Variable expressivity of a transmitted pathogenic KAT6B variant

Area of Science:

• Genetics
• Molecular Biology
• Clinical Medicine

Background:

• Pathogenic variants in Lysine acetyltransferase 6B (KAT6B) are linked to Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GPS).
• Recent findings suggest KAT6B disorders represent a spectrum with overlapping clinical features.
• KAT6B variants are predominantly de novo, with few reported inherited cases.

Purpose of the Study:

• To report clinical and molecular findings of a novel pathogenic KAT6B variant in a three-generation family.
• To investigate the inheritance pattern and phenotypic variability of KAT6B disorders.
• To contribute to the understanding of KAT6B disorders as a broad clinical spectrum.

Main Methods:

• Clinical evaluation of affected individuals across three generations.
• Molecular genetic analysis to identify and confirm the KAT6B variant.
• Segregation analysis within the family to establish inheritance patterns.

Main Results:

• A previously unreported pathogenic KAT6B variant was identified and segregated within the family.
• The variant was associated with a phenotype distinct from classic SBBYSS or GPS.
• Significant variable expressivity and intra-familial variability were observed, including inheritance from mildly affected parents.

Conclusions:

• KAT6B disorders should be viewed as a broad clinical spectrum, encompassing phenotypes beyond SBBYSS and GPS.
• Pathogenic KAT6B variants can be inherited from parents with mild or unrecognized symptoms.
• This study underscores the importance of considering familial inheritance and variable expressivity in KAT6B-related disorders.