Numerous BAF complex genes are mutated in Coffin-Siris syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Coffin-Siris syndrome (CSS) is a rare congenital disorder.
• Characterized by intellectual disability, coarse facial features, hypertrichosis, and nail hypoplasia.
• Autosomal dominant inheritance is suspected due to sporadic cases.

Purpose of the Study:

• To identify the genetic basis of Coffin-Siris syndrome.
• To investigate the role of BAF complex genes in CSS.
• To expand the understanding of genetic mutations causing CSS.

Main Methods:

• Whole exome sequencing (WES) was performed on CSS patients.
• Comprehensive sequencing of SMARCB1 and other BAF complex subunit genes.
• Analysis of a large cohort of CSS patients.

Main Results:

• De novo mutations in SMARCB1 were identified in initial CSS patients.
• Mutations in six BAF complex genes (SMARCA4, SMARCB1, SMARCA2, SMARCE1, ARID1A, ARID1B) were found in 20 out of 23 patients.
• Mutations in five BAF complex genes were identified in 37 out of 71 CSS patients across two cohorts.

Conclusions:

• Mutations in BAF complex genes are a significant cause of Coffin-Siris syndrome.
• SMARCA2 mutations may indicate Nicolaides-Baraitser syndrome, distinct from CSS.
• The genetic landscape of CSS is complex, with more causative genes likely yet to be discovered.