细化突变谱和基因表型与脑桥小脑发育不全相关：多中心研究的结果,Journal of Medical Genetics

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细化突变谱和基因表型与脑桥小脑发育不全相关：多中心研究的结果
Journal of Medical Genetics ( IF 4 ) Pub Date : 2022-04-01 , DOI: 10.1136/jmedgenet-2020-107497
Sara Nuovo ₁ , Alessia Micalizzi ₂ , Romina Romaniello ₃ , Filippo Arrigoni ₄ , Monia Ginevrino _{2,

5} , Antonella Casella _{6,

7} , Valentina Serpieri ₇ , Stefano D'Arrigo ₈ , Marilena Briguglio ₉ , Grazia Gabriella Salerno ₁₀ , Sara Rossato ₁₁ , Stefano Sartori ₁₂ , Vincenzo Leuzzi ₁ , Roberta Battini _{13,

14} , Bruria Ben-Zeev _{15,

16} , Claudio Graziano ₁₇ , Marisol Mirabelli Badenier _{18,

19} , Vesna Brankovic ₂₀ , Nardo Nardocci ₂₁ , Ronen Spiegel _{22,

23} , Danijela Petković Ramadža ₂₄ , Giovanni Vento ₂₅ , Itxaso Marti ₂₆ , Alessandro Simonati ₂₇ , Savina Dipresa ₂₈ , Elena Freri ₂₁ , Tommaso Mazza ₂₉ , Maria Teresa Bassi ₃₀ , Luca Bosco ₃₁ , Lorena Travaglini ₃₁ , Ginevra Zanni ₃₁ , Enrico Silvio Bertini ₃₁ , Nicola Vanacore ₃₂ , Renato Borgatti _{33,

34} , Enza Maria Valente _{7,

35}

Affiliation

Department of Human Neuroscience, Sapienza University of Rome, Roma, Italy.
Laboratory of Medical Genetics, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.
Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
Neuroimaging Lab, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Roma, Italy.
IRCCS Mondino Foundation, Pavia, Italy.
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Department of Developmental Neurology, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milano, Italy.
Interdepartmental Program "Autism 0-90", "G. Martino" University Hospital of Messina, Messina, Italy.
Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
U.O.C. Pediatria, Ospedale San Bortolo, Vicenza, Italy.
Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy.
Pediatric Neurology Department, The Edmond and Lilly Safra Pediatric Hospital, Sheba Medical Center, Tel Hashomer, Israel.
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Medical Genetics Unit, AOU Policlinico di S. Orsola, Bologna, Italy.
Fondazione Istituto David Chiossone Onlus, Genova, Italy.
Child Neuropsychiatry Unit, Department of Neurosciences and Rehabilitation, Istituto G. Gaslini, Genova, Italy.
Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia.
Department of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy.
Department of Pediatrics B, Emek Medical Center, Afula, Israel.
Rappaport School of Medicine, Technion, Haifa, Israel.
Department of Pediatrics, University Hospital Centre, Zagreb, Croatia.
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.
Pediatric Neurology, Hospital Universitario Donostia, Biodonostia, Universidad del País Vasco UPV-EHU, San Sebastian, Spain.
Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona School of Medicine and Department of Clinical Neuroscience AOUI Verona, Verona, Italy.
Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy.
Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy.
Laboratory of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.
National Center for Disease Prevention and Health Promotion, Italian National Institute of Health, Roma, Italy.
Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
IRCCS Mondino Foundation, Pavia, Italy

背景脑桥小脑发育不全 (PCH) 包括一组遗传异质性疾病，其特征是脑桥和小脑同时发育不全以及不同的临床和影像学特征。目前的分类包括 13 个亚型，约 20 个已知致病基因。已经尝试描绘与特定 PCH 基因相关的表型谱，但临床和神经放射学特征在研究中并不一致，因此难以定义基因特异性结果。方法我们对 56 名神经放射学诊断为 PCH 的先证者进行了深度临床和影像表型分析，他们接受了基于 NGS 的 PCH 基因面板测序和 MLPA 进行 CASK 重排。下一个，我们进行了基于表型的无监督层次聚类分析，以研究基因与特定表型簇之间的关联。结果 43 名先证者（77%）获得了基因诊断。最常见的致病基因是 CASK ，占近一半（45％），并且在女性中发生突变，偶尔在男性中发生突变。TSEN54 中的欧洲创始人突变 p.Ala307Ser 和 EXOSC3 中的致病变异分别占病例的 18% 和 9%。VLDLR 、 TOE1 和 RARS2 在单个患者中发生突变。我们只能确认少数先前报道的关联，包括与 TSEN54 的抖动和阵挛以及与 EXOSC3 的下运动神经元体征。当同时考虑多个特征时，只有 EXOSC3 才出现与表型簇的明确关联。结论 CASK是意大利PCH的主要致病基因。与 PCH 最常见的遗传原因相关的表型变异性比以前认为的要广泛，CASK 和 TSEN54 相关疾病之间存在显着重叠。所有与研究相关的数据都包含在文章中或作为补充信息上传。所有与研究相关的数据都包含在文章中或作为在线补充信息上传。

"点击查看英文标题和摘要"

Refining the mutational spectrum and gene–phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study

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. 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.

更新日期：2022-03-23

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