DIP2B CGG repeat expansion in siblings with neurodevelopmental disability and progressive movement disorder

Background: Trinucleotide repeat expansions are an emerging class of genetic variants associated with several movement disorders. Unbiased genome-wide analyses can reveal novel genotype-phenotype associations and provide a diagnosis for patients and families. Objectives: To identify the genetic cause of a severe progressive movement disorder phenotype in two affected brothers. Methods: A family of two affected brothers and unaffected parents had extensive phenotyping and natural history followed since birth. Whole-genome and long-read sequencing methods were used to characterize genetic variants and methylation status. Results: We describe a CGG repeat expansion in the 5'-untranslated region of DIP2B in two affected male siblings presenting with a novel DIP2B phenotype including neurodevelopmental disability, dysmorphic traits, and a severe progressive movement disorder (prominent chorea, dystonia, and ataxia). Conclusions: This is the first report of a severe progressive movement disorder phenotype attributed to a CGG repeat expansion in the DIP2B 5'-UTR.