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

Valentina Napoli¹SILVIA GUERRERA^1*Francesco Demaria¹Gabriele Piccolo²Alessia Cianfa¹Sara Passarini^1,3Maria Grazia Logrieco⁴Ginevra Zanni^5*Giovanni Valeri¹Stefano Vicari^1,6

• ¹Child and Adolescent Neuropsychiatry Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
• ²Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
• ³Department of Dynamic, Clinical Psychology and Health, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Lazio, Italy
• ⁴Department of Humanities, University of Foggia, Foggia, Apulia, Italy
• ⁵Developmental Neurology and Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
• ⁶Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Lazio, Italy

Background: Rett Syndrome (RTT) is an X-linked progressive disease affecting 1 in 10,000 females. MECP2 p.R133C is the second most common variant, present in more than 4% of all RTT cases. GABBR1 pathogenic variants have recently been associated with psychomotor delay, epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD).Material and Methods: We report a 13.9-year-old girl with a complex neurodevelopmental disorder, including ASD and ID, with the onset at 9 years of age of vocal and motor tics involving the upper limbs and trunk, suggestive of Tourette syndrome (TS). Tics were also observed in the mother and grandmother. The patient was followed for approximately 10 years and underwent regular clinical and neuropsychological evaluations. Trio-based WES and segregation analysis were performed in relevant family members.Results: A de novo MECP2 variant (p.R133C) was detected in the proband. In addition, a maternally inherited class 3 VoUS in GABBR1 (p.F692S) was identified in the proband and segregated in the mother and grandmother. No functional studies confirm the pathogenicity of this GABBR1 variant, and TS has not previously been linked to GABBR1. Based on familial segregation, we hypothesize that this variant may exacerbate the MECP2-related phenotype and underlie TS symptoms in all carriers. Tourette phenotypes have not been reported with MECP2 variants alone. Although Rett features are mainly due to MECP2 loss-of-function, MECP2 deficiency disrupts GABAergic signaling. The GABBR1 variant may further impair GABA_B receptor function, contributing to late-onset regression, complex tics, skin-picking, and behavioral dysregulation beyond classic Z-RTT/PSV. Despite pharmacological therapy, hypertonia and behavioral issues persisted. The patient improved in engagement and emotional regulation during music therapy.Conclusion: We describe the developmental trajectory of an adolescent with overlapping Rett and Tourette syndromes carrying MECP2 and GABBR1 variants. Further studies are needed to clarify genotype-phenotype correlations and guide personalized therapeutic strategies.