Case Report: Diagnostic assessment, developmental trajectory and treatment approaches in a case of a complex neurodevelopmental syndrome associated with non- synonymous variants in MECP2 (p. R133C) and GABBR1

Background: Rett Syndrome (RTT) is an X-linked progressive disease affecting 1in 10,000 females. MECP2 p.R133C, is the second most common variantaffecting more than 4% of all RTT cases. GABBR1 pathogenic variants havebeen recently associated with mild to severe psychomotor delay, epilepsy,intellectual disability (ID), autism (ASD), attention deficit hyperactivity disorder(ADHD) and oppositional defiant disorder (ODD).Material and methods: We report a 13.9-year-old girl, with a complexneurodevelopmental disorder including ASD, ID with the appearance, at 9years of age, of vocal and motor tics involving the upper limbs and trunk,suggesting a diagnosis of Tourette’s syndrome (TS). Tics were also present inthe mother and grandmother. The patient was followed-up for approximately10 years and underwent periodic clinical and neuropsychological evaluations.We performed Trio-based WES analysis and segregation analysis in relevantfamily members.Results: Ade novo MECP2 variant (p. R133C) was detected in the proband.Moreover, a maternally inherited VoUS class 3 in GABBR1 (p. F692S), wasidentified in the proband, and segregated in the mother and grandmother. Nofunctional studies confirm the pathogenicity of this GABBR1 variant, and Tourettephenotypes have not been previously linked to GABBR1. Based on familialsegregation, we hypothesize that this variant may worsen the MECP2-relatedphenotype and underlie the Tourette symptoms seen in all carriers. Tourettephenotypes have never been reported with MECP2 variants alone. AlthoughRett-like features are mainly due to MECP2 loss-of-function, MECP2 deficiencydisrupts GABAergic signaling, making GABA modulators potential therapeutictargets. The presence of the GABBR1 variant may further impair GABA receptorneurotransmission. Thus, the GABBR1 variant may be a modifying factor in this ase, though its pathogenicity remains uncertain. Despite attempts to manage hercondition with appropriate pharmacological therapies, progressive musclehypertonia and behavioral issues, persisted. The patient showed improvements inengagement and emotional regulation, during music therapy sessions.Conclusion: We describe the developmental trajectory of an adolescent withoverlapping features of Rett and Tourette syndromes, carrying MECP2 andGABBR1 variants. Future studies are essential to better characterize thegenotype-phenotype correlates and optimize therapeutic strategies, to tacklethe unique needs of the patient and her family.