The First Case of Congenital Nephrogenic Diabetes Insipidus Caused by AVPR2 Disruption Because of 4q25 Insertional Translocation

Abstract

Letter to the Editor Diagnostic GeneticsDear Editor, Congenital nephrogenic diabetes insipidus (NDI) is characterized by an impaired renal response to arginine vasopressin (AVP) [1]. Approximately 90% of patients with NDI have mutations in the AVP receptor 2 gene (AVPR2) [2]. Mutations in AVPR2 located in chromosome X result in X-linked NDI, which presents characteristic symptoms, including polyuria, polydipsia, and fever in male infants.A two-month-old boy (Pt #1) presented to Seoul National University Hospital with irritability, polyuria, and mild fever in March 2023. Informed consent was obtained from the patient's guardian. During a water deprivation test, he exhibited an elevated serum sodium level and a continuous decrease in urine osmolality, which were not alleviated by subcutaneous vasopressin injection. The family history indicated X-linked recessive inheritance (Fig. 1A). The patient's second uncle (Pt #2) with similar symp-tom as his nephew had also been diagnosed as having NDI as an infant.We performed whole-exome sequencing of a blood sample of Pt #2. A soft-clipped region was observed in intron 2 of AVPR2, using Integrative Genomics Viewer (Fig. 1B). Analysis of chimeric reads revealed a putative chromosomal translocation between the long arms of chromosome 4 and chromosome X. Primers for the suspected breakpoints were designed, and PCR was performed. Subsequent Sanger sequencing revealed breakpoints at chrX:153,170,697 and chr4:109,062,641 (Fig. 1C). Karyotyping was performed to confirm the translocation. Surprisingly, chromosomal analysis revealed normal findings (data not shown). Subsequently, a chromosomal microarray assay was performed on peripheral blood from Pt #1, using the CytoScan Dx Assay