Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder

Pathogenic variants in the SETD5 gene cause a neurodevelopmental disorder characterized by intellectual disability, autism, and facial dysmorphisms, with incomplete penetrance. To date, no distinctive neurological, psychiatric, electroencephalographic, and neuroimaging features have been identified in this condition. We expand the clinical phenotype of SETD5-related disorder by describing 28 previously unreported patients, 26 carrying single nucleotide variants, and 2 with copy number variations involving SETD5 gene, focusing on neurological, psychiatric, EEG, and brain MRI data. In our cohort neurological symptoms include hypotonia (39.2 %), hyperkinetic movement disorders including stereotypies and chorea (21.4 %) and gait abnormalities ranging from tip-toe or unsteady walking and alterations of fine motor skills (35.7 %). Epilepsy was present in about 14 % of patients, including different types of seizures as epileptic spasms, focal motor, and non-motor seizures. Concerning the cognitive phenotype, intellectual disability or global developmental delay depending on age, ranging from mild to severe, was present in 75 % of cohort, 21.4 % exhibit borderline intellectual functioning while an individual has a normal intelligence quotient. Other psychiatric comorbidities include autism, ADHD, psychotic disorder and other internalizing and externalizing symptoms. Finally, we conduct a comprehensive review of the available literature, suggesting a possible genotype-phenotype correlation.