chain reaction (PCR) amplifications. The mother showed clear balanced heterozygous peaks for c.3876 C > A, consistent with constitutional carrier status. Biallelic inheritance in trans configuration was confirmed. No pathogenic or likely pathogenic variants were identified in PKHD1, PKD2, or other cystic kidney disease genes assessed by the panel (Fig. 2).

Fig. 2.

Pedigree and molecular genetic analysis. (A) Family pedigree showing inheritance pattern. The proband (arrow) is a male infant who died at day 2 of life (gestational age 27 + 1 weeks). The father demonstrates somatic mosaicism for the PKD1 c.11343 C > A variant. The mother is a constitutional heterozygous carrier of PKD1 c.3876 C > A. (B) PKD1 gene and polycystin-1 protein structure with variant locations. Top: PKD1 gene structure (46 exons on chromosome 16p13.3) with variant-containing exons 11 and 39 highlighted in orange. Middle: Polycystin-1 protein (4,302 amino acids) showing major domains including signal peptide, 16 PKD repeat domains (aa 1289–1775), 11 transmembrane helices (aa 3100–3850), and C-terminal tail. Bottom: Variant annotations with the maternal non-truncating hypomorphic variant (c.3876 C > A, Phe1292Leu) in the PKD domain and paternal truncating variant (c.11343 C > A, p.Tyr3781Ter) in the transmembrane region. (C) Sanger sequencing chromatograms confirming compound heterozygous PKD1 variants. The paternally inherited truncating variant c.11343 C > A (red circles) showed imbalanced heterozygous peaks in the father with reduced mutant allele signal intensity (approximately 30–40% of wild-type peak), consistent with somatic mosaicism. The maternally inherited non-truncating hypomorphic variant c.3876 C > A (red circles) showed balanced heterozygous peaks in the mother, consistent with constitutional carrier status. The proband inherited both variants in trans configuration, confirmed by segregation analysis

Discussion

This case represents the first molecularly characterized VEO-ADPKD in Korea caused by biallelic PKD1 mutations. Despite the father’s asymptomatic adult-onset ADPKD phenotype, the infant exhibited severe fetal-onset disease and neonatal death, powerfully demonstrating the gene dosage effect mechanism.

Recent genomic autopsy studies confirm that fetal and neonatal ADPKD represents a qualitatively distinct entity from adult-onset disease, primarily driven by biallelic PKD1 mutations [4]. The present case exemplifies this: while the father (monoallelic mutation) retains approximately 50% polycystin-1 expression and remains asymptomatic, the infant (biallelic mutations) had polycystin-1 levels below the critical threshold and developed prenatal disease at 24 weeks and died on DOL 2.

The combination of a null allele (0% functional protein) and a hypomorphic allele results in significantly reduced total polycystin-1 levels. The father with a monoallelic mutation retains approximately 50% polycystin-1 expression [8]. In contrast, compound heterozygosity for null and hypomorphic variants reduces functional protein below the critical threshold required for normal kidney development [9, 10]. The specific reduction in functional polycystin-1 varies depending on the residual activity of the hypomorphic allele.

This dramatic phenotypic contrast within one family illustrates how the combination of a null allele (c.11343 C > A) and a hypomorphic allele (c.3876 C > A) reduces polycystin-1 below the critical threshold required for normal fetal kidney development [9, 10].

Moreover, this case also illustrates an important diagnostic scenario in which severe neonatal disease led to the discovery of previously unrecognized parental mosaicism. Targeted parental Sanger sequencing revealed that the father harbors somatic mosaicism for the c.11343 C > A variant, with imbalanced heterozygous peaks indicating mosaic carrier status. This explains his relatively mild phenotype at age 31 (bilateral renal cysts, preserved renal function with an eGFR of 98 mL/min/1.73 m², and normotensive) compared with typical constitutional PKD1 carriers. The balanced variant allele frequencies in the proband’s NGS data (c.11343 C > A: 49.2%; c.3876 C > A: 50.1%) support constitutional inheritance despite paternal somatic mosaicism. This has important implications for genetic counseling, as mosaic parents have unpredictable recurrence risks that cannot be precisely determined from peripheral blood analysis, highlighting the value of preimplantation genetic testing for this couple.

Sharova et al. (2026) systematically analyzed this “pseudo-recessive” inheritance pattern, demonstrating wide clinical variability in prenatal-onset ADPKD [5]. While some cases with severe prenatal ultrasonographic findings survive or maintain stable renal function, our case represents the lethal extreme of this spectrum. This underscores that accurate genotypic analysis and functional evaluation of each variant are essential for prognostication and genetic counseling.

Compared to ARPKD, where an Omani cohort showed a median age of kidney failure onset at 3 years [11], our VEO-ADPKD case manifested at 24 weeks of gestation with neonatal death on DOL 2, suggesting that certain biallelic PKD1 genotypes can be significantly more lethal and present earlier than typical ARPKD. This underscores the need to consider biallelic PKD1 mutations in severe neonatal cystic kidney disease with a negative PKHD1 test result. While biallelic PKD2 involvement is theoretically possible, severe neonatal-lethal phenotypes are primarily associated with biallelic PKD1 mutations [4, 5].

Neonatal PKD is often radiologically indistinguishable from ARPKD, making differential diagnosis challenging [3]. In this case, severe oligohydramnios, enlarged echogenic kidneys, and neonatal respiratory distress perfectly mimicked ARPKD. Frank et al. (2025) demonstrated the utility of genomic autopsy in distinguishing ADPKD from ARPKD when traditional autopsy fails [4]. Despite lacking a physical autopsy, our genomic analysis provided a definitive diagnosis, accurate recurrence risk calculation (25%), and enabled preimplantation genetic testing (PGT) planning for future pregnancies—clinical value exceeding traditional autopsy.

Accumulating evidence indicates that significant proportions of suspected ARPKD cases are VEO-ADPKD phenocopies caused by PKD1 mutations [12]. This case underscores that biallelic PKD1 mutations should be considered in severe neonatal cystic kidney disease, even in the absence of a positive PKHD1 test. Differential diagnosis should also exclude renal tubular dysgenesis, TSC2/PKD1 contiguous deletion syndrome, monoallelic NEK8 variants (which can phenocopy severe ARPKD despite dominant inheritance) [13], and other conditions like PDIA6-related cystic kidney disease, though the latter typically presents with systemic manifestations such as asphyxiating thoracic dystrophy or neonatal diabetes [14–16].

Garel et al. (2019) reported cases initially misidentified as ARPKD on prenatal ultrasonography that were subsequently confirmed to have PKD1 mutations [3]. Similarly, although the present case was suspicious for ARPKD due to severe oligohydramnios and radiologic findings, precise genetic analysis identified it as VEO-ADPKD, underscoring the limitations of imaging alone and the necessity of molecular diagnosis.

The diagnostic approach aligns with the 2025 KDIGO guidelines, which emphasize genetic testing in pediatric PKD [17]. The molecular diagnosis enables comprehensive reproductive counseling. With each pregnancy, this couple faces: (1) a 25% risk of compound heterozygosity (both variants inherited), resulting in severe neonatal-lethal VEO-ADPKD as observed in this case; (2) a 50% risk of inheriting a single pathogenic variant (either the truncating or hypomorphic allele), resulting in typical autosomal dominant ADPKD with adult-onset symptoms; and (3) a 25% risk of inheriting neither variant.

Given the family history of ADPKD (paternal grandfather requiring dialysis at age 55) and the severe outcome of compound heterozygosity in this pregnancy, preimplantation genetic testing for monogenic disorders (PGT-M) represents a valuable reproductive option. PGT-M can enable the selection of embryos that are either completely unaffected or carry only a single variant, thereby eliminating the risk of severe neonatal disease while potentially avoiding the typical ADPKD phenotype, if desired by the family [18, 19].

Study limitations include the absence of a renal biopsy or physical autopsy, which precludes direct histological evaluation of tubular dilatation and assessment of primary cilia. Variant pathogenicity was not experimentally validated through functional studies. Nevertheless, genomic autopsy successfully elucidated molecular mechanisms using established evidence from the literature, demonstrating its clinical utility when traditional autopsy is not feasible.

Conclusions

This first Korean VEO-ADPKD case demonstrates that biallelic PKD1 mutations cause a neonatal-lethal disease phenotype that phenocopies ARPKD via gene-dosage effects. The null+hypomorphic combination reduced polycystin-1 below critical thresholds. While the father retains approximately 50% polycystin-1 expression and remains asymptomatic at age 31, the infant with reduced functional protein below the critical threshold developed prenatal disease at 24 weeks and died on DOL 2.

VEO-ADPKD phenocopies ARPKD on prenatal imaging, highlighting inherent imaging limitations in differential diagnosis. Genomic autopsy proved essential, distinguishing VEO-ADPKD from ARPKD and enabling accurate counseling (25% recurrence risk) and PGT planning for future pregnancies. VEO-ADPKD should be considered in severe neonatal cystic kidney disease even with negative PKHD1 testing. Accurate genotypic analysis and functional variant evaluation are indispensable for precise prognosis and comprehensive familial counseling.

Author contributions

DHL and HHK drafted the manuscript and reviewed the literature. JP and JKK contributed to patient management and critically revised the manuscript. All authors read and approved the final manuscript.

Funding

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2025-02313278). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2025-00553891).

Data availability

The compound heterozygous PKD1 variants identified in the proband have been deposited in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) and can be accessed using the following accession numbers: SCV007537780 for the paternal truncating variant (NM_001009944.3:c.11343C>A, p.Tyr3781Ter) and SCV007537782 for the maternal non-truncating hypomorphic variant (NM_001009944.3:c.3876C>A, p.Phe1292Leu). Additional deidentified clinical data are available from the corresponding author upon reasonable request, subject to institutional ethics approval. All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Jeonbuk National University Hospital (Approval No.: CUH 2026-02-022) and was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. The IRB waived the requirement for informed consent due to the retrospective nature of the case report and the patient’s deceased status. This case report has been reported in line with the CARE guidelines.

Consent for publication

Written informed consent for publication of this case report and any accompanying images was obtained from the patient’s parents. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.

Competing interests

The authors declare no competing interests.