Velmans, Clara ORCID: 0000-0002-3352-1035, O'Donnell-Luria, Anne H., Argilli, Emanuela, Tran Mau-them, Frederic, Vitobello, Antonio ORCID: 0000-0003-3717-8374, Chan, Marcus C. Y., Fung, Jasmine Lee-Fong, Rech, Megan, Abicht, Angela, Aubert Mucca, Marion, Carmichael, Jason, Chassaing, Nicolas, Clark, Robin, Coubes, Christine, Denomme-Pichon, Anne-Sophie ORCID: 0000-0002-8986-8222, de Dios, John Karl ORCID: 0000-0001-9125-0117, 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, Daphne, 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. and Erger, Florian . O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum. J. Med. Genet.. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Velmans, ClaraUNSPECIFIEDorcid.org/0000-0002-3352-1035UNSPECIFIED
O'Donnell-Luria, Anne H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Argilli, EmanuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tran Mau-them, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vitobello, AntonioUNSPECIFIEDorcid.org/0000-0003-3717-8374UNSPECIFIED
Chan, Marcus C. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fung, Jasmine Lee-FongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rech, MeganUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abicht, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aubert Mucca, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carmichael, JasonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chassaing, NicolasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clark, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coubes, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denomme-Pichon, Anne-SophieUNSPECIFIEDorcid.org/0000-0002-8986-8222UNSPECIFIED
de Dios, John KarlUNSPECIFIEDorcid.org/0000-0001-9125-0117UNSPECIFIED
England, EleinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Funalot, BenoitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerard, MarionUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joseph, MariesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kennedy, ColleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumps, CamilleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willems, MarjolaineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van de Laar, Ingrid M. B. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aarts-Tesselaar, CoranneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Slegtenhorst, MarjonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehalle, DaphneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leppig, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lessmeier, LennartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pais, Lynn S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paterson, HeatherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramanathan, SubhadraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodan, Lance H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Superti-Furga, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chung, Brian H. Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sherr, ElliottUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Netzer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaaf, Christian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erger, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-606533
DOI: 10.1136/jmedgenet-2020-107470
Journal or Publication Title: J. Med. Genet.
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-6244
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
JOINT CONSENSUS RECOMMENDATION; MEDICAL GENETICS; AMERICAN-COLLEGE; SEX-DIFFERENCES; TBL1XR1 CAUSES; AUTISM; GUIDELINES; MUTATIONS; STANDARDS; VARIANTSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60653

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