Noncanonical Splice Site Disruption: +4 Intronic Variant in Phosphate-Regulating Endopeptidase Homolog, X-linked...

X-linked hypophosphatemic rickets (XLH) is the most common inherited cause of renal phosphate wasting. It is typically caused by pathogenic variants in the phosphate-regulating endopeptidase homolog, X-linked (PHEX gene), which lead to increased levels of fibroblast growth factor 23 (FGF23). However, noncanonical intronic variants represent a significant diagnostic challenge, as they may not be detected by conventional genetic studies and require interpretation supported by bioinformatic tools. We present the case of a pediatric patient with postnatal short stature and progressive genu varum. Biochemical studies revealed hypophosphatemia with reduced tubular reabsorption of phosphate, while calcium, parathyroid hormone (PTH), and vitamin D levels were within normal ranges. Radiological findings were consistent with rickets. Initial clinical exome sequencing was negative. Subsequently, a targeted gene panel identified a previously unreported intronic variant in the PHEX gene (c.1768+4dup; chrX:22,219,105 T>TA). In silico analysis using SpliceAI demonstrated a high probability of donor splice site loss (DS_DL = 0.80), while Pangolin predicted a splice-disrupting effect (score = 0.72); collectively, these findings support a deleterious effect on mRNA splicing. This case highlights the importance of integrating clinical, biochemical, genetic, and computational data for the interpretation of noncanonical intronic variants, expanding the mutational spectrum described for PHEX in XLH.