A Fast Association Test for Identifying Pathogenic Variants Involved in Rare Diseases.

Am J Hum Genet. 2017 Jul 06;101(1):104-114

Authors: Greene D, NIHR BioResource, Richardson S, Turro E

Abstract
We present a rapid and powerful inference procedure for identifying loci associated with rare hereditary disorders using Bayesian model comparison. Under a baseline model, disease risk is fixed across all individuals in a study. Under an association model, disease risk depends on a latent bipartition of rare variants into pathogenic and non-pathogenic variants, the number of pathogenic alleles that each individual carries, and the mode of inheritance. A parameter indicating presence of an association and the parameters representing the pathogenicity of each variant and the mode of inheritance can be inferred in a Bayesian framework. Variant-specific prior information derived from allele frequency databases, consequence prediction algorithms, or genomic datasets can be integrated into the inference. Association models can be fitted to different subsets of variants in a locus and compared using a model selection procedure. This procedure can improve inference if only a particular class of variants confers disease risk and can suggest particular disease etiologies related to that class. We show that our method, called BeviMed, is more powerful and informative than existing rare variant association methods in the context of dominant and recessive disorders. The high computational efficiency of our algorithm makes it feasible to test for associations in the large non-coding fraction of the genome. We have applied BeviMed to whole-genome sequencing data from 6,586 individuals with diverse rare diseases. We show that it can identify multiple loci involved in rare diseases, while correctly inferring the modes of inheritance, the likely pathogenic variants, and the variant classes responsible.

PMID: 28669401 [PubMed - indexed for MEDLINE]

Electronic Health Record Based Algorithm to Identify Patients with Autism Spectrum Disorder.

PLoS One. 2016;11(7):e0159621

Authors: Lingren T, Chen P, Bochenek J, Doshi-Velez F, Manning-Courtney P, Bickel J, Wildenger Welchons L, Reinhold J, Bing N, Ni Y, Barbaresi W, Mentch F, Basford M, Denny J, Vazquez L, Perry C, Namjou B, Qiu H, Connolly J, Abrams D, Holm IA, Cobb BA, Lingren N, Solti I, Hakonarson H, Kohane IS, Harley J, Savova G

Abstract
OBJECTIVE: Cohort selection is challenging for large-scale electronic health record (EHR) analyses, as International Classification of Diseases 9th edition (ICD-9) diagnostic codes are notoriously unreliable disease predictors. Our objective was to develop, evaluate, and validate an automated algorithm for determining an Autism Spectrum Disorder (ASD) patient cohort from EHR. We demonstrate its utility via the largest investigation to date of the co-occurrence patterns of medical comorbidities in ASD.
METHODS: We extracted ICD-9 codes and concepts derived from the clinical notes. A gold standard patient set was labeled by clinicians at Boston Children's Hospital (BCH) (N = 150) and Cincinnati Children's Hospital and Medical Center (CCHMC) (N = 152). Two algorithms were created: (1) rule-based implementing the ASD criteria from Diagnostic and Statistical Manual of Mental Diseases 4th edition, (2) predictive classifier. The positive predictive values (PPV) achieved by these algorithms were compared to an ICD-9 code baseline. We clustered the patients based on grouped ICD-9 codes and evaluated subgroups.
RESULTS: The rule-based algorithm produced the best PPV: (a) BCH: 0.885 vs. 0.273 (baseline); (b) CCHMC: 0.840 vs. 0.645 (baseline); (c) combined: 0.864 vs. 0.460 (baseline). A validation at Children's Hospital of Philadelphia yielded 0.848 (PPV). Clustering analyses of comorbidities on the three-site large cohort (N = 20,658 ASD patients) identified psychiatric, developmental, and seizure disorder clusters.
CONCLUSIONS: In a large cross-institutional cohort, co-occurrence patterns of comorbidities in ASDs provide further hypothetical evidence for distinct courses in ASD. The proposed automated algorithms for cohort selection open avenues for other large-scale EHR studies and individualized treatment of ASD.

PMID: 27472449 [PubMed - indexed for MEDLINE]

The ethical framework for performing research with rare inherited neurometabolic disease patients.

Eur J Pediatr. 2017 Mar;176(3):395-405

Authors: Giannuzzi V, Devlieger H, Margari L, Odlind VL, Ragab L, Bellettato CM, D'Avanzo F, Lampe C, Cassis L, Cortès-Saladelafont E, Cazorla ÁG, Barić I, Cvitanović-Šojat L, Fumić K, Dali CI, Bartoloni F, Bonifazi F, Scarpa M, Ceci A

Abstract
The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families.
CONCLUSION: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and information on how these rules have been applied.

PMID: 28093642 [PubMed - indexed for MEDLINE]

Activity of Pazopanib and Trabectedin in Advanced Alveolar Soft Part Sarcoma.

Oncologist. 2017 Jul 28;:

Authors: Stacchiotti S, Mir O, Le Cesne A, Vincenzi B, Fedenko A, Maki RG, Somaiah N, Patel S, Brahmi M, Blay JY, Boye K, Sundby Hall K, Gelderblom H, Hindi N, Martin-Broto J, Kosela H, Rutkowski P, Italiano A, Duffaud F, Kobayashi E, Casali PG, Provenzano S, Kawai A

Abstract
BACKGROUND: Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin.
MATERIALS AND METHODS: From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method.
RESULTS: Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months.
CONCLUSION: The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS.
IMPLICATIONS FOR PRACTICE: This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.

PMID: 28754721 [PubMed - as supplied by publisher]

'You two - There must be some mistake!'

Emerg Med Australas. 2016 Dec;28(6):758

Authors: Brown AF, Zia M, Symons P, Moore N

PMID: 27796071 [PubMed - indexed for MEDLINE]

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

Am J Hum Genet. 2017 May 04;100(5):695-705

Authors: Boycott KM, Rath A, Chong JX, Hartley T, Alkuraya FS, Baynam G, Brookes AJ, Brudno M, Carracedo A, den Dunnen JT, Dyke SOM, Estivill X, Goldblatt J, Gonthier C, Groft SC, Gut I, Hamosh A, Hieter P, Höhn S, Hurles ME, Kaufmann P, Knoppers BM, Krischer JP, Macek M, Matthijs G, Olry A, Parker S, Paschall J, Philippakis AA, Rehm HL, Robinson PN, Sham PC, Stefanov R, Taruscio D, Unni D, Vanstone MR, Zhang F, Brunner H, Bamshad MJ, Lochmüller H

Abstract
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

PMID: 28475856 [PubMed - indexed for MEDLINE]

Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis.

J Exp Med. 2016 Jul 25;213(8):1497-512

Authors: Rowe RG, Wang LD, Coma S, Han A, Mathieu R, Pearson DS, Ross S, Sousa P, Nguyen PT, Rodriguez A, Wagers AJ, Daley GQ

Abstract
For appropriate development, tissue and organ system morphogenesis and maturation must occur in synchrony with the overall developmental requirements of the host. Mistiming of such developmental events often results in disease. The hematopoietic system matures from the fetal state, characterized by robust erythrocytic output that supports prenatal growth in the hypoxic intrauterine environment, to the postnatal state wherein granulocytes predominate to provide innate immunity. Regulation of the developmental timing of these myeloerythroid states is not well understood. In this study, we find that expression of the heterochronic factor Lin28b decreases in common myeloid progenitors during hematopoietic maturation to adulthood in mice. This decrease in Lin28b coincides with accumulation of mature let-7 microRNAs, whose biogenesis is regulated by Lin28 proteins. We find that inhibition of let-7 in the adult hematopoietic system recapitulates fetal erythroid-dominant hematopoiesis. Conversely, deletion of Lin28b or ectopic activation of let-7 microRNAs in the fetal state induces a shift toward adult-like myeloid-dominant output. Furthermore, we identify Hmga2 as an effector of this genetic switch. These studies provide the first detailed analysis of the roles of endogenous Lin28b and let-7 in the timing of hematopoietic states during development.

PMID: 27401346 [PubMed - indexed for MEDLINE]

Limb Amputation after Multiple Treatments of Tenosynovial Giant Cell Tumour: Series of 4 Dutch Cases.

Case Rep Orthop. 2017;2017:7402570

Authors: Mastboom MJL, Verspoor FGM, Gelderblom H, van de Sande MAJ

Abstract
In Tenosynovial Giant Cell Tumours (TGCT), previously named Pigmented Villonodular Synovitis (PVNS), a distinction is made between a single nodule (localized-type) and multiple nodules (diffuse-type). Diffuse-type is considered locally aggressive. Onset and extermination of this orphan disease remain unclear. Surgical resection is the most commonly performed treatment. Unfortunately, recurrences often occur (up to 92%), necessitating reoperations and adjuvant treatments. Once all treatments fail or if severe complications occur, limb amputation may become unavoidable. We describe four cases of above-knee amputation after TGCT diagnosis.

PMID: 28744388 [PubMed]

Dealing with Uncertainty and Accounting for Social Value Judgments in Assessments of Orphan Drugs: Evidence from Four European Countries.

Value Health. 2017 Jul - Aug;20(7):919-926

Authors: Nicod E, Berg Brigham K, Durand-Zaleski I, Kanavos P

Abstract
OBJECTIVES: To better understand the reasons for differences in reimbursement decisions for orphan drugs in four European countries that were not readily apparent from health technology assessment (HTA) reports and operating procedures.
METHODS: Semistructured interviews with representatives of HTA bodies in England, Scotland, Sweden, and France were conducted. An interview topic guide was developed on the basis of findings from a systematic comparison of HTA decisions for 10 orphan drugs. Qualitative thematic data analysis was applied to the interview transcripts using the framework approach.
RESULTS: Eight representatives from the four HTA bodies were interviewed between March and June 2015. Evidentiary requirements and approaches to dealing with imperfect or incomplete evidence were explored, including trial design and duration, study population and subgroups, comparators, and end points. Interviewees agreed that decisions regarding orphan drugs are made in a context of lower quality evidence, and the threshold of acceptable uncertainty varied by country. Some countries imposed higher evidentiary standards for greater clinical claims, which may be more challenging for orphan diseases. The acceptability of surrogate end points was not consistent across countries nor were the validation requirements. The most common social value judgments identified related to innovation, disease severity, and unmet need. Differences were seen in the way these concepts were defined and accounted for across countries.
CONCLUSIONS: Although agreement was seen in evidentiary requirements or preferences, there were subtle differences in the circumstances in which uncertain evidence may be considered acceptable, possibly explaining differences in HTA recommendations across countries.

PMID: 28712621 [PubMed - indexed for MEDLINE]

Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report.

Value Health. 2017 Jul - Aug;20(7):838-855

Authors: Benjamin K, Vernon MK, Patrick DL, Perfetto E, Nestler-Parr S, Burke L

Abstract
BACKGROUND: Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals.
OBJECTIVE: To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials.
GOOD PRACTICES FOR OUTCOMES RESEARCH: This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition's natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient's perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use.
CONCLUSIONS: This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

PMID: 28712612 [PubMed - indexed for MEDLINE]

Molecular oncogenesis of chondrosarcoma: impact for targeted treatment.

Curr Opin Oncol. 2016 Jul;28(4):314-22

Authors: Speetjens FM, de Jong Y, Gelderblom H, Bovée JV

Abstract
PURPOSE OF REVIEW: The prognosis of patients with unresectable or metastatic chondrosarcoma of the bone is poor. Chondrosarcomas are in general resistant to chemotherapy and radiotherapy. This review discusses recent developments in the characterization of molecular pathways involved in the oncogenesis of chondrosarcoma that should be explored to improve prognosis of patients with advanced chondrosarcoma.
RECENT FINDINGS: The different oncogenic pathways for chondrosarcoma have become better defined. These include alterations in pathways such as isocitrate dehydrogenase mutation, hedgehog signalling, the retinoblastoma protein and p53 pathways, apoptosis and survival mechanisms, and several tyrosine kinases. These specific alterations can be employed for use in clinical interventions in advanced chondrosarcoma.
SUMMARY: As many different genetic alterations in chondrosarcoma have been identified, it is of the utmost importance to classify druggable targets that may improve the prognosis of chondrosarcoma patients. In recent years an increased number of trials evaluating targeted therapies are being conducted. As chondrosarcoma is an orphan disease consequently all studies are performed with small numbers of patients. The results of clinical studies so far have been largely disappointing. Therapeutic intervention studies of these new targets emerging from preclinical studies are of highest importance to improve prognosis of chondrosarcoma patients with advanced disease.

PMID: 27166664 [PubMed - indexed for MEDLINE]

Identification of a rare COCH mutation by whole-exome sequencing : Implications for personalized therapeutic rehabilitation in an Austrian family with non-syndromic autosomal dominant late-onset hearing loss.

Wien Klin Wochenschr. 2017 Jul 21;:

Authors: Parzefall T, Frohne A, Koenighofer M, Kirchnawy A, Streubel B, Schoefer C, Gstoettner W, Frei K, Lucas T

Abstract
BACKGROUND: Non-syndromic autosomal dominant hearing impairment is characteristically postlingual in onset. Genetic diagnostics are essential for genetic counselling, disease prognosis and understanding of the molecular mechanisms of disease. To date, 36 causative genes have been identified, many in only individual families. Gene selection for genetic screening by traditional methods and genetic diagnosis in autosomal dominant patients has therefore been fraught with difficulty. Whole-exome sequencing provides a powerful tool to analyze all protein-coding genomic regions in parallel, thus allowing the comprehensive screening of all known genes and associated alterations.
METHODS: In this study, a previously undiagnosed late-onset progressive autosomal dominant hearing loss in an Austrian family was investigated by means of whole-exome sequencing. Results were confirmed by Sanger sequencing.
RESULTS: A previously described c.151C>T missense (p.Pro51Ser) mutation in the LCCL (limulus factor C, cochlin, late gestation lung protein Lgl1) domain of the cochlin gene (COCH) was identified as causative and segregated with disease in five members of the family. Molecular diagnostics led to the decision to perform cochlear implantation in an index patient who subsequently showed excellent postoperative auditory performance. The c.151C>T mutation was not found in 18 screened Austrian families with autosomal dominant hearing loss but was represented alongside other known pathogenic mutant COCH alleles in the Genome Aggregation Database (gnomAD) in European populations. A combined allele frequency of 0.000128 implies an orphan disease frequency for COCH-induced hearing loss of 1:3900 in Europe.
CONCLUSIONS: Exome sequencing successfully resolved the genetic diagnosis in a family suffering from autosomal dominant hearing impairment and allowed prediction of purported auditory outcome after cochlear implantation in an index patient. Personalized treatment approaches based on the molecular mechanisms of disease may become increasingly important in the future.

PMID: 28733840 [PubMed - as supplied by publisher]

FungiScope(™) -Global Emerging Fungal Infection Registry.

Mycoses. 2017 Aug;60(8):508-516

Authors: Seidel D, Durán Graeff LA, Vehreschild MJGT, Wisplinghoff H, Ziegler M, Vehreschild JJ, Liss B, Hamprecht A, Köhler P, Racil Z, Klimko N, Sheppard DC, Herbrecht R, Chowdhary A, Cornely OA, FungiScope Group

Abstract
Rare invasive fungal diseases (IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScope(™) is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases. FungiScope(™) was founded in 2003, and today, collaborators from 66 countries support the registry. So far, clinical data of 794 cases have been entered using a web-based approach. Within the growing network of experts, new collaborations developed, leading to several publications of comprehensive analyses of patient subgroups identified from the registry. Data extracted from FungiScope(™) have also been used as the sole control group for the approval of a new antifungal drug. Due to the rarity of these diseases, a global registry is an appropriate method of pooling the scarce and scattered information. Joining efforts across medical specialities and geographical borders is key for researching rare IFD. Here, we describe the structure and management of the FungiScope(™) registry.

PMID: 28730644 [PubMed - in process]

Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals.

JIMD Rep. 2017 Jul 20;:

Authors: Wojcik MH, Wierenga KJ, Rodan LH, Sahai I, Ferdinandusse S, Genetti CA, Towne MC, Peake RWA, James PM, Beggs AH, Brownstein CA, Berry GT, Agrawal PB

Abstract
Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase) deficiency is a genetic disorder characterized by impaired isoleucine catabolism and ketone body utilization that predisposes to episodic ketoacidosis. It results from biallelic pathogenic variants in the ACAT1 gene, encoding mitochondrial beta-ketothiolase. We report two cases of beta-ketothiolase deficiency presenting with acute ketoacidosis and "metabolic stroke." The first patient presented at 28 months of age with metabolic acidosis and pallidal stroke in the setting of a febrile gastrointestinal illness. Although 2-methyl-3-hydroxybutyric acid and trace quantities of tiglylglycine were present in urine, a diagnosis of glutaric acidemia type I was initially suspected due to the presence of glutaric and 3-hydroxyglutaric acids. A diagnosis of beta-ketothiolase deficiency was ultimately made through whole exome sequencing which revealed compound heterozygous variants in ACAT1. Fibroblast studies for beta-ketothiolase enzyme activity were confirmatory. The second patient presented at 6 months of age with ketoacidosis, and was found to have elevations of urinary 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. Sequencing of ACAT1 demonstrated compound heterozygous presumed causative variants. The patient exhibited choreoathethosis 2 months after the acute metabolic decompensation. These cases highlight that, similar to a number of other organic acidemias and mitochondrial disorders, beta-ketothiolase deficiency can present with metabolic stroke. They also illustrate the variability in clinical presentation, imaging, and biochemical evaluation that make screening for and diagnosis of this rare disorder challenging, and further demonstrate the value of whole exome sequencing in the diagnosis of metabolic disorders.

PMID: 28726122 [PubMed - as supplied by publisher]

Less is more - time to concentrate experience to improve outcomes?

Colorectal Dis. 2016 Sep;18(9):837-8

Authors: Myrelid P

PMID: 27586702 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/07/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Global Carrier Rates of Rare Inherited Disorders Using Population Exome Sequences.

PLoS One. 2016;11(5):e0155552

Authors: Fujikura K

Abstract
Exome sequencing has revealed the causative mutations behind numerous rare, inherited disorders, but it is challenging to find reliable epidemiological values for rare disorders. Here, I provide a genetic epidemiology method to identify the causative mutations behind rare, inherited disorders using two population exome sequences (1000 Genomes and NHLBI). I created global maps of carrier rate distribution for 18 recessive disorders in 16 diverse ethnic populations. Out of a total of 161 mutations associated with 18 recessive disorders, I detected 24 mutations in either or both exome studies. The genetic mapping revealed strong international spatial heterogeneities in the carrier patterns of the inherited disorders. I next validated this methodology by statistically evaluating the carrier rate of one well-understood disorder, sickle cell anemia (SCA). The population exome-based epidemiology of SCA [African (allele frequency (AF) = 0.0454, N = 2447), Asian (AF = 0, N = 286), European (AF = 0.000214, N = 4677), and Hispanic (AF = 0.0111, N = 362)] was not significantly different from that obtained from a clinical prevalence survey. A pair-wise proportion test revealed no significant differences between the two exome projects in terms of AF (46/48 cases; P > 0.05). I conclude that population exome-based carrier rates can form the foundation for a prospectively maintained database of use to clinical geneticists. Similar modeling methods can be applied to many inherited disorders.

PMID: 27219052 [PubMed - indexed for MEDLINE]

Discovering the Unexpected with the Utilization of NGS in Diagnostics of Non-syndromic Hearing Loss Disorders: The Family Case of ILDR1-Dependent Hearing Loss Disorder.

Front Genet. 2017;8:95

Authors: Kovač J, Klančar G, Trebušak Podkrajšek K, Battelino S

Abstract
Sensorineural hearing loss (SNHL) is a heterogeneous family of hearing disabilities with congenital (including genetic) as well as acquired etiology. Congenital SNHL of genetic etiology is further sub-divided into autosomal dominant, autosomal recessive and X-linked SNHL. More than 60 genes are involved in the etiology of autosomal recessive non-syndromic hearing loss (ARNSHL) commonly manifesting as heterogeneous pre-lingual profound to severe non-progressive clinical phenotype. ILDR1-dependent ARNSHL (DFNB42, OMIM: # 609646) is a very rare sub-type of hearing disability, with unknown prevalence, caused by function-damaging genetic variants in ILDR1 gene reported in families of Middle-Eastern origin. ILDR1 (Immunoglobulin-Like Domain-containing Receptor 1) is involved in the development of semicircular canal, tricellular tight junction and auditory hair cells. An apparently non-consanguineous family of European ancestry with two affected siblings with profound progressive hearing loss characterized in their infancy and successfully treated with cochlear implants (CI) is presented. Genetic analysis of common ARNSHL genetic causes in the population of origin was negative, thus the next-generation sequencing (NGS) and family segregation analysis to identify underlying causative genetic variant was performed. Unexpectedly and atypical for the population of origin a homozygous non-sense variant ILDR1 c.942C > A (p.Cys314Ter) inherited from both heterozygous parents was identified in both patients. Contrary to the commonly reported phenotype, indices of a progressive hearing loss and potential compensatory mechanism of vestibular function were revealed with the analysis of clinical data. The utilization of NGS was demonstrated as an invaluable tool for the detection of atypical rare variants in diagnostics of unidentified hearing loss disorders.

PMID: 28713423 [PubMed]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/07/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2017/07/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.