Expansion of the Genotypic and Phenotypic Spectrum of SETD5 Disorder Using Data From the National Brain Gene Registry

ABSTRACT Haploinsufficiency of SETD5 , which facilitates gene transcription and histone modification, causes intellectual disability. However, the full phenotypic spectrum of SETD5 Disorder is not well characterized. We summarized clinical features of participants with SETD5 Disorder enrolled in the National Brain Gene Registry (BGR). We analyzed data from 13 individuals with a molecular diagnosis of SETD5 Disorder, ages 2–37 years, using data from electronic health records, standardized surveys, and direct assessments. We also determined the number of participants for whom 10 pre‐selected clinical features were present based on ICD‐10 billing codes in comparison to manual review of clinical documentation. In the cohort, there were 11 unique pathogenic/likely pathogenic variants in 13 individuals from 11 different families. Of these 11 unique variants, 6 were nonsense, 4 were frameshift, and one was splice site. Participants in our cohort had features not previously reported, including brain and musculoskeletal abnormalities. One participant had cerebral palsy. For the 10 pre‐selected clinical features, we showed satisfactory representation of these features by ICD‐10 billing codes. This report highlights novel genotype and phenotype associations with SETD5 Disorder. Examination of larger patient cohorts with SETD5 Disorder is needed to evaluate the true prevalence of these medical conditions in this disorder.