Complex X chromosome rearrangement associated with multiorgan autoimmunity

BACKGROUND: Turner syndrome, a congenital condition that affects 1/2,500 births, results from absence or structural alteration of the second sex chromosome. Turner syndrome is usually associated with short stature, gonadal dysgenesis and variable dysmorphic features. The classical 45,X karyotype accounts approximately for half of all patients, the remainder exhibit mosaicism or structural abnormalities of the X chromosome. However, complex intra-X chromosomal rearrangements involving more than three breakpoints are extremely rare. RESULTS: We present a unique case of a novel complex X chromosome rearrangement in a young female patient presenting successively a wide range of autoimmune diseases including insulin dependent diabetes mellitus, Hashimoto's thyroiditis, celiac disease, anaemia perniciosa, possible inner ear disease and severe hair loss. For the genetic evaluation, conventional cytogenetic analysis and FISH with different X specific probes were initially performed. The complexity of these results and the variety of autoimmune problems of the patient prompted us to identify the exact composition and breakpoints of the rearranged X as well as methylation status of the X chromosomes. The high resolution array-CGH (assembly GRCh37/hg19) detected single copy for the whole chromosome X short arm. Two different sized segments of Xq arm were present in three copies: one large size of 80,3 Mb from Xq11.1 to Xq27.3 region and another smaller (11,1 Mb) from Xq27.3 to Xq28 region. An 1,6 Mb Xq27.3 region of the long arm was present in two copies. Southern blot analysis identified a skewed X inactivation with approximately 70:30 % ratios of methylated/unmethylated fragments. The G-band and FISH patterns of the rearranged X suggested the aspect of a restructured i(Xq) chromosome which was shattered and fortuitously repaired. The X-STR genotype analysis of the family detected that the patient inherited intact maternal X chromosome and a rearranged paternal X chromosome. The multiple Xq breakages and fusions as well as inverted duplication would have been expected to cause a severe Turner phenotype. However, the patient lacks many of the classic somatic features of Turner syndrome, instead she presented multiorgan autoimmune diseases. CONCLUSIONS: The clinical data of the presented patient suggest that fragmentation of the i(Xq) chromosome elevates the risk of autoimmune diseases

The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations)

Are pangenomes adaptive or not?

No description supplie

Oculopharyngodistal myopathy is a distinct entity Clinical and genetic features of 47 patients

WOS: 000286371900008PubMed ID: 21242490Background: Oculopharyngodistal myopathy (OPDM) has been reported as a rare, adult-onset hereditary muscle disease with putative autosomal dominant and autosomal recessive inheritance. Patients with OPDM present with progressive ocular, pharyngeal, and distal limb muscle involvement. The genetic defect causing OPDM has not been elucidated. Methods: Clinical and genetic findings of 47 patients from 9 unrelated Turkish families diagnosed with OPDM at the Department of Neurology, Istanbul Faculty of Medicine, between 1982 and 2009 were evaluated. Results: The mean age at onset was around 22 years. Both autosomal dominant and autosomal recessive traits were observed, without any clear difference in clinical phenotype or severity. The most common initial symptom was ptosis, followed by oropharyngeal symptoms and distal weakness, which started after the fifth disease year. Intrafamilial variability of disease phenotype and severity was notable in the largest autosomal dominant family. Atypical presentations, such as absence of limb weakness in long-term follow-up in 9, proximal predominant weakness in 4, and asymmetric ptosis in 3 patients, were observed. Swallowing difficulty was due to oropharyngeal dysphagia with myopathic origin. Serum creatine kinase levels were slightly increased and EMG revealed myopathic pattern with occasional myotonic discharges. Myopathologic findings included rimmed and autophagic vacuoles and chronic myopathic changes. Importantly, a considerable proportion of patients developed respiratory muscle weakness while still ambulant. Linkage to the genetic loci for all known muscular dystrophies, and for distal and myofibrillar myopathies, was excluded in the largest autosomal dominant and autosomal recessive OPDM families. Conclusions: We suggest that OPDM is a clinically and genetically distinct myopathy. Neurology (R) 2011; 76:227-235American Academy of Neurology; European Neurological Society (ENS); Genzyme CorporationGenzyme Corporation; European UnionEuropean Union (EU); MRC Translational Research Centre; Association Francaise contre les myopathies (AFM)Association Francaise contre les Myopathies; German Ministry for Education and ResearchFederal Ministry of Education & Research (BMBF); AVI BioPharma, Inc.; PTC Therapeutics, Inc.; Muscular Dystrophy CampaignMuscular Dystrophy Association; Medical Research Council (MRC) through the Centre for Neuromuscular DiseasesMedical Research Council UK (MRC); Association Francaise contes les Myopathies (AFM, France)Association Francaise contre les Myopathies; Medical Research CouncilMedical Research Council UK (MRC) [G0601943]Dr. Durmus received an International Scholarship Award from the American Academy of Neurology and is supported by the European Neurological Society (ENS) through a fellowship. Dr. Laval reports no disclosures. Dr. Deymeer serves on the editorial board of Neuromuscular Disorders. Dr. Parman, Dr. Kiyan, and Dr. Gokyigit report no disclosures. Dr. Ertekin serves on the editorial board of Clinic Neurophysiologique. Dr. Ercan, Dr. Solakoglu, and Dr. Karcagi report no disclosures. Dr. Straub serves on scientific advisory boards for Genzyme Corporation and Acceleron Pharma; has received funding for travel and honoraria from Genzyme Corporation; serves on the editorial board of Neuromuscular Disorders; and receives research support from the European Union, the MRC Translational Research Centre, the Association Francaise contre les myopathies (AFM), and the German Ministry for Education and Research. Prof. Bushby serves on scientific advisory boards for Prosensa, Acceleron Pharma, AVI BioPharma, Inc., Debiopharm Group, PTC Therapeutics, Inc., and Santhera Pharmaceuticals; has received funding for travel or honoraria for lectures or educational activities not sponsored by industry; serves on the editorial board of Neuromuscular Disorders; receives research support from AVI BioPharma, Inc., PTC Therapeutics, Inc., the European Union, the MRC Translational Research Centre, the Association Francaise contre les myopathies (AFM), and the Muscular Dystrophy Campaign; and holds stock in GlaxoSmithKline. Dr. Lochmuller and Dr. Serdaroglu-Oflazer report no disclosures.; Supported by the American Academy of Neurology through an International Scholarship Award to H. D., the European Neurological Society (ENS) through a fellowship to H. D., Science City Newcastle, the Medical Research Council (MRC) through the Centre for Neuromuscular Diseases, and the Association Francaise contes les Myopathies (AFM, France). Newcastle University is the coordinating partner of the TREAT-NMD network of excellence (EC 036825)