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.
- human genetics
- genetic counselling
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Presented at Excerpts from this study have been previously presented at the European Society of Human Genetics conference 2020.
Contributors CV: Data collection, data analysis, manuscript writing, manuscript editing. AHO-L/EA/FTM-T/AV/MCC/JL-FF/MR/AA/MAM/JC/NC/RC/CC/A-SD-P/JKdD/EE/BF/MG/MJ/CKe/CKu/MW/IMBHvdL/CA-T/MvS/DL/KL/LL/LSP/HP/SR/LHR/AS-F/BHYC/ES: Data collection, manuscript editing. CN/CPS: Study conception, data collection, manuscript writing, manuscript editing. FE: Study conception, data collection, data analysis, manuscript writing, manuscript editing. All authors have read and approved the final manuscript.
Funding AHO-L, EME and ES: Sequencing and analysis for some of the patients were provided by the Broad Institute of MIT and Harvard Centre for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by the National Human Genome Research Institute grant R01 HG009141. BHYC, MCYC, and JL-FF: Funding and support of the Society for the Relief of Disabled Children contributed to this project.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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