RT Journal Article SR Electronic 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 FD BMJ Publishing Group Ltd SP jmedgenet-2020-107497 DO 10.1136/jmedgenet-2020-107497 A1 Sara Nuovo A1 Alessia Micalizzi A1 Romina Romaniello A1 Filippo Arrigoni A1 Monia Ginevrino A1 Antonella Casella A1 Valentina Serpieri A1 Stefano D'Arrigo A1 Marilena Briguglio A1 Grazia Gabriella Salerno A1 Sara Rossato A1 Stefano Sartori A1 Vincenzo Leuzzi A1 Roberta Battini A1 Bruria Ben-Zeev A1 Claudio Graziano A1 Marisol Mirabelli Badenier A1 Vesna Brankovic A1 Nardo Nardocci A1 Ronen Spiegel A1 Danijela Petković Ramadža A1 Giovanni Vento A1 Itxaso Marti A1 Alessandro Simonati A1 Savina Dipresa A1 Elena Freri A1 Tommaso Mazza A1 Maria Teresa Bassi A1 Luca Bosco A1 Lorena Travaglini A1 Ginevra Zanni A1 Enrico Silvio Bertini A1 Nicola Vanacore A1 Renato Borgatti A1 Enza Maria Valente YR 2021 UL http://jmg.bmj.com/content/early/2021/03/05/jmedgenet-2020-107497.abstract AB 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.