Functional Characterization of a Novel GPC3 Missense Variant in Simpson-Golabi-Behmel Syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Simpson-Golabi-Behmel syndrome 1 (SGBS1) is a rare X-linked recessive disorder.
• It is characterized by overgrowth and multiple congenital anomalies.
• SGBS1 results from pathogenic variants in the Glypican-3 (GPC3) gene, crucial for cellular signaling.

Purpose of the Study:

• To identify the genetic cause of SGBS1 in a family with affected individuals.
• To functionally characterize a novel GPC3 missense variant.
• To reclassify the variant's significance based on new evidence.

Main Methods:

• Exome sequencing to identify genetic variants.
• Segregation analysis within the affected family.
• In vitro functional studies using HEK293T cells to assess protein localization.

Main Results:

• A novel GPC3 missense variant (c.695C>A; p.(Ala232Asp)) was identified.
• The variant segregated with SGBS1 in the family.
• Functional studies showed mis-localization of the mutant GPC3 protein.

Conclusions:

• The novel GPC3 missense variant is likely pathogenic and causes SGBS1.
• This finding upgrades the variant's classification from uncertain significance to likely pathogenic.
• Understanding GPC3 protein function is critical for SGBS1 pathogenesis.