A new SARS-CoV-2 variant poorly detected by RT-PCR on nasopharyngeal samples, with high lethality: an observational study

International audienceObjectives - In early January 2021 an outbreak of nosocomial cases of coronavirus disease 2019 (COVID-19) emerged in Western France; RT-PCR tests were repeatedly negative on nasopharyngeal samples but positive on lower respiratory tract samples. Whole-genome sequencing (WGS) revealed a new variant, currently defining a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.616. In March, the WHO classified this as a 'variant under investigation' (VUI). We analysed the characteristics and outcomes of COVID-19 cases related to this new variant. Methods - Clinical, virological, and radiological data were retrospectively collected from medical charts in the two hospitals involved. We enrolled those inpatients with: (a) positive SARS-CoV-2 RT-PCR on a respiratory sample, (b) seroconversion with anti-SARS-CoV-2 IgG/IgM, or (c) suggestive symptoms and typical features of COVID-19 on a chest CT scan. Cases were categorized as B.1.616, a variant of concern (VOC), or unknown. Results - From 1st January to 24th March 2021, 114 patients fulfilled the inclusion criteria: B.1.616 (n = 39), VOC (n = 32), and unknown (n = 43). B.1.616-related cases were older than VOC-related cases (81 years, interquartile range (IQR) 73-88 versus 73 years, IQR 67-82, p < 0.05) and their first RT-PCR tests were rarely positive (6/39, 15% versus 31/32, 97%, p < 0.05). The B.1.616 variant was independently associated with severe disease (multivariable Cox model HR 4.0, 95%CI 1.5-10.9) and increased lethality (28-day mortality 18/39 (46%) for B.1.616 versus 5/32 (16%) for VOC, p = 0.006). Conclusion - We report a nosocomial outbreak of COVID-19 cases related to a new variant, B.1.616, which is poorly detected by RT-PCR on nasopharyngeal samples and is associated with high lethality

O’Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum

BackgroundO'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.MethodsAffected 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.ResultsWe 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.ConclusionOur 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

O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum

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