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Imputation servers offer the exclusive possibility to harness the largest public reference panels which have been shown to deliver very high precision in the imputation of European genomes. Many studies have nonetheless stressed the importance of 'study specific panels' (SSPs) as an alternative and have shown the benefits of combining public reference panels with SSPs. But such combined approaches are not attainable when using external imputation servers. To investigate how to confront this challenge, we imputed 550 French individuals using either the University of Michigan imputation server with the Haplotype Reference Consortium (HRC) panel or an in-house SSP of 850 whole-genome sequenced French individuals. With approximate geo-localization of both our target and SSP individuals we are able to pinpoint different scenarios where SSP-based imputation would be preferred over server-based imputation or vice-versa. This is achieved by showing to a high degree of resolution the importance of the proximity of the reference panel to target individuals; with a focus on the clear added value of SSPs for estimating haplotype phase and for the imputation of rare variants (minor allele-frequency below 0.01). Such benefits were most evident for individuals from the same geographical regions in France as the SSP individuals. Overall, only 42.3% of all 125,442 variants evaluated were better imputed with an SSP from France compared to an external reference panel, however this rises to 58.1% for individuals from geographic regions well covered by the SSP. By investigating haplotype sharing and population fine-structure in France, we show the importance of including SSP haplotypes for imputation but also that they should ideally be combined with large public panels. In the absence of the unattainable results from a combined panel of the HRC and our French SSP, we put forward a pragmatic solution where server-based and SSP-based imputation outcomes can be combined based on comparing posterior genotype probabilities. We show that such an approach can give a level of imputation accuracy in excess of what could be achieved with either strategy alone. The results presented provide detailed insights into the accuracy of imputation that should be expected from different strategies for European populations. [ABSTRACT FROM AUTHOR]

Background: Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as DNA methyltransferase 3 alpha ( DNMT3A )-overgrowth syndrome (DOS), was first described by Tatton-Brown in 2014. This syndrome is characterised by overgrowth, intellectual disability and distinctive facial features and is the consequence of germline loss-of-function variants in DNMT3A , which encodes a DNA methyltransferase involved in epigenetic regulation. Somatic variants of DNMT3A are frequently observed in haematological malignancies, including acute myeloid leukaemia (AML). To date, 100 individuals with TBRS with de novo germline variants have been described. We aimed to further characterise this disorder clinically and at the molecular level in a nationwide series of 24 French patients and to investigate the correlation between the severity of intellectual disability and the type of variant., Methods: We collected genetic and medical information from 24 individuals with TBRS using a questionnaire released through the French National AnDDI-Rares Network., Results: Here, we describe the first nationwide French cohort of 24 individuals with germline likely pathogenic/pathogenic variants in DNMT3A , including 17 novel variants. We confirmed that the main phenotypic features were intellectual disability (100% of individuals), distinctive facial features (96%) and overgrowth (87%). We highlighted novel clinical features, such as hypertrichosis, and further described the neurological features and EEG results., Conclusion: This study of a nationwide cohort of individuals with TBRS confirms previously published data and provides additional information and clarifies clinical features to facilitate diagnosis and improve care. This study adds value to the growing body of knowledge on TBRS and broadens its clinical and molecular spectrum., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)