Reclassification of PAPSS2 Missense Variants in Turkish Patients with Brachyolmia Type 4: Multi-Modal Computational...

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• Loss-of-function variants in PAPSS2 gene cause autosomal recessive brachyolmia type 4, a skeletal dysplasia.
• Over 90 cases are documented, yet many variants remain of uncertain significance (VUS).

Purpose of the Study:

• To perform integrated in silico analysis of two novel PAPSS2 missense variants.
• To reclassify the significance of these variants using ACMG/AMP guidelines.

Main Methods:

• Whole-exome sequencing identified two homozygous missense variants: c.227T>A p.(Leu76Gln) and c.143C>G p.(Thr48Arg).
• Multi-modal in silico analysis included AlphaMissense, REVEL, CADD Phred, evolutionary conservation, and AlphaFold2 structural modeling.
• Variant reclassification followed 2015 ACMG/AMP guidelines.

Main Results:

• Both variants met criteria for reclassification from VUS to Likely Pathogenic (PS3, PM1, PM2, PP3).
• p.(Leu76Gln) disrupts hydrophobic core stability; p.(Thr48Arg) causes active-site steric hindrance.
• Probands exhibited platyspondyly, short stature, and DHEA-sulfate depletion; prepubertal cases had normal androgens.

Conclusions:

• Multi-modal computational analysis supports likely pathogenic classification of the studied PAPSS2 variants.
• This reclassification facilitates precision genetic counseling and deepens the understanding of skeletal and endocrine heterogeneity.
• The PAPSS2 variant registry is expanded to over 92 cases globally.