# Novel Variants and Clinical Heterogeneity in Pediatric Calcium Metabolism Disorders Identified Through High-Yield Tiered Genetic Testing in a Taiwanese Cohort

## TL;DR

This study identifies new genetic variants and diverse clinical features in rare calcium metabolism disorders among children in Taiwan using a systematic genetic testing approach.

## Contribution

The study introduces novel genetic variants and expands the mutational spectrum of pediatric calcium metabolism disorders in a Taiwanese cohort.

## Key findings

- A tiered genetic testing strategy achieved a high diagnostic yield in 12 out of 13 pediatric cases.
- Two novel variants (CASR p.Val836Ile and GNAS c.719-30A>T) were identified, expanding the known mutational spectrum.
- Phenotypic heterogeneity was observed, including incomplete penetrance and multisystem involvement in some cases.

## Abstract

Background and Objectives: Inherited disorders of calcium metabolism are rare pediatric conditions with diverse manifestations, including seizures, growth impairment, and renal or skeletal complications. Precise molecular diagnosis is crucial for effective management and informed genetic counseling. This study aimed to develop a systematic diagnostic approach, broaden the mutational spectrum, and characterize initial clinical features. Material and Methods: We retrospectively analyzed 13 pediatric cases at a tertiary center in southern Taiwan (2020–2025). Clinical, biochemical, and imaging data were reviewed. Genetic testing followed a tiered strategy to identify copy number variations and single-nucleotide variants. Variants were classified according to the ACMG/AMP guidelines and assessed by in silico tools. Results: The pediatric cohort (8 males, 5 females) had a median diagnostic age of 2 years and a mean follow-up of 7.7 years. Hypoparathyroidism was most common (n = 7), followed by PTH resistance (n = 3), hyperparathyroidism (n = 1), calcipenic rickets (n = 1), and syndromic hypercalcemia (n = 1). Genetic diagnoses were established in 12 children and one parent, involving CASR, GNAS, PRKAR1A, CYP27B1, and KMT2D. Two novel variants were identified (CASR p.Val836Ile and GNAS c.719-30A>T). Phenotypic heterogeneity included incomplete penetrance in autosomal dominant hypocalcemia and variable multisystem involvement in syndromic cases. Conclusions: A stepwise genetic testing strategy achieved a high diagnostic yield in pediatric calcium metabolism disorders. The discovery of novel and population-specific variants expands the mutational spectrum, supporting precision medicine in pediatric endocrinology.