[Uncovering rare diseases in medical data-coding]. / Seltene Erkrankungen in den Daten sichtbar machen ­ Kodierung.

The ICD-10-GM coding system used in the German healthcare system only captures a minority of rare disease diagnoses. Therefore, information on the incidence and prevalence of rare diseases as well as necessary (financial) resources for the expert care required for evidence-based decisions by health insurers, care providers, and politicians are lacking. Furthermore, the missing information complicates and sometimes even precludes the generation of scientific knowledge on rare diseases. Therefore, starting in 2023, all in-patient cases in Germany with a rare disease diagnosis must be coded by an ORPHAcode using the Alpha-ID-SE file.The file Alpha-ID-SE links the ICD-10-GM codes to the internationally established ORPHAcodes for rare diseases. Commercially available software tools progressively support the coding of rare diseases. In several centers for rare diseases linked to university hospitals, IT tools and procedures were established to realize a complete coding of rare diseases. These include financial incentives for the institutions providing rare disease codes, systematic queries asking for rare disease codes during the coding process, and a semi-automated coding process for all patients with a rare disease previously seen at the institution. A combination of the different approaches probably results in the most complete coding.To get the complete picture of rare disease epidemiology and care requirements, a specific and unique coding of out-patient cases is also desirable. Furthermore, a structured reporting of phenotype is required, especially for complex rare diseases and for yet undiagnosed cases.

PanelDesign: Integrating Epidemiological Information into the Design of Diagnostic NGS Gene Panels.

We report upon PanelDesign, a framework to support the design of diagnostic next generation DNA sequencing panels with epidemiological information. Two publicly available resources, namely Genomics England PanelApp and Orphadata, were combined into a single data set to allow genes in a given NGS panel to be ranked according to the frequency of the associated diseases, thereby highlighting potential core genes as defined by the Eurogenetest/ESHG guidelines for diagnostic next generation DNA sequencing. In addition, PanelDesign can be used to evaluate the contribution of different genes to a given disease following ACMG (American College of Medical Genetics) technical standards.

Clinical Practice Guidelines for Rare Diseases: The Orphanet Database.

Clinical practice guidelines (CPGs) for rare diseases (RDs) are scarce, may be difficult to identify through Internet searches and may vary in quality depending on the source and methodology used. In order to contribute to the improvement of the diagnosis, treatment and care of patients, Orphanet (www.orpha.net) has set up a procedure for the selection, quality evaluation and dissemination of CPGs, with the aim to provide easy access to relevant, accurate and specific recommendations for the management of RDs. This article provides an analysis of selected CPGs by medical domain coverage, prevalence of diseases, languages and type of producer, and addresses the variability in CPG quality and availability. CPGs are identified via bibliographic databases, websites of research networks, expert centres or medical societies. They are assessed according to quality criteria derived from the Appraisal of Guidelines, REsearch and Evaluation (AGREE II) Instrument. Only open access CPGs and documents for which permission from the copyright holders has been obtained are disseminated on the Orphanet website. From January 2012 to July 2015, 277 CPGs were disseminated, representing coverage of 1,122 groups of diseases, diseases or subtypes in the Orphanet database. No language restriction is applied, and so far 10 languages are represented, with a predominance of CPGs in English, French and German (92% of all CPGs). A large proportion of diseases with identified CPGs belong to rare oncologic, neurologic, hematologic diseases or developmental anomalies. The Orphanet project on CPG collection, evaluation and dissemination is a continuous process, with regular addition of new guidelines, and updates. CPGs meeting the quality criteria are integrated to the Orphanet database of rare diseases, together with other types of textual information and the appropriate services for patients, researchers and healthcare professionals in 40 countries.

Funding of rare disease research in Germany: a pilot study.

Collectively, rare diseases are of major public health impact, but research on rare diseases poses major challenges. There are many deterrents for researchers to initiate rare disease projects and for funding agencies to grant support. It can be expected that rare disease research is underfunded, but no systematic assessments on rare disease funding practices were found in the literature. The recipients of grants for rare disease research were identified through the research reports of four German medical faculties, and data on external funding of individual projects were obtained through questionnaires and database mining. Response rates to questionnaires were unsatisfactory. The analysis was thus concentrated on a single faculty, Hannover Medical School, for which 100% data ascertainment was obtained. External funding for rare disease research at this faculty comprises 5.8% of all external research funding in 2006, and 3.8% in 2007. As the first study of this kind, this survey indicates enormous deficits and inequities in rare disease research.

TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder characterized by manifestations in the cardiovascular, skeletal, ocular, and other organ systems. MFS type1 (MFS1) is caused by mutations in the gene encoding fibrillin (FBN1). Recently, the transforming growth factor-beta receptor-2 gene, TGFBR2, has been shown to be associated with a second type of this disorder with typically mild or absent ocular involvement (MFS type 2; MFS2). Several point mutations were found in the highly conserved serine/threonine kinase domain of TGFBR2. Mutations in both TGFBR1 and TGFBR2 are associated with Loeys-Dietz aortic aneurysm syndrome (LDS). We searched for TGFBR1 and TGFBR2 mutations in 41 unrelated patients fulfilling the diagnostic criteria of Ghent nosology or with the tentative diagnosis of Marfan syndrome, in whom mutations in the FBN1 coding region were not identified. In TGFBR1, two mutations and two polymorphisms were detected. In TGFBR2, five mutations and six polymorphisms were identified. Reexamination of patients with a TGFBR1 or TGFBR2 mutation revealed extensive clinical overlap between patients with MFS1, MFS2, and LDS.

Sequence variations in the 5' upstream regions of the FBN1 gene associated with Marfan syndrome.

Marfan syndrome (MFS; OMIM#154700) is a connective tissue disorder characterized by manifestations in the ocular, skeletal and cardiovascular systems. MFS is caused by mutation in the fibrillin-1 gene (FBN1; OMIM#134797) and more than 550 mutations have been identified so far. FBN1 is approximately 230 kb in size and contains three evolutionarily conserved alternatively spliced exons B, A and C at the 5'end. In a first systematic attempt to associate sequence variations in the FBN1 5' alternatively spliced exons with MFS, we investigated 41 individuals fulfilling the diagnostic criteria of Ghent nosology or with features of MFS including at least one major criterion or involvement of two organ systems but not fulfilling a strict interpretation of the Ghent nosology, and known to be negative for mutations in the FBN1 exons 1-65 as well as the TGFBR2 and TGFBR1 coding regions. We identified five novel and one previously reported variants in the six unrelated probands and provide preliminary evidence for their role in pathogenesis.

Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome.

Marfan syndrome (MFS) is an autosomal-dominant disorder of the fibrous connective tissue that is typically caused by mutations in the gene coding for fibrillin-1 (FBN1), a major component of extracellular microfibrils. The clinical spectrum of MFS is highly variable and includes involvement of the cardiovascular, skeletal, ocular, and other organ systems; however, the genotype-phenotype correlations have not been well developed. Various screening methods have led to the identification of about 600 different mutations (FBN1-UMD database; www.umd.be). In this study we performed SSCP and/or direct sequencing to analyze all 65 exons of the FBN1 gene in 116 patients presenting with classic MFS or related phenotypes. Twenty-nine novel and nine recurrent mutations were identified in 38 of the analyzed patients. The mutations comprised 18 missense (47%), eight nonsense (21%), and five splice site (13%) mutations. Seven further mutations (18%) resulted from deletion, insertion, or duplication events, six of which led to a frameshift and subsequent premature termination. Additionally, we describe new polymorphisms and sequence variants. On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutation-positive patients for whom comprehensive clinical data were available. Most strikingly, there was a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon (PTC) or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration.

Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations.

Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the "hybrid" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before.