GENOMIC CHARACTERIZATION AND IDENTIFICATION OF THERAPEUTIC APPROACHES IN UNRESOLVED HEREDITARY LEUKODYSTROPHIES

Hereditary leukodystrophies and neurodevelopmental disorders represent heterogeneous groups of rare pediatric neurological diseases that remain difficult to diagnose despite advances in genomic medicine. Many affected individuals remain without a molecular diagnosis, reflecting the complexity of the underlying genetic architecture and the limitations of conventional sequencing approaches. This thesis aimed to improve the molecular diagnosis and characterization of unresolved leukodystrophies and neurodevelopmental disorders through the integration of advanced genomic technologies, detailed clinical phenotyping, and functional validation. Patients were recruited through international collaborations across neurogenetics centres in Italy and the United Kingdom and underwent comprehensive clinical evaluation, neuroimaging, and genomic analyses using whole exome sequencing, whole genome sequencing, and long read sequencing. The study identified novel variants in known disease genes and expanded the genetic and phenotypic spectrum of several neurogenetic conditions, including ATP6V1B2, SLC9A1, ITPR1, VPS13D, TUBB4A, and SLC25A15. In addition, translational investigations led to the identification of MED11 as a novel disease gene and the nomination of eEF2K as a candidate gene for hypomyelinating leukodystrophy. Overall, this work highlights the value of integrating genomic sequencing, functional studies, and international collaboration to reduce the diagnostic gap in rare neurogenetic disorders and to advance the understanding of the molecular mechanisms underlying leukodystrophies and neurodevelopmental diseases.