A novel gain-of-function mutation (W818R) of calcium-sensing receptor in a family with autosomal dominant hypocalcemia type 1.

INTRODUCTION

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare inherited disorder caused by gain-of-function mutations in the calcium-sensing receptor (CASR) gene, with clinical manifestations ranging from asymptomatic hypocalcemia to recurrent seizures.

METHODS

Clinical evaluation and genetic testing were performed. Through activation of the MAPK signaling pathway,cellular functional validation was conducted to confirm the pathogenicity of this variant.

RESULTS

We report a two-generation family in which the proband presented with lifelong recurrent convulsive episodes and was misdiagnosed with epilepsy for decades, resulting in persistent symptoms despite antiepileptic therapy. His son exhibited similar manifestations. A whole-exome sequencing (WES) analysis was identified a previously unreported heterozygous CASR mutation, c.2452T>C (p.Trp818Arg). Functional cellular analyses confirmed that it caused a novel gain-of-function CASR mutant.

CONCLUSION

This case highlights the critical role of genetic testing in the diagnosis of ADH1, particularly in patients with recurrent seizures or neonatal hypocalcemia with hyperphosphatemia and normal renal function. Once the diagnosis is established, treatment options for symptomatic patients include calcium supplementation and calcitriol, aiming to maintain serum calcium at the lower end of the reference range and relieve symptoms.