De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies

Area of Science:

• Epigenetics
• Neurodevelopmental Biology
• Genetics

Background:

• Polycomb group proteins are crucial epigenetic regulators involved in transcriptional repression.
• Pathogenic variants in Polycomb group genes are linked to numerous neurodevelopmental disorders.
• The specific role of RYBP, a component of the noncanonical Polycomb Repressor Complex 1, in disease pathogenesis remained unclear.

Purpose of the Study:

• To investigate the role of RYBP in neurodevelopmental disorders.
• To characterize the functional consequences of RYBP variants.

Main Methods:

• Functional assessment of RYBP variants using in vitro cellular assays.
• In vivo studies utilizing Drosophila melanogaster models.
• Clinical evaluation of individuals with RYBP variants.

Main Results:

• Seven individuals with heterozygous de novo RYBP variants presented with severe developmental delay, dysmorphisms, and multiple congenital anomalies.
• All identified RYBP variants were located in the N-terminal domain, affecting the zinc-finger and ubiquitin-binding regions.
• In vitro and in vivo studies demonstrated that RYBP variants, particularly those affecting the C44 residue, lead to reduced protein expression and altered function, suggesting a potential RYBP-related disorder episignature.

Conclusions:

• Heterozygous de novo variants in RYBP are associated with a distinct syndromic neurodevelopmental disorder.
• This disorder is characterized by multiple congenital anomalies and developmental delays.
• RYBP variants disrupt epigenetic regulation, contributing to neurodevelopmental deficits.