RT Journal Article SR Electronic T1 SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2021-108114 DO 10.1136/jmedgenet-2021-108114 A1 Valentina Serpieri A1 Fulvio D’Abrusco A1 Jennifer C Dempsey A1 Yong-Han Hank Cheng A1 Filippo Arrigoni A1 Janice Baker A1 Roberta Battini A1 Enrico Silvio Bertini A1 Renato Borgatti A1 Angela K Christman A1 Cynthia Curry A1 Stefano D'Arrigo A1 Joel Fluss A1 Michael Freilinger A1 Simone Gana A1 Gisele E Ishak A1 Vincenzo Leuzzi A1 Hailey Loucks A1 Filippo Manti A1 Nancy Mendelsohn A1 Laura Merlini A1 Caitlin V Miller A1 Ansar Muhammad A1 Sara Nuovo A1 Romina Romaniello A1 Wolfgang Schmidt A1 Sabrina Signorini A1 Sabrina Siliquini A1 Krzysztof Szczałuba A1 Gessica Vasco A1 Meredith Wilson A1 Ginevra Zanni A1 Eugen Boltshauser A1 Dan Doherty A1 Enza Maria Valente A1 , YR 2021 UL http://jmg.bmj.com/content/early/2022/01/12/jmedgenet-2021-108114.abstract AB 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.