O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum. Issue 7 (28th July 2021)

• Record Type: Journal Article
• Authors: Velmans, Clara; O'Donnell-Luria, Anne H; Argilli, Emanuela; Tran Mau-them, Frederic; Vitobello, Antonio; Chan, Marcus CY; Fung, Jasmine Lee-Fong; Rech, Megan; Abicht, Angela; Aubert Mucca, Marion; Carmichael, Jason; Chassaing, Nicolas; Clark, Robin; Coubes, Christine; Denommé-Pichon, Anne-Sophie; de Dios, John Karl; England, Eleina; Funalot, Benoit; Gerard, Marion; Joseph, Maries; Kennedy, Colleen; Kumps, Camille; Willems, Marjolaine; van de Laar, Ingrid M B.H; Aarts-Tesselaar, Coranne; van Slegtenhorst, Marjon; Lehalle, Daphné; Leppig, Kathleen; Lessmeier, Lennart; Pais, Lynn S; Paterson, Heather; Ramanathan, Subhadra; Rodan, Lance H; Superti-Furga, Andrea; Chung, Brian H.Y.; Sherr, Elliott; Netzer, Christian; Schaaf, Christian P; Erger, Florian;
• Is Part Of: Journal of medical genetics. Volume 59:Issue 7(2022)
• Page Start: 697
• Page End: 705
• Publication Date: 2021-07-28
• Subjects: human genetics -- genetic counselling -- genetics -- behavioural -- mutation; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2020-107470
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: O'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E . It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility. Methods: Affected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible. Results: We report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E . We confirm and refine the phenotypic spectrum of the KMT2E -related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances. Conclusion: Our study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.