Timely Diagnosis of PAX2-Related Disorder by Rapid Whole-Genome Sequencing in a Critically Ill Neonate with Bilateral Renal Hypoplasia: A Three-Generation Case Report

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Neonatal Med. 2025;32(2):97-101

Publication date (electronic) : 2025 November 30

doi : https://doi.org/10.5385/nm.2025.32.2.97

Jinhee Kim, MD¹, Hyeseon Kim, MD¹, So Yoon Ahn, MD, PhD^1,2, Se In Sung, MD, PhD^1,2, Yun Sil Chang, MD, PhD^1,2,3, Mi-Ae Jang, MD, PhD⁴, Sohyun Lee, MS⁵, Go Hun Seo, MD, PhD⁵, Misun Yang, MD, PhD^,1,2

¹Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Cell and Gene Therapy Institute for Future Medicine, Samsung Medical Center, Seoul, Korea

³Department of Health Science and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea

⁴Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

⁵Division of Medical Genetics, 3billion Inc., Seoul, Korea

Correspondence to: Misun Yang, MD, PhD Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-0651 E-mail: misun.yang@samsung.com

Received 2025 October 31; Revised 2025 November 17; Accepted 2025 November 17.

Abstract

INTRODUCTION

Paired box 2 (PAX2), located on chromosome 10q24.31, belongs to the paired box (PAX) family of transcription factors and plays a crucial role in the embryonic development of the urinary system, eyes, ears, and central nervous system [1-3]. Pathogenic variants of PAX2 lead to a broad phenotypic spectrum, primarily involving renal and ocular abnormalities, with occasional extrarenal manifestations such as hearing loss, central nervous system malformations, and, in some cases, congenital heart or skeletal defects [4,5].

Although PAX2 mutations have been reported globally, their prevalence is likely underestimated because of variable presentations and the limited use of genetic testing [4]. The same mutation may result in markedly different phenotypes even among members of the same family, ranging from mild renal disease to end-stage renal disease [4]. To date, approximately 90 pathogenic PAX2 variants have been identified [6], most of which are located within the paired domain (exons 2–4) and homeodomain. The most common pathogenic variant is a frameshift mutation (NM_003990.3:c.76dup, p.V26Gfs*28), which has been reported most frequently [4].

Rapid whole-genome sequencing (WGS) enables timely and comprehensive genetic diagnosis in critically ill neonates, dramatically reducing the turnaround time from several weeks to a few days compared with conventional tests. Although rapid WGS has demonstrated substantial clinical utility and improved outcomes in neonatal intensive care units (NICUs) worldwide, its clinical implementation in Korea remains limited due to regulatory and financial barriers [7].

Here, we report the case of a neonate with bilateral renal hypoplasia and life-threatening respiratory failure who was diagnosed with a PAX2 variant through rapid trio WGS. Subsequent three-generation genetic analysis confirmed paternal inheritance of the mutation. This case highlights the importance of early genetic diagnosis and family-based genetic evaluation in patients with congenital renal hypoplasia.

CASE REPORT

A newborn girl was delivered via cesarean section at 38 weeks and 3 days of gestation due to breech presentation, with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. The birth weight was 3,110 g (45th percentile), and the length was 46 cm (9th percentile). Prenatal ultrasonography at 28 weeks and 5 days revealed oligohydramnios with an amniotic fluid index of 2 cm. A follow-up scan at 32 weeks and 1 day showed anhydramnios with non-visualization of both kidneys and renal arteries, suggesting bilateral renal hypoplasia. Fetal magnetic resonance imaging confirmed bilateral small kidneys measuring approximately 1.9 cm on the right and 1.4 cm on the left. The parents were nonconsanguineous and of Korean ethnicity. The father was diagnosed with minimal-change disease (MCD), the paternal grandfather had undergone kidney transplantation for chronic renal disease, and the paternal family had a history of renal disease of unknown etiology (Figure 1).

Figure 1.

Pedigree of the family with the paired box 2 (PAX2) gene mutation. The proband (IV:2), her father (III:3), and paternal grandfather (II:3) were found to carry a heterozygous missense variant in PAX2 (NM_000278.5:c.187G>A, NP_000269.3:p. Gly63Ser) as confirmed by rapid trio whole-genome sequencing. Family members III:1, III:6, III:8, IV:1, IV:3, and IV:4 also underwent Sanger sequencing but tested negative for PAX2. Individuals I:1, II:1, II:3, II:5, III:3, and IV:2 were clinically diagnosed with kidney disease.

Physical examination at birth revealed prominent chest wall retraction and tachypnea without other morphological anomalies. She developed respiratory failure secondary to pneumothorax and respiratory distress syndrome immediately after birth, requiring invasive ventilator support and chest tube insertion. Although the patient began to void on the second day of life, she exhibited persistent oliguria. Laboratory evaluation demonstrated progressively increasing blood urea nitrogen and creatinine levels, which rose to 23.1 and 3.1 mg/dL, respectively, by day 3 of life, consistent with progressive azotemia. Persistent elevation of renal function markers was accompanied by an electrolyte imbalance, with hyperkalemia (K⁺ 7.0 mmol/L) noted on day 7.

Postnatal abdominal ultrasonography performed immediately after birth confirmed bilateral renal hypoplasia, with both kidneys measuring approximately 1.4 cm and showing almost no intrarenal vascularity (Figure 2). Based on these findings and the strong family history, a hereditary renal disorder was suspected (Figure 1). Given the patient’s rapidly worsening respiratory status and the possibility of a limited diagnostic window, rapid trio WGS was urgently performed on day 2 of life for the patient and both parents to identify a potential hereditary renal disorder, including those associated with impaired lung development, enabling prompt etiologic diagnosis and guiding critical management decisions. On day 5, a heterozygous missense variant of PAX2 (NM_000278.5:c.187G>A; NP_000269.3: p. Gly63Ser) was identified in both the patient and her father, confirming paternal inheritance of a PAX2-related disorder (Figure 3). This variant, classified as likely pathogenic, is located within the paired domain of PAX2 and is associated with autosomal dominant papillorenal syndrome (OMIM 120330).

Figure 2.

Postnatal ultrasonography. (A, B) Ultrasonographic and Doppler images of the left kidney showing markedly small size (1.39 cm) with almost absent vascularity. (C, D) Ultrasonographic and Doppler images of the right kidney showing markedly small size (1.40 cm) with almost absent vascularity.

Figure 3.

Integrative genomics viewer (IGV) visualization of PAX2 c.187G>A (p.Gly63Ser) variant. IGV screenshots showing the heterozygous PAX2 c.187G>A (p.Gly63Ser) variant in the family. (A) The proband shows a heterozygous G>A substitution at chr10:100,749,889 (GRCh38). (B) The same variant is present in the father, confirming paternal inheritance. (C) The variant is absent in the mother. The variant position is indicated by a vertical green bar representing the alternate A allele.

Given the possible extrarenal involvement, ophthalmological, auditory, and central nervous system evaluations were performed, all of which showed normal findings. Pulmonary hypoplasia was initially suspected; however, her respiratory status gradually stabilized with intensive care, allowing successful extubation several days later. Following confirmation of the PAX2 mutation on day 5, an early nephrology consultation was performed to establish a timely dialysis plan. Due to persistent azotemia and oliguria accompanied by hyperkalemia, continuous renal replacement therapy (CRRT) and subsequent peritoneal dialysis (PD) were considered. Given that the genetic diagnosis indicated a high likelihood of long-term renal replacement therapy, a double-lumen central venous catheter for CRRT (Gambro) and a PD catheter were surgically placed during the same procedure on day 11. Unexpectedly, urine output improved thereafter, evolving into a non-oliguric acute kidney injury pattern, and hyperkalemia was controlled with conservative management, including potassium-binding resin (Kallimate), sodium chloride supplementation, modification of total parenteral nutrition, and a low-potassium formula; therefore, CRRT was not initiated, and full PD was ultimately started on day 28. The patient was discharged on day 56 and continued home PD, with stable renal function and growth. Extended family testing using Sanger sequencing identified the same PAX2 mutation in the paternal grandfather, whereas the asymptomatic paternal uncle, paternal cousin, father’s cousin, and second paternal cousin tested negative (Figures 1, 4). Great-uncle with renal disease could not be tested owing to poor clinical condition.

Figure 4.

Sanger sequencing confirmation of the paired box 2 (PAX2) variant in extended family members. (A) The paternal grandfather (individual II:3 on Figure 1) shows a heterozygous PAX2 c.187G>A (p.Gly63Ser) variant. (B–E) The paternal uncle (III:1), paternal cousin (IV:1), father’s cousin (III:6), and paternal second cousin (IV:3) showed wild-type sequences at the same position.

DISCUSSION

PAX2-related disorders, also known as renal coloboma syndrome, encompass a wide phenotypic spectrum involving renal, ocular, and extrarenal manifestations. According to previous reports, renal disease and ocular abnormalities are present in approximately 92% and 77% of affected individuals, respectively [4]. Among the renal findings, bilateral renal hypoplasia is one of the most common and may lead to early-onset renal failure. However, diagnosis is often delayed because of variable clinical features and limited access to genetic testing [8,9].

In the present case, a hereditary renal disorder was suspected antenatally based on the presence of oligohydramnios and the absence of visible kidneys on prenatal imaging. Rapid trio WGS performed on the second day of life confirmed the presence of a heterozygous PAX2 variant (NM_000278.5:c.187G>A, NP_ 000269.3:p. Gly63Ser), leading to early planning of PD and proactive evaluation of potential PAX2-related extrarenal manifestations [10]. This variant is absent from the gnomAD v4.1 database and has been previously reported in individuals with papillorenal syndrome (currently referred to as renal coloboma syndrome) [11]. Amino acid substitutions occur within a functionally important domain in which multiple pathogenic variants have been described [4], and in silico prediction tools indicate a deleterious impact on protein function (rare exome variant ensemble learner [REVEL]: 0.89, 3Cnet: 0.97) [12].

Segregation analysis revealed paternal inheritance across three generations. The same PAX2 variant was identified in the affected paternal grandfather, whereas the paternal uncle, cousin, father’s cousin, and second cousins were all asymptomatic and tested negative for the variant, demonstrating a clear genotype–phenotype correlation within the family [13-15]. The patient’s father, who carried the same variant, was diagnosed with MCD and exhibited only mild proteinuria, illustrating the phenotypic variability and incomplete penetrance of PAX2-related disorders [13-15]. His genetic diagnosis was revealed only after the variant was identified in his daughter. Although MCD is not a typical feature of PAX2-related disorders, a similar case has been reported in which the father presented with MCD, while the child exhibited bilateral renal agenesis [16]. In general, glomerular diseases, such as focal segmental glomerulosclerosis and nephrotic syndrome, are more commonly associated with PAX2 variants, suggesting that PAX2 haploinsufficiency may increase susceptibility to podocyte injury. This observation may help explain the phenotypic variability observed in the family.

Although PAX2-related disorders can be identified using targeted next-generation sequencing panels, such tests typically require longer turnaround times and may be impractical for critically ill neonates at risk of early mortality. By contrast, rapid WGS provides an unbiased and comprehensive approach capable of detecting both known and novel variants within a clinically actionable timeframe, which can be lifesaving for unstable neonates. The introduction of rapid WGS as an early diagnostic approach for critically ill newborns with unexplained genetic conditions was a significant milestone in neonatal precision medicine. This technology has already been integrated into clinical care pathways in several countries, including the United States, the United Kingdom, the Netherlands, Sweden, and Australia [7]. However, in Korea, clinical implementation of genome sequencing remains limited. Neither whole-exome sequencing nor WGS is yet reimbursed under the National Health Insurance System, and only a limited number of hospitals are capable of performing such testing. These financial and technical barriers restrict the timely and comprehensive genetic diagnosis of critically ill neonates. Consequently, timely genetic diagnosis of critically ill neonates is often challenging, underscoring the urgent need for broader accessibility and institutional support for genomic medicine. In addition, this case prompted refinement of our institutional indications for rapid WGS within the current research framework. In particular, we prioritize rapid WGS referral for acutely and critically ill neonates who require rapid therapeutic decision-making and in whom a monogenic disorder is suspected, especially when there is a family history of a similar phenotype. In our previous single-center pilot study involving 20 critically ill neonates, rapid trio WGS achieved a diagnostic yield of 50% with a mean turnaround time of 5.5 days, demonstrating its clinical utility in the NICU. Building on these findings, a nationwide multicenter study was initiated under the coordination of the Korea Disease Control and Prevention Agency as part of an expanded investigation to further validate the feasibility and diagnostic impact of rapid genomic testing in Korea.

In conclusion, this case facilitated early identification of the underlying genetic cause across three generations, illustrating the familial nature of the disease. Rapid WGS can support timely diagnosis and guide early management in critically ill neonates with severe or rapidly progressive conditions while also providing essential information for family counseling and future reproductive planning.

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