Missense variant contribution to USP9X-female syndrome

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• USP9X, an X-chromosome gene escaping inactivation, is crucial for neurodevelopment.
• Loss-of-function in USP9X causes neurodevelopmental disorders in both sexes.
• USP9X-female syndrome is primarily associated with de novo heterozygous complete loss-of-function mutations in females.

Purpose of the Study:

• To investigate the role of USP9X missense and small in-frame deletion variants in USP9X-female syndrome.
• To assess the pathogenicity of eleven such variants, including ten novel ones.
• To compare the phenotypic spectrum of USP9X-female syndrome with USP9X-male associated neurodevelopmental disorders.

Main Methods:

• Utilized variant prediction algorithms.
• Employed protein structure modeling.
• Applied clinically relevant guidelines for variant assessment.

Main Results:

• Eleven USP9X variants (ten novel) were scrutinized for pathogenicity.
• All assessed variants were supported as pathogenic by computational and clinical assessments.
• The phenotype of the studied cohort overlapped with known USP9X-female syndrome but showed increased variability.
• Analysis of 35 females with pathogenic USP9X variants confirmed the syndrome and highlighted sex-specific differences compared to males.

Conclusions:

• USP9X missense and small in-frame deletion variants contribute to USP9X-female syndrome.
• These findings expand the understanding of genetic causes for USP9X-female syndrome.
• USP9X-female syndrome exhibits distinct features compared to male-associated USP9X neurodevelopmental disorders.