Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

Area of Science:

• Genetics
• Epigenetics
• Developmental Biology

Background:

• Epigenetic dysregulation is linked to inherited disorders.
• RBBP5, a core component of the histone-modifying complex, has not been previously associated with human disease.

Purpose of the Study:

• To investigate the role of RBBP5 in human disease.
• To determine the pathogenicity of de novo RBBP5 variants identified in individuals with neurodevelopmental symptoms.

Main Methods:

• Identification of de novo heterozygous variants in RBBP5 in five unrelated individuals.
• Protein structural analysis of missense variants.
• Functional investigation using transgenic Drosophila models.

Main Results:

• Identified three nonsense/frameshift and two missense variants in individuals with global developmental delay, intellectual disability, microcephaly, and short stature.
• Missense variants p.(T232I) and p.(E296D) affect conserved amino acids at the RBBP5-nucleosome interface.
• Drosophila models demonstrated that RBBP5 variants act through partial loss-of-function mechanisms, impacting brain size.

Conclusions:

• Haploinsufficiency of RBBP5, caused by de novo null and hypomorphic loss-of-function variants, is associated with a syndromic neurodevelopmental disorder.
• This study establishes RBBP5 as a gene implicated in human neurodevelopmental disorders.