Polycystic kidney disease (PKD) is primarily a genetic disorder that causes fluid-filled cysts and kidney failure, although it can occasionally occur without gene mutations [1]. It is mainly caused by mutations in the PKD1 (78%) and PKD2 (15%) genes, which are associated with autosomal dominant PKD (ADPKD). Additional variants, such as autosomal recessive PKD and other types, arise from rare genetic causes [2]. As accurate diagnosis is possible through genetic testing in 17% of PKD patients whose diagnosis is unclear or inaccurate [3], identifying the genetic cause of PKD is paramount to achieving an accurate diagnosis that allows healthcare professionals to provide targeted genetic counseling, accurately evaluate renal prognosis, screen for possible extra-renal manifestations, and offer tailored treatment options when available.

Oral-facial-digital syndrome type I (OFD1) is an X-linked dominant disorder (MIM #311200) caused by the OFD1 gene. It leads to anomalies in the oral cavity, face, and digits, such as a lobulated tongue, cleft palate, widely spaced eyes, and digital abnormalities. Approximately 60% of individuals with OFD1 also have PKD [4,5].

To date, only one case of suspected OFD1 has been reported in Korea [6]. However, in that report, genetic testing turned up no mutations in the OFD1 gene. In this letter, we report the first documented OFD1 case in Korea and identify a novel, likely pathogenic variant in the OFD1 gene.

A 55-year-old woman presented to the neurosurgery outpatient clinic complaining of back pain. During L-spine magnetic resonance imaging (MRI), bilateral PKD was incidentally detected, and the patient was referred to the nephrology clinic for further evaluation. Before presenting with back pain, the patient had been living a normal life without any cognitive or neurologic issues. Laboratory tests revealed a blood urea nitrogen (BUN) of 23 mg/dL, creatinine (Cr) of 1.18 mg/dL, estimated glomerular filtration rate (eGFR) of 50.6 mL/min/1.73 m², and urine protein/creatinine ratio of 0.209 g/g*Cr. Abdominal computed tomography confirmed the diagnosis of PKD (Fig. 1). The patient was classified as Mayo IA, with a total kidney volume of 387 mL and height-adjusted total kidney volume of 244.9 mL. Tongue nodules were observed (Fig. 2), but no other abnormalities were found. There was no family history of miscarriage, neurological disease, or renal disease including PKD, and the patient’s father had died of alcoholic liver cirrhosis. Screening tests were conducted on the adult daughter, which showed an eGFR of 119.962 mL/min/1.73 m², a normal urinalysis, and no evidence of PKD on contrast-enhanced computed tomography of the abdomen. Given that ADPKD is the most common diagnosis in patients with imaging findings of PKD, and considering the possibility of an incomplete family history, the patient was diagnosed with ADPKD and followed up accordingly. Throughout the year, the patient’s total kidney volume and height-adjusted total kidney volume demonstrated minimal increase, reaching 393 mL and 247.4 mL, respectively. However, during the same period, there was a noticeable decline in kidney function, as indicated by a BUN of 34 mg/dL and Cr of 1.71 mg/dL, eGFR of 32.1 mL/min/1.73 m². The findings were inconsistent with the typical clinical manifestations of ADPKD. Therefore, genetic testing was performed to confirm the PKD diagnosis and assess the patient’s management plan and prognosis.

We performed a multigene panel test for PKD for the proband. This panel included 34 genes (ALG8, ALG9, ANKS6, CEP164, CEP290, CEP83, COL4A1, COL4A4, DNAJB11, DZIP1L, ETFA, FLCN, GANAB, HNF1B, INVS, LRP5, MAPKBP1, NOTCH2, NPHP1, NPHP3, NPHP4, PAX2, PKD1, PKD2, PKHD1, PMM2, SEC61A1, TMEM67, TSC1, TSC2, TTC21B, UMOD, VHL, WDR19) associated with PKD, including PKD1 and PKD2. There were no disease-related variants in the PKD1 or PKD2 genes. However, a novel heterozygous variant, c.2184del; p.Thr729Leufs*88, was identified in the OFD1 gene (Fig. 3).

The c.2184del variant was not found in gnomAD (https://gnomad.broadinstitute.org/) or the Korean Variant Archive (https://www.kobic.re.kr/kova/). This c.2184del variant can be classified as a likely pathogenic variant according to the 2015 American College of Medical Genetics and Genomics and the Association guidelines [7]. This classification is supported by two criteria: the variant is predicted to result in premature termination, and it is not present in large population databases.

Although bilateral multiple renal cysts are a prevalent feature observed in most patients with ADPKD, they are also observed in a subset of patients with OFD1. Such patients with OFD1 have a history of cleft palate, brachydactyly, and idiopathic intracranial hypertension [8]. Despite the absence of apparent facial or digital abnormalities in this particular patient, the presence of PKD and tongue nodules raised the suspicion of a potential link to OFD1. PKD has been observed in approximately one-third of OFD1 patients; these patients have a high likelihood of renal failure, with more than half progressing to end-stage kidney disease by a median age of 34 years [9]. In contrast, the median age at the onset of endstage kidney disease is approximately 60 years for PKD1 patients and around 78 years for PKD2 patients [10,11]. The high likelihood of kidney failure in OFD1 patients emphasizes the critical importance of timely diagnosis and effective management strategies. In addition, genetic testing is essential to accurately diagnose PKD in patients without other clinical features of OFD1.

In summary, we identified a novel likely pathogenic variant (c.2184del; p.Thr729Leufs*88) in the OFD1 gene. This case represents the first confirmed genetic diagnosis of OFD1 in Korea. Our findings highlight the valuable role of panel sequencing for accurately diagnosing PKD. Our results enhance knowledge of the genetic characteristics of Korean patients with OFD1.