PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue...

Area of Science:

• Genetics
• Developmental Biology
• Molecular Medicine

Background:

• Mosaicism, particularly in the PIK3CA gene, is increasingly implicated in developmental disorders.
• PIK3CA mutations are linked to a wide spectrum of overgrowth phenotypes and vascular malformations.

Purpose of the Study:

• To investigate PIK3CA mutations in individuals with brain and/or body overgrowth using advanced sequencing techniques.
• To correlate clinical features with molecular findings in PIK3CA-related overgrowth disorders.

Main Methods:

• Targeted next-generation sequencing (NGS) with molecular inversion probes and amplicon sequencing.
• Analysis of 241 samples from 181 individuals with overgrowth phenotypes.
• Comparison with mutations identified through other sequencing methods (panel, WES, Sanger).

Main Results:

• PIK3CA mutations were identified in 60 individuals via targeted NGS and 12 individuals through other methods.
• The cohort segregated into three groups based on mutation type and clinical presentation: severe focal overgrowth, predominantly brain overgrowth, and intermediate phenotypes.
• Sixteen novel PIK3CA mutations were discovered, and constitutional mutations were found in 10 patients.

Conclusions:

• PIK3CA-related overgrowth disorders represent a discontinuous spectrum.
• The severity and distribution of PIK3CA mutations correlate with distinct clinical phenotypes.
• Advanced sequencing methods are crucial for identifying mosaic PIK3CA mutations in developmental disorders.