Familial White-Sutton Syndrome Caused by a Pathogenic POGZ p.Arg508* Variant: Intrafamilial Variability from...

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Human Genetics

Background:

• White-Sutton syndrome (WHSUS) is a rare neurodevelopmental disorder linked to POGZ gene mutations.
• Most WHSUS cases are sporadic, with inherited forms being exceptionally rare.

Purpose of the Study:

• To describe a familial case of WHSUS with a heterozygous POGZ nonsense variant.
• To highlight intra-familial phenotypic variability and expand the clinical spectrum of POGZ-related disorders.

Main Methods:

• Clinical evaluation and multidisciplinary assessments.
• Clinical exome sequencing (CES) for genetic testing, followed by Sanger confirmation and segregation analysis.
• Copy number variation (CNV) detection using NGS data and chromosomal microarray (aCGH).

Main Results:

• Identified a heterozygous pathogenic POGZ variant (c.1522C>T, p.Arg508*) inherited maternally.
• Observed marked phenotypic variability, with the mother showing an attenuated phenotype and affected children presenting with developmental delay and dysmorphic features.
• A de novo microduplication at Xp11.22 was identified in one affected child.

Conclusions:

• This report documents a rare familial occurrence of WHSUS with highly variable expressivity.
• Findings broaden the phenotypic and molecular characterization of POGZ-related disorders.
• Emphasizes the importance of comprehensive segregation studies and early genomic diagnosis for WHSUS.