Clinical and molecular insights into BAFopathies

Abstract

BAFopathies are neurodevelopmental disorders caused by pathogenic variants in genes encoding components of the BAF chromatin remodeling complex. Coffin-Siris syndrome (CSS) is the most well-known and prevalent BAFopathy. CSS patients have a distinct clinical phenotype and also a CSS patients also display a specific blood DNA methylation pattern, which is valuable for distinguishing pathogenic variants from variants of uncertain significance (VUS).

With the growing use of next-generation sequencing (NGS), more variants in BAFopathy-related genes are being identified. While many are clearly pathogenic, a considerable proportion remain VUS, posing a significant challenge. Careful phenotype comparison and additional tools, such as episignatures and facial analysis, are essential for accurate classification. This highlights the need for solid genotype-phenotype studies to broaden our understanding of the BAFopathy-associated phenotype as well as for tools, such as episignatures and facial analysis, to aid in variant interpretation.

Another pressing clinical challenge in the field of BAFopathies is the lack of disease specific treatments. Clinical trials for rare diseases like BAFopathies are particularly complex, facing obstacles such as small patient populations, phenotypic variability, and high expectations from families. Therefore, it is essential to design trials with disease-specific—and potentially even patient-specific—outcomes, while carefully considering the feasibility of the study design. The aims of the first part of this thesis were to provide further insight into the phenotypic spectrum associated with pathogenic variants in BAFopathy genes and to discover new (epi)genetic features linked to these disorders. The aims of the second part of this thesis were to develop an in vitro model to study the disease mechanisms underlying CSS and to explore potential therapeutic options, particularly for patients with ARID1B-related disorders.