Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Floating-Harbor syndrome (FHS) is a rare genetic disorder characterized by short stature, delayed bone maturation, language deficits, and distinct facial features.
• While often sporadic, FHS can be inherited, suggesting a genetic basis.
• The chromatin remodeler SRCAP interacts with CREB-binding protein (CBP), a known factor in Rubinstein-Taybi syndrome (RTS).

Purpose of the Study:

• To identify the genetic cause of Floating-Harbor syndrome.
• To investigate the role of SRCAP mutations in FHS pathogenesis.
• To explore the relationship between FHS and Rubinstein-Taybi syndrome.

Main Methods:

• Whole-exome sequencing was used to identify mutations in individuals with sporadic FHS.
• Sanger sequencing was employed to confirm mutations in additional affected individuals.
• Parental DNA was analyzed to determine if mutations were de novo.

Main Results:

• Heterozygous truncating mutations in the SRCAP gene were identified in individuals with FHS.
• Mutations were found to be de novo in all tested familial cases.
• Five distinct SRCAP mutations, including recurrent ones, were discovered, clustered in the gene's final exon.
• These mutations are predicted to disrupt DNA-binding motifs while preserving other functional domains.

Conclusions:

• Mutations in SRCAP are the predominant genetic cause of Floating-Harbor syndrome.
• The identified SRCAP mutations provide a molecular explanation for FHS.
• The findings highlight clinical overlap between FHS and Rubinstein-Taybi syndrome due to shared pathways involving SRCAP and CBP.