Contiguous gene deletion in a Chinese family with X-linked nephrogenic diabetes insipidus: challenges in early diagnosis and implications for affected families

Abstract

Nephrogenic diabetes insipidus (NDI) is a rare disorder of the renal collecting tubules, characterized by an inability to concentrate urine due to an impaired response to arginine vasopressin (AVP), resulting in dilute urine and polyuria. Causes of NDI are heterogeneous and diagnosing congenital NDI (cNDI) in young infants is clinically challenging, as typical symptoms are often unappreciated or inconspicuous. Instead, young infants may present with non-specific signs such as vomiting, poor feeding, failure to thrive, unexplained fevers, irritability, constipation or diarrhea. We report a 37-day-old infant who presented with polyuria and severe hypernatremic dehydration that was unresponsive to vasopressin. The patient was treated with amiloride, indomethacin and hydrochlorothiazide. Genetic analysis revealed a novel contiguous deletion involving the entire AVPR2 gene and the last exon of the adjacent ARHGAP4 gene. A study of the family confirmed the carrier status in the mother. This case illustrates the importance of molecular testing in confirming the diagnosis in the index patient, as well as in identifying asymptomatic at-risk female carriers so that appropriate genetic counselling can be given for reproductive planning. All pediatric patients with suspected cNDI should undergo genetic analysis for a definitive diagnosis.

New developments and concepts in the diagnosis and management of diabetes insipidus (AVP‐deficiency and resistance)

“…Congenital nephrogenic DI (cNDI) results from mutations leading to loss of function of the AVPR2 or AQP2, leading to variable degrees of resistance to AVP. 64,65 These mutations include deletions, insertions or even missense pathogenic variants of the AVPR2 (Figure 2). The binding of ΑVP to AVPR2 activates adenylyl cyclase, increasing intracellular cAMP levels and activating cAMPdependent protein kinase A (PKA).…”

“…(MIM*300538) account for over 90% of cNDI cases. 63,65 To date, more than 280 disease-causing variants have been identified affecting different parts of the receptor protein, with considerable phenotypic variability. Missense mutations, small insertions and deletions account for around 90% of AVPR2 alterations.…”

“…Missense mutations, small insertions and deletions account for around 90% of AVPR2 alterations. 65 Approximately half (55.8%) of the reported AVPR2 mutations are missense, whereas the remainder comprise nonsense mutations and small frameshift deletions. 66 Missense mutations can lead to partial preserved receptor expression and function, and hence a milder cNDI phenotype.…”

“…104 Large deletions leading to complete loss of the whole AVPR2 and parts of the neighbouring gene ARHGAP4 have been also recently identified, leading to a X-linked cNDI. 65,[105][106][107] The ARHGAP4…”

“…All of these mutants impair AVP binding to the V2 receptor 63 ( Figure 2 ). Congenital nephrogenic DI (cNDI) results from mutations leading to loss of function of the AVPR2 or AQP2, leading to variable degrees of resistance to AVP 64,65 . These mutations include deletions, insertions or even missense pathogenic variants of the AVPR2 (Figure 2).…”