AUTHORS
Valentina Serpieri, Fulvio D’Abrusco, Jennifer C Dempsey, Yong-Han Hank Cheng, Filippo Arrigoni, Janice Baker, Roberta Battini, Enrico Silvio Bertini, Renato Borgatti, Angela K Christman, Cynthia Curry, Stefano D’Arrigo, Joel Fluss, Michael Freilinger, Simone Gana, Gisele E Ishak, Vincenzo Leuzzi, Hailey Loucks, Filippo Manti, Nancy Mendelsohn, Laura Merlini, Caitlin V Miller, Ansar Muhammad, Sara Nuovo, Romina Romaniello, Wolfgang Schmidt, Sabrina Signorini, Sabrina Siliquini, Krzysztof Szczałuba, Gessica Vasco, Meredith Wilson, Ginevra Zanni, Eugen Boltshauser, Dan Doherty, Enza Maria Valente, University of Washington Center for Mendelian Genomics (UW-CMG) group
J Med Genet. 2022 Sep;59(9):888-894. doi: 10.1136/jmedgenet-2021-108114. Epub 2021 Oct 21.
ABSTRACT
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.
PMID:34675124 | PMC:PMC9411896 | DOI:10.1136/jmedgenet-2021-108114
