Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Pathogenic variants in ATP-dependent chromatin remodeling proteins are linked to neurodevelopmental disorders (NDDs).
• The Nucleosome Remodeling Factor (NURF) complex, comprising BPTF and either SNF2H (SMARCA5) or SNF2L (SMARCA1), is crucial for chromatin remodeling.
• Previous studies implicated pathogenic variants in BPTF and SMARCA5 in NDDs.

Purpose of the Study:

• To identify and characterize novel genetic causes of NDDs.
• To investigate the role of the SMARCA1 gene in neurodevelopment.
• To explore the clinical spectrum associated with SMARCA1 variants.

Main Methods:

• Described 40 individuals from 30 families with de novo or maternally inherited pathogenic SMARCA1 variants.
• Analyzed clinical phenotypes including intellectual disability (ID)/developmental delay (DD), speech development, and facial dysmorphisms.
• Examined genome-wide DNA methylation profiles and macrocephaly in individuals with SMARCA1 loss-of-function variants.
• Utilized Smarca1, Smarca5, and Bptf single and double mouse knockouts for genetic dissection of the NURF complex and forebrain development.

Main Results:

• Identified a novel NDD associated with pathogenic SMARCA1 variants.
• Observed mild to severe ID/DD, delayed or regressive speech, and recurrent facial dysmorphisms in affected individuals.
• Found a mild genome-wide DNA methylation profile and high penetrance of macrocephaly in individuals with SMARCA1 loss-of-function variants.
• Demonstrated the importance of NURF complex composition and dosage for forebrain development through mouse models.

Conclusions:

• Pathogenic variants in SMARCA1 represent a newly identified cause of neurodevelopmental disorders.
• SMARCA1 variants are associated with a distinct clinical phenotype including ID/DD, speech impairment, and macrocephaly.
• Alterations in different NURF complex components can lead to NDDs with a broad clinical spectrum, underscoring the complex's role in neurodevelopment.