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Original research
Refining the mutational spectrum and gene–phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study
  1. Sara Nuovo1,
  2. Alessia Micalizzi2,
  3. Romina Romaniello3,
  4. Filippo Arrigoni4,
  5. Monia Ginevrino2,5,
  6. Antonella Casella6,7,
  7. Valentina Serpieri7,
  8. Stefano D'Arrigo8,
  9. Marilena Briguglio9,
  10. Grazia Gabriella Salerno10,
  11. Sara Rossato11,
  12. Stefano Sartori12,
  13. Vincenzo Leuzzi1,
  14. Roberta Battini13,14,
  15. Bruria Ben-Zeev15,16,
  16. Claudio Graziano17,
  17. Marisol Mirabelli Badenier18,19,
  18. Vesna Brankovic20,
  19. Nardo Nardocci21,
  20. Ronen Spiegel22,23,
  21. Danijela Petković Ramadža24,
  22. Giovanni Vento25,
  23. Itxaso Marti26,
  24. Alessandro Simonati27,
  25. Savina Dipresa28,
  26. Elena Freri21,
  27. Tommaso Mazza29,
  28. Maria Teresa Bassi30,
  29. Luca Bosco31,
  30. Lorena Travaglini31,
  31. Ginevra Zanni31,
  32. Enrico Silvio Bertini31,
  33. Nicola Vanacore32,
  34. Renato Borgatti33,34,
  35. Enza Maria Valente6,7
  1. 1 Department of Human Neuroscience, Sapienza University of Rome, Roma, Italy
  2. 2 Laboratory of Medical Genetics, IRCCS Bambino Gesù Children's Hospital, Roma, Italy
  3. 3 Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
  4. 4 Neuroimaging Lab, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
  5. 5 Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy
  6. 6 IRCCS Mondino Foundation, Pavia, Italy
  7. 7 Department of Molecular Medicine, University of Pavia, Pavia, Italy
  8. 8 Department of Developmental Neurology, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milano, Italy
  9. 9 Interdepartmental Program "Autism 0-90", "G. Martino" University Hospital of Messina, Messina, Italy
  10. 10 Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
  11. 11 U.O.C. Pediatria, Ospedale San Bortolo, Vicenza, Italy
  12. 12 Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
  13. 13 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
  14. 14 Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy
  15. 15 Pediatric Neurology Department, The Edmond and Lilly Safra Pediatric Hospital, Sheba Medical Center, Tel Hashomer, Israel
  16. 16 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  17. 17 Medical Genetics Unit, AOU Policlinico di S. Orsola, Bologna, Italy
  18. 18 Fondazione Istituto David Chiossone Onlus, Genova, Italy
  19. 19 Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto G. Gaslini, Genova, Italy
  20. 20 Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia
  21. 21 Department of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
  22. 22 Department of Pediatrics B, Emek Medical Center, Afula, Israel
  23. 23 Rappaport School of Medicine, Technion, Haifa, Israel
  24. 24 Department of Pediatrics, University Hospital Centre, Zagreb, Croatia
  25. 25 Division of Neonatology, Department of Woman and Child Health and Public Health, Child Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS-Università Cattolica del Sacro Cuore, Roma, Italy
  26. 26 Pediatric Neurology, Hospital Universitario Donostia, Biodonostia, Universidad del País Vasco UPV-EHU, San Sebastian, Spain
  27. 27 Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona School of Medicine and Department of Clinical Neuroscience AOUI Verona, Verona, Italy
  28. 28 Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
  29. 29 Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy
  30. 30 Laboratory of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
  31. 31 Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy
  32. 32 National Center for Disease Prevention and Health Promotion, Italian National Institute of Health, Roma, Italy
  33. 33 Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy
  34. 34 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
  1. Correspondence to Professor Enza Maria Valente, Department of Molecular Medicine, University of Pavia, Pavia, Lombardia, Italy; enzamaria.valente{at}


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
  • congenital
  • hereditary
  • and neonatal diseases and abnormalities
  • genotype
  • phenotype
  • genetics
  • medical

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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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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  • 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.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.