No abstract

For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient’s data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe.

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics.

Odonata (dragonflies and damselflies) is a small order at the base of flying insects (Pterygota). Resolving family-level phylogenetic relationships within this order receives great attention. Hereby, genetic data already resulted in various changes, which are however still under discussion. Mitochondrial genomes may further enhance such phylogenies. This study presents the complete mitochondrial genome of the Neotropical damselfly Megaloprepus caerulatus based on next generation sequencing (NGS) data on total genomic DNA. The total length comprises 16,094 bp and includes the standard metazoan set of 37 genes together with a 1376 bp long A þ T rich (control) region. Gene content, gene arrangement and base frequency are consistent with other odonate mitochondrial genomes. It further contains four intergenic spacer regions, indicating a possible family specific feature for the Coenagrionidae and its close relatives.

Background Pathogenic variants in 5 genes (GCH1, TH, PTS, SPR, and QDPR), involved in dopamine/tetrahydrobiopterin biosynthesis or recycling, have been linked to Dopa‐responsive dystonia (DRD). Diagnosis and treatment are often delayed due to high between‐ and within‐group variability. Objectives Comprehensively analyzed individual genotype, phenotype, treatment response, and biochemistry information. Methods 734 DRD patients and 151 asymptomatic GCH1 mutation carriers were included using an MDSGene systematic literature review and an automated classification approach to distinguish between different forms of monogenic DRDs. Results Whereas dystonia, L‐Dopa responsiveness, early age at onset, and diurnal fluctuations were identified as red flags, parkinsonism without dystonia was rarely reported (11%) and combined with dystonia in only 18% of patients. While sex was equally distributed in autosomal recessive DRD, there was female predominance in autosomal dominant DYT/PARK‐GCH1 patients accompanied by a lower median age at onset and more dystonia in females compared to males. Accordingly, the majority of asymptomatic heterozygous GCH1 mutation carriers (>8 years of age) were males. Multiple other subgroup‐specific characteristics were identified, showing high accuracy in the automated classification approach: Seizures and microcephaly were mostly seen in DYT/PARK‐PTS, autonomic symptoms appeared commonly in DYT/PARK‐TH and DYT/PARK‐PTS, and sleep disorders and oculogyric crises in DYT/PARK‐SPR. Biochemically, homovanillic acid and 5‐hydroxyindoleacetic acid in CSF were reduced in most DRDs, but neopterin and biopterin were increased only in DYT/PARK‐PTS and DYT/PARK‐SPR. Hyperphenylalaninemia was seen in DYT/PARK‐PTS, DYT/PARK‐QDPR, and rarely reported in autosomal recessive DYT/PARK‐GCH1. Conclusions Our indicators will help to specify diagnosis and accelerate start of treatment. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Here we report the complete mitochondrial genome of the emperor dragonfly, Anax imperator (Odonata: Aeshnidae) as the first of its genus. Data were generated via next generation sequencing (NGS) and assembled using an iterative approach. The typical metazoan set of 37 genes (13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes) was detected in the same gene order as in other odonate mitogenomes. However, only three intergenic spacer regions are present in A. imperator lacking the distinct s5 spacer, which was regarded as informative feature of the odonate suborder Anisoptera (dragonflies) but absent in Zygoptera (damselflies). With 16,087 bp, it is the longest anisopteran mitogenome to date, mainly due to the long A + T-rich control region of 1291 bp.

Damselflies of the genus Ischnura emerge as organisms with high potential in ecological, evolutionary and developmental research at the base of flying insects. Ischnura elegans and Ischnura hastata are for example one of the few odonate species where a complete life cycle over generations can be reared under laboratory conditions. We here report the complete mitochondrial genome of Ischnura elegans as a valuable genomic resource for future eco-evo-devo studies at the base of flying insects. The genome has a total length of 15,962 bp and displays all typical features of Odonata (dragonflies and damselflies) mitochondrial genomes in gene content and order as well as A + T content. Start and stop codons of all protein-coding genes are consistent. Most interestingly, we found four intergenic spacer regions and a long A + T rich (control) region of 1196 bp, which is almost double the size of the close relative Ischnura pumilio . We assume that the adequate insert size and iterative mapping may be more efficient in assembling this duplicated and repetitive region.

We present a female patient in her early twenties with global development delay, progressive ataxia, epilepsy, and myoclonus caused by a stop mutation in the SEMA6B gene. Truncating DNA variants located in the last exon of SEMA6B have recently been identified as a cause of autosomal dominant progressive myoclonus epilepsy. In many cases, myoclonus in the context of progressive myoclonic epilepsy is refractory to medical treatment. In the present case, treatment with zonisamide caused clinical improvement, particularly of positive and negative truncal myoclonus, considerably improving patient's gait and thus mobility.