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.
- cerebellar diseases
- and neonatal diseases and abnormalities
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Contributors SN, EMV and RB planned the study; SN, AM, RR, FA, GZ and ESB collected the data; AM, TM, MG, AC, VS, MTB, LB and LT performed molecular or bioinformatic analyses; FA reviewed MRI exams of the recruited patients; SN and NV performed statistical analyses; SN and EMV wrote the first draft of the manuscript, tables and figures; all the remaining authors clinically diagnosed and followed up the patients. All the authors revised the manuscript for important intellectual content and approved the final version.
Funding This work was supported by the Ministry of Health (Ricerca Finalizzata NET-2013–02356160 to EMV, NV, ESB, RB and RR; grant # RC2018-2019-2020 and 5X Mille to MTB and RR, Ricerca Corrente 2020 to IRCCS Mondino Foundation), European Research Council (ERC Starting Grant 260888), Italian Ministry of University and Research (Progetto Dipartimenti di Eccellenza) and Pierfranco and Luisa Mariani Foundation (PADAPORT project).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The project was approved by the ethics committee of the University of Pavia (Prot.20180077857/12-09-2018).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as online supplementary information.
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