TY - JOUR T1 - <em>SUFU</em> haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2021-108114 SP - jmedgenet-2021-108114 AU - Valentina Serpieri AU - Fulvio D’Abrusco AU - Jennifer C Dempsey AU - Yong-Han Hank Cheng AU - Filippo Arrigoni AU - Janice Baker AU - Roberta Battini AU - Enrico Silvio Bertini AU - Renato Borgatti AU - Angela K Christman AU - Cynthia Curry AU - Stefano D'Arrigo AU - Joel Fluss AU - Michael Freilinger AU - Simone Gana AU - Gisele E Ishak AU - Vincenzo Leuzzi AU - Hailey Loucks AU - Filippo Manti AU - Nancy Mendelsohn AU - Laura Merlini AU - Caitlin V Miller AU - Ansar Muhammad AU - Sara Nuovo AU - Romina Romaniello AU - Wolfgang Schmidt AU - Sabrina Signorini AU - Sabrina Siliquini AU - Krzysztof Szczałuba AU - Gessica Vasco AU - Meredith Wilson AU - Ginevra Zanni AU - Eugen Boltshauser AU - Dan Doherty AU - Enza Maria Valente A2 - , Y1 - 2021/10/21 UR - http://jmg.bmj.com/content/early/2022/01/12/jmedgenet-2021-108114.abstract N2 - Background Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%–75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.Methods We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.Results Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.Conclusion Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.All data relevant to the study are included in the article or uploaded as supplementary information. ER -