eP106: BRSK2-related neurodevelopmental disorder: Novel pathogenic variant and review of literature

BRSK2 (BR Serine/Threonine Kinase 2) (OMIM# *609236) plays a crucial role in neurodevelopmental processes including axonogenesis and neuronal polarization. BRSK2 interacts with genes including TSC2 and PTEN, which are strongly associated with other neurological conditions. These interactions support the role of pathogenic BRSK2 variants in neurodevelopmental disorders (NDDs). BRSK2-related neurodevelopmental disorder is an ultra-rare NDD with less than 10 reported cases ranging in age from 3-19 years. Amongst the described patients, the clinical features reported were intellectual disability ranging from mild to severe (8/9), developmental delays including speech (9/9) and motor delays (7/9), autism (7/9), and behavioral conditions (7/9) including ADD/ADHD, stereotypies, and temper tantrums. Parental testing was available for 6/9 patients; all variants were found to have arisen de novo. Here, we present an additional patient with a novel BRSK2 pathogenic variant. We present a 5-year-old patient who was born at term gestation to a pregnancy complicated by polyhydramnios, gestational diabetes mellitus in the third trimester, and maternal drug use. Limited family history information is available. The patient’s biological mother is reported to have cognitive impairment. His maternal half-sister and paternal half-brother have autism. Concern for autism spectrum disorder was first noted at 12-18 months of age due to repetitive hand movements. Neuropsychology evaluation identified level 3 autism spectrum disorder, intellectual disability, and global developmental delays. He started walking at the age of 30 months. He is currently non-verbal and is generally uninterested in social interactions but does make limited eye contact with others. He exhibits aggressive and self-injurious behaviors. Other medical concerns include patchy vitiligo and hyperopia. Facial features include small and deep-set eyes with long eyelashes and bilateral tiny epicanthal folds. Initial workup included metabolic labs (plasma acylcarnitine, plasma amino acids, and free and total carnitine) which were normal, as well as chromosomal microarray and Fragile X testing which returned negative. Singleton exome sequencing (ES) was subsequently performed. A pathogenic, heterozygous frameshift variant in the BRSK2 gene was detected: c.1301_1307delCCTCACC (p.P434QfsX73) (NM_001256627.1). Parental samples were not available to determine if the variant was inherited or de novo in this patient. We present the phenotypic findings of an additional patient with BRSK2-related neurodevelopmental disorder, bringing the total case count to 10. This patient has findings consistent with other reports of patient’s with BRSK2-related disorder including intellectual disability, developmental delays, autism spectrum disorder, and behavioral concerns. He did not have other body system involvement, suggesting that BRSK2-related disorder is associated with a primarily neurodevelopmental phenotype. Identification of this novel frameshift BRSK2-variant provides further evidence of damaging variation in the BRSK2 gene as an underlying cause of an NDD.