TY - JOUR T1 - Refining the mutational spectrum and gene–phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2020-107497 SP - jmedgenet-2020-107497 AU - Sara Nuovo AU - Alessia Micalizzi AU - Romina Romaniello AU - Filippo Arrigoni AU - Monia Ginevrino AU - Antonella Casella AU - Valentina Serpieri AU - Stefano D'Arrigo AU - Marilena Briguglio AU - Grazia Gabriella Salerno AU - Sara Rossato AU - Stefano Sartori AU - Vincenzo Leuzzi AU - Roberta Battini AU - Bruria Ben-Zeev AU - Claudio Graziano AU - Marisol Mirabelli Badenier AU - Vesna Brankovic AU - Nardo Nardocci AU - Ronen Spiegel AU - Danijela Petković Ramadža AU - Giovanni Vento AU - Itxaso Marti AU - Alessandro Simonati AU - Savina Dipresa AU - Elena Freri AU - Tommaso Mazza AU - Maria Teresa Bassi AU - Luca Bosco AU - Lorena Travaglini AU - Ginevra Zanni AU - Enrico Silvio Bertini AU - Nicola Vanacore AU - Renato Borgatti AU - Enza Maria Valente Y1 - 2021/03/05 UR - http://jmg.bmj.com/content/early/2021/03/05/jmedgenet-2020-107497.abstract N2 - Background Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes.Methods We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters.Results A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK, which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in TSEN54 and pathogenic variants in EXOSC3 accounted for 18% and 9% of cases, respectively. VLDLR, TOE1 and RARS2 were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with TSEN54 and lower motor neuron signs with EXOSC3. When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for EXOSC3.Conclusion CASK represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between CASK and TSEN54-associated disorders. ER -