GENE-02. GERMLINE MUTATIONS WITHIN THE SWI/SNF COMPLEX PREDICT PATIENTS’ AGE OF ONSET AND TYPE OF DISEASE

Abstract

Germline mutations affecting the SWI/SNF chromatin remodeling complex are associated with a broad spectrum of different diseases, including malignant and benign tumors as well as neurodevelopmental disorders. Such mutations are detected in multiple genes of the complex and encompass a variety of mutation types. However, due to the rarity of mutation carriers, very little is known about the impact of specific SWI/SNF mutations on the phenotype of the affected individual. In this meta-analysis, we link genetic and clinical data from more than 400 families and more than 500 patients affected by SWI/SNF germline alterations, including over 40 so far unpublished patients. Here we demonstrate that large deletions and truncating mutations of a gene tend to be associated with malignancy and early-onset-disease, while non-truncating mutations may cause non-malignant disorders, such as Coffin-Siris-syndrome or late onset tumors like Schwannomas or Meningiomas (p=<0.0001). Importantly, germline SWI/SNF mutations may also be detected in healthy relatives, although this does not hold true for families with whole gene deletions. Our data may have important implications for genetic counseling of affected families and will pave the way for functional mutation analyses that may improve the understanding of SWI/SNF-related disorders.