P4.A009: Mosaic Intersectin-1 gene related neurodevelopmental disorder: A case report

Introduction: The Intersectin-1 (ITSN1) gene is located on chromosome 21 and is involved in many processes, including neuronal migration via the Reelin pathway, dendritic spine development, synaptic plasticity, learning, and memory. Previous studies demonstrate strong deficits in spatial learning and memory when this gene is knocked out in mice. The ITSN1 gene is overexpressed in individuals with Down syndrome, and has been shown to lead to cognitive deficits, epilepsy, and neurodegeneration. We report a case of mosaic ITSN1 gene related neurodevelopmental disorder in a toddler which has rarely been reported in the literature.

Case Description: A 19-month-old boy born at 38 weeks to non-consanguineous healthy parents of Mexican descent, completed a genetic evaluation due to severe global developmental delay (first word spoken at 15 months, crawling began at 19 months). Severe obesity (BMI >99th percentile) with hyperphagia started in early infancy and improved at 19 months of age. The family history is significant for severe autism in a male maternal first cousin. Examination at 18 months showed normal head circumference, obesity, features of autism (hand flapping, head banging, decreased eye contact), diffuse hypotonia, and global developmental delay. Neuroimaging at 21 months identified an incidental 4 mm Rathke cleft cyst. At 26 months, he is clinically improving with speech and physical therapy. He can run, climb stairs, speak 50 words, and speaks some 2-word phrases.
Trio whole exome sequencing (WES) revealed a mosaic de novo heterozygous likely pathogenic variant in the ITSN1 gene in 25% sequencing reads from a buccal sample.

Discussion: This patient presented at 19 months with severe global developmental delay and was found to have a diagnosis of ITSN1-related neurodevelopmental disorder. Bruel, et al. characterized fourteen patients from eight unrelated families and found that seven of these individuals had a de novo variant in the ITSN1 gene. All patients presented with neurodevelopmental disorders, including autism, intellectual disability, and epilepsy, highlighting ITSN1 as a new gene for neurodevelopmental disorders. The developmental delays in our patient are less severe at 26 months, likely due to early intervention services and the mosaic nature of his genetic condition. Pathogenesis of mosaic genetic variants has been established to generally present with a less severe phenotype.

Conclusion: Neurodevelopmental disorders affect more than 5% of children worldwide. WES has a higher detection rate than traditional microarray and karyotype testing and may identify single gene disorders in mildly to severely affected individuals. This case supports the American College of Medical Genetics and Genomics recommendation for WES for all individuals with developmental delay at the time of diagnosis and demonstrates the presence of a genetic condition in an individual with resolving developmental delays.