Genotype-Driven Diagnosis Enables Targeted Pharmacological Treatment in Brunner Syndrome: A Novel Splice-Site MAOA Variant and Case-Based Review

Brunner syndrome is a rare X-linked neurodevelopmental disorder caused by loss-of-function (LOF) variants in the monoamine oxidase A gene (MAOA), which encodes monoamine oxidase A, a key enzyme involved in the degradation of monoamine neurotransmitters such as serotonin, norepinephrine, and epinephrine. Impaired MAOA activity leads to abnormal monoamine accumulation and disruption of monoaminergic signalling, resulting in intellectual disability and behavioural dysregulation. Here, we systematically summarize the molecular landscape and report a genotype-driven diagnosis of MAOA deficiency in a patient presenting with intellectual disability and no reported family history. Clinical exome sequencing (cES) identified a novel splice-site variant in the MAOA gene that had not been detected by first-line diagnostic approaches. Functional analysis of patient-derived mRNA demonstrated intron 8 retention leading to a premature stop codon, consistent with a LOF mechanism. Based on the molecular diagnosis, the patient received treatment with serotonin antagonist and reuptake inhibitor (SARI) class medication, which was associated with improvement in social behaviour and sleep disturbances. Notably, to the best of our knowledge, this represents the first reported use of SARI therapy in MAOA deficiency. Although SARI therapy in this condition remains off-label, this observation provides preliminary evidence suggesting a potential therapeutic benefit. Our findings expand the mutational spectrum of the MAOA gene and highlight the importance of molecular diagnosis driving personalized management in rare neurogenetic disorders.