Case Report: Deep intronic PHEX variant causing aberrant splicing identified by whole genome and targeted RNA sequencing in X-linked hypophosphatemia - Summary - MDSpire
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Case Report: Deep intronic PHEX variant causing aberrant splicing identified by whole genome and targeted RNA sequencing in X-linked hypophosphatemia
To identify a previously undetected genetic cause of X-linked hypophosphatemia (XLH) in a patient with a clear clinical phenotype but negative genetic testing results.
Approach:
Genetic Testing: Conducted short-read whole exome sequencing (WES) followed by short-read whole genome sequencing (WGS) to identify genetic variants.
RNA Analysis: Extracted RNA from peripheral blood, amplified via RT-PCR, and analyzed using Nanopore long-read sequencing to confirm splice effects.
Key Findings:
Identified a novel deep intronic variant in the PHEX gene (c.2070 + 601C>T) confirmed as de novo.
The variant caused two aberrant transcripts with pseudoexon inclusions, leading to premature stop codons.
Interpretation:
The findings highlight the diagnostic value of comprehensive genomic analysis and RNA sequencing for identifying deep intronic variants in XLH.
Limitations:
The study focuses on a single case, limiting generalizability.
Long-term effects of Burosumab therapy were not assessed in this report.
Conclusion:
This case expands the known PHEX mutation spectrum.
In a pooled analysis of two randomized crossover trials, reducing nightly sleep by about 1.5 hours for 6 weeks was associated with modest increases in body weight and waist circumference without measurable changes in body composition.
