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

These pubmed results were generated on 2017/10/05

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A systems-level analysis of drug-target-disease associations for drug repositioning.

Brief Funct Genomics. 2017 Aug 17;:

Authors: Rutherford KD, Mazandu GK, Mulder NJ

Abstract
Drug repositioning is the process of finding new therapeutic uses for existing, approved drugs-a process thathas value when considering the exorbitant costs of novel drug development. Several computational strategies exist as a way to predict these alternative applications. In this study, we used datasets on: (1) human biological drug targets and (2) disease-associated genes and, based on a direct functional interaction between them, searched for potential opportunities for drug repositioning. From the set of 1125 unique drug targets and their 88 490 interactions with disease-associated genes, 30 drug targets were analyzed and (3) discussed in detail for the purpose of this article. The current indications of the drugs thattarget them were validated through the interactions, and new opportunities for repositioning were predicted. Among the set of drugs for potential repositioning werebenzodiazepines for the treatment of autism spectrum disorders; nortriptyline for the treatment of melanoma, glioma and other cancers; and vitamin B6 in prevention of spontaneous abortions and cleft palate birth defects. Special emphasis was also placed on those new potential indications that pertained to orphan diseases-these are diseases whose rarity means that development of novel treatment is not financially viable. This computational drug repositioning approach uses existing information on drugs and drug targets, and insights into the genetic basis of disease, as a means to systematically generate the most probable new uses for the drugs on offer, and in this way harness their true therapeutic power.

PMID: 28968683 [PubMed - as supplied by publisher]

Four Cases of Pneumatosis Cystoides Intestinalis Complicated by Connective Tissue Diseases.

Intern Med. 2017;56(9):1101-1106

Authors: Suzuki E, Kanno T, Hazama M, Kobayashi H, Watanabe H, Ohira H

Abstract
Pneumatosis cystoides intestinalis (PCI) is a rare disease that involves the presence of gas in the intestinal wall. Connective tissue disease (CTD) is a major cause of secondary PCI. In addition to the nature of CTDs, the use of prednisolone and some immunosuppressants, and the presence of complicating diseases such as diabetes mellitus, constipation and pulmonary diseases are involved in the development of PCI. This report describes four cases of PCI with different CTDs (granulomatosis with polyangiitis, rheumatoid arthritis, dermatomyositis, and overlap syndrome) and discusses the background of each patient and common risk factors for the occurrence of PCI.

PMID: 28458320 [PubMed - indexed for MEDLINE]

Isolated Gastric Varices Refractory to Balloon-occluded Retrograde Transvenous Obliteration (BRTO) Successfully Treated by Shunt-occluded Endoscopic Injection Sclerotherapy (SO-EIS): A Case Report and Review of the Literature.

Intern Med. 2017;56(9):1041-1048

Authors: Hatanaka T, Kakizaki S, Suzuki Y, Ueno T, Shimada Y, Takizawa D, Katakai K, Sato K, Kusano M, Yamada M

Abstract
Balloon-occluded retrograde transvenous obliteration (BRTO) is widely used to treat isolated gastric varices (IGVs) in Japan. However, BRTO is difficult to perform for IGVs with many small collateral veins, and no secondary treatment has been established. We herein report a rare case of IGVs refractory to BRTO successfully treated by shunt-occluded endoscopic injection sclerotherapy (SO-EIS), which is a combination therapy of major shunt occlusion by a balloon catheter and endoscopic injection sclerotherapy. Since SO-EIS can be performed regardless of the IGVs' anatomical configuration, it may be a promising alternative treatment for IGVs refractory to BRTO.

PMID: 28458309 [PubMed - indexed for MEDLINE]

The Human Phenotype Ontology in 2017.

Nucleic Acids Res. 2017 Jan 04;45(D1):D865-D876

Authors: Köhler S, Vasilevsky NA, Engelstad M, Foster E, McMurry J, Aymé S, Baynam G, Bello SM, Boerkoel CF, Boycott KM, Brudno M, Buske OJ, Chinnery PF, Cipriani V, Connell LE, Dawkins HJ, DeMare LE, Devereau AD, de Vries BB, Firth HV, Freson K, Greene D, Hamosh A, Helbig I, Hum C, Jähn JA, James R, Krause R, F Laulederkind SJ, Lochmüller H, Lyon GJ, Ogishima S, Olry A, Ouwehand WH, Pontikos N, Rath A, Schaefer F, Scott RH, Segal M, Sergouniotis PI, Sever R, Smith CL, Straub V, Thompson R, Turner C, Turro E, Veltman MW, Vulliamy T, Yu J, von Ziegenweidt J, Zankl A, Züchner S, Zemojtel T, Jacobsen JO, Groza T, Smedley D, Mungall CJ, Haendel M, Robinson PN

Abstract
Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

PMID: 27899602 [PubMed - indexed for MEDLINE]

Bilateral Internal Carotid Artery Segmental Agenesis: Embryology, Common Collateral Pathways, Clinical Presentation, and Clinical Importance of a Rare Condition.

World Neurosurg. 2016 Nov;95:620.e9-620.e15

Authors: Alexandre AM, Visconti E, Schiarelli C, Frassanito P, Pedicelli A

Abstract
BACKGROUND: Bilateral segmental agenesis of the internal carotid artery is a rare congenital anomaly. We present a case of bilateral internal carotid artery segmental agenesis in an asymptomatic 18-year-old man. Embryology, common collateral pathways, clinical presentation, and clinical importance of this condition are discussed. According to our review of the literature, this report is the first to describe bilateral internal carotid artery segmental agenesis in a patient studied with magnetic resonance imaging, computed tomography, Doppler ultrasonography, and digital subtraction angiography.
CASE DESCRIPTION: An 18-year-old man presented to our hospital complaining of occasional mild headaches. Neurologic examination was unremarkable. Imaging findings consisted of bilateral segmental agenesis of the internal carotid arteries.
CONCLUSION: Bilateral segmental agenesis of internal carotid artery may be completely asymptomatic and harmless, but associated conditions, such as cerebral aneurysms or abnormal collateral circulation, should alert clinicians to the possibilities of subarachnoid hemorrhage or cerebral ischemia.

PMID: 27535626 [PubMed - indexed for MEDLINE]

The Challenge of Guideline Development When Evidence Is Sparse.

Otolaryngol Head Neck Surg. 2017 Sep;157(3):383-384

Authors: Scharpf J

Abstract
Although best-practice standards for clinical guidelines have been released by the Institute of Medicine and Guidelines International Network, a great challenge remains for guideline development for patients afflicted with rare diseases. This article reviews the challenge of guideline development under these circumstances with an emphasis on strategies to overcome these challenges. Guideline development and use in practice have become integral components in the contemporary care of patients to optimize outcome results. The guidelines are developed through an objective, evidence-based process conducted by experts and stakeholders for a given disease process.

PMID: 28675089 [PubMed - indexed for MEDLINE]

Facial paralysis due to Ramsay Hunt syndrome - A rare condition.

Rev Assoc Med Bras (1992). 2017 Apr;63(4):301-302

Authors: Paiva ALC, Araujo JLV, Ferraz VR, Veiga JCE

Abstract
Ramsay Hunt syndrome (or herpes zoster oticus) is a rare complication of herpes zoster in which reactivation of latent varicella zoster virus infection in the geniculate ganglion occurs. Usually, there are auricular vesicles and symptoms and signs such otalgia and peripheral facial paralysis. In addition, rarely, a rash around the mouth can be seen. Immunodeficient patients are more susceptible to this condition. Diagnosis is essentially based on symptoms. We report the case of a diabetic female patient who sought the emergency department with a complaint of this rare entity.

PMID: 28614529 [PubMed - indexed for MEDLINE]

Simultaneous meningioma and brain metastasis from renal cell carcinoma - a rare presentation. Case report.

Sao Paulo Med J. 2017 May-Jun;135(3):296-301

Authors: Campos Paiva AL, Vitorino Araujo JL, Ferraz VR, Esteves Veiga JC

Abstract
CONTEXT:: Brain metastases are the most common tumors of the central nervous system. Because of their high frequency, they may be associated with rare situations. Among these are tumor-to-tumor metastasis and an even a rarer situation called simultaneous brain tumors, which are more related to primary tumors of the reproductive and endocrine systems.
CASE REPORT:: A 56-year-old male patient with a history of renal cell carcinoma (which had previously been resected) presented with a ventricular lesion (suggestive of metastatic origin) and simultaneous olfactory groove lesion (probably a meningioma). First, only the ventricular lesion was dealt with, but after a year, the meningothelial lesion increased and an occipital lesion appeared. Therefore, both of these were resected in a single operation. All the procedures were performed by the same neurosurgeon. The patient evolved without neurological deficits during the postoperative period. After these two interventions, the patient remained well and was referred for adjuvant treatment.
CONCLUSIONS:: This study provides the first description of an association between these two tumors. Brain metastases may be associated with several lesions, and rare presentations such as simultaneity with meningioma should alert neurosurgeons to provide the best oncological treatment.

PMID: 28562734 [PubMed - indexed for MEDLINE]

Construction and implications of structural equation modeling network for pediatric cataract: a data mining research of rare diseases.

BMC Ophthalmol. 2017 May 19;17(1):74

Authors: Long E, Xu S, Liu Z, Wu X, Zhang X, Wang J, Li W, Liu R, Chen Z, Chen K, Yu T, Wu D, Zhao X, Chen J, Lin Z, Cao Q, Lin D, Li X, Cai J, Lin H

Abstract
BACKGROUND: The majority of rare diseases are complex diseases caused by a combination of multiple morbigenous factors. However, uncovering the complex etiology and pathogenesis of rare diseases is difficult due to limited clinical resources and conventional statistical methods. This study aims to investigate the interrelationship and the effectiveness of potential factors of pediatric cataract, for the exploration of data mining strategy in the scenarios of rare diseases.
METHODS: We established a pilot rare disease specialized care center to systematically record all information and the entire treatment process of pediatric cataract patients. These clinical records contain the medical history, multiple structural indices, and comprehensive functional metrics. A two-layer structural equation model network was applied, and eight potential factors were filtered and included in the final modeling.
RESULTS: Four risk factors (area, density, location, and abnormal pregnancy experience) and four beneficial factors (axis length, uncorrected visual acuity, intraocular pressure, and age at diagnosis) were identified. Quantifiable results suggested that abnormal pregnancy history may be the principle risk factor among medical history for pediatric cataracts. Moreover, axis length, density, uncorrected visual acuity and age at diagnosis served as the dominant factors and should be emphasized in regular clinical practice.
CONCLUSIONS: This study proposes a generalized evidence-based pattern for rare and complex disease data mining, provides new insights and clinical implications on pediatric cataract, and promotes rare-disease research and prevention to benefit patients.

PMID: 28526015 [PubMed - indexed for MEDLINE]

New Drugs for Rare Diseases in Children.

Clin Ther. 2017 Feb;39(2):246-252

Authors: Rose K

Abstract
PURPOSE: United States (US) Pediatric Legislation (PL) was introduced in 1997 to improve children's health. The European Union PL (EUPL) has been in force since 2007. Both PLs facilitate additional pediatric research on primarily adult drugs. The EUPL declares that the forces of the market are not sufficient for children. Without a pediatric investigation plan, new drugs can no longer be registered with the European Union. New ways on how to facilitate drug development for rare pediatric diseases are being proposed.
METHODS: US PL, EUPL, and implications of modern labels for medical decision making are discussed.
FINDINGS: Modern drug labels constituted a step from eminence-based towards data-based medical decision making. However, approval by regulatory authorities did not replace knowledge transfer in medicine, which continued in university education, through conferences, consensus papers, and so on. Children were successfully treated with off-label drugs in pediatric oncology and in many other diseases. Describing children as "therapeutic orphans" reflected an overestimation of drug labels and an underestimation of nonregulatory systematic clinical testing. Therapeutic breakthroughs have occurred, for example, in acute myelogenous leukemia and cystic fibrosis. Rare diseases need new innovative drugs and therapeutic concepts for further breakthroughs.
IMPLICATIONS: The focus of PL on additional pediatric measures for predominantly adult new drugs reflects a tunnel view. Similar to the introduction of modern pharmaceutical legislation that triggered comparable laws in most countries worldwide after 1962, we currently need new worldwide steps to reward innovative treatment concepts for rare diseases-not against, but through the market. Created by philanthropy, parents, and other supporters, new therapeutic concepts should be rewarded upon meeting regulatory milestones. This market is limited today. It needs not only a boost by pioneers, but also acceptance, welcome, and re-thinking about drug development in academia, politics, and by the general public.

PMID: 28161117 [PubMed - indexed for MEDLINE]

Clinical trial network for the promotion of clinical research for rare diseases in Japan: muscular dystrophy clinical trial network.

BMC Health Serv Res. 2016 Jul 11;16:241

Authors: Shimizu R, Ogata K, Tamaura A, Kimura E, Ohata M, Takeshita E, Nakamura H, Takeda S, Komaki H

Abstract
BACKGROUND: Duchenne muscular dystrophy (DMD) is the most commonly inherited neuromuscular disease. Therapeutic agents for the treatment of rare disease, namely "orphan drugs", have recently drawn the attention of researchers and pharmaceutical companies. To ensure the successful conduction of clinical trials to evaluate novel treatments for patients with rare diseases, an appropriate infrastructure is needed. One of the effective solutions for the lack of infrastructure is to establish a network of rare diseases.
METHODS: To accomplish the conduction of clinical trials in Japan, the Muscular dystrophy clinical trial network (MDCTN) was established by the clinical research group for muscular dystrophy, including the National Center of Neurology and Psychiatry, as well as national and university hospitals, all which have a long-standing history of research cooperation.
RESULTS: Thirty-one medical institutions (17 national hospital organizations, 10 university hospitals, 1 national center, 2 public hospitals, and 1 private hospital) belong to this network and collaborate to facilitate clinical trials. The Care and Treatment Site Registry (CTSR) calculates and reports the proportion of patients with neuromuscular diseases in the cooperating sites. In total, there are 5,589 patients with neuromuscular diseases in Japan and the proportion of patients with each disease is as follows: DMD, 29 %; myotonic dystrophy type 1, 23 %; limb girdle muscular dystrophy, 11 %; Becker muscular dystrophy, 10 %. We work jointly to share updated health care information and standardized evaluations of clinical outcomes as well. The collaboration with the patient registry (CTSR), allows the MDCTN to recruit DMD participants with specific mutations and conditions, in a remarkably short period of time.
CONCLUSION: Counting with a network that operates at a national level is important to address the corresponding national issues. Thus, our network will be able to contribute with international research activity, which can lead to an improvement of neuromuscular disease treatment in Japan.

PMID: 27401940 [PubMed - indexed for MEDLINE]

Heparanase: a rainbow pharmacological target associated to multiple pathologies including rare diseases.

Future Med Chem. 2016 Apr;8(6):647-80

Authors: Rivara S, Milazzo FM, Giannini G

Abstract
In recent years, heparanase has attracted considerable attention as a promising target for innovative pharmacological applications. Heparanase is a multifaceted protein endowed with enzymatic activity, as an endo-β-D-glucuronidase, and nonenzymatic functions. It is responsible for the cleavage of heparan sulfate side chains of proteoglycans, resulting in structural alterations of the extracellular matrix. Heparanase appears to be involved in major human diseases, from the most studied tumors to chronic inflammation, diabetic nephropathy, bone osteolysis, thrombosis and atherosclerosis, in addition to more recent investigation in various rare diseases. The present review provides an overview on heparanase, its biological role, inhibitors and possible clinical applications, covering the latest findings in these areas.

PMID: 27057774 [PubMed - indexed for MEDLINE]

The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis.

Kidney Int. 2017 May;91(5):1243-1255

Authors: Palazzo V, Provenzano A, Becherucci F, Sansavini G, Mazzinghi B, Orlandini V, Giunti L, Roperto RM, Pantaleo M, Artuso R, Andreucci E, Bargiacchi S, Traficante G, Stagi S, Murer L, Benetti E, Emma F, Giordano M, Rivieri F, Colussi G, Penco S, Manfredini E, Caruso MR, Garavelli L, Andrulli S, Vergine G, Miglietti N, Mancini E, Malaventura C, Percesepe A, Grosso E, Materassi M, Romagnani P, Giglio S

Abstract
Primary distal renal tubular acidosis is a rare genetic disease. Mutations in SLC4A1, ATP6V0A4, and ATP6V1B1 genes have been described as the cause of the disease, transmitted as either an autosomal dominant or recessive trait. Particular clinical features, such as sensorineural hearing loss, have been mainly described in association with mutations in one gene instead of the others. Nevertheless, the diagnosis of distal renal tubular acidosis is essentially based on clinical and laboratory findings, and the series of patients described so far are usually represented by small cohorts. Therefore, a strict genotype-phenotype correlation is still lacking, and questions about whether clinical and laboratory data should direct the genetic analysis remain open. Here, we applied next-generation sequencing in 89 patients with a clinical diagnosis of distal renal tubular acidosis, analyzing the prevalence of genetic defects in SLC4A1, ATP6V0A4, and ATP6V1B1 genes and the clinical phenotype. A genetic cause was determined in 71.9% of cases. In our group of sporadic cases, clinical features, including sensorineural hearing loss, are not specific indicators of the causal underlying gene. Mutations in the ATP6V0A4 gene are quite as frequent as mutations in ATP6V1B1 in patients with recessive disease. Chronic kidney disease was frequent in patients with a long history of the disease. Thus, our results suggest that when distal renal tubular acidosis is suspected, complete genetic testing could be considered, irrespective of the clinical phenotype of the patient.

PMID: 28233610 [PubMed - indexed for MEDLINE]

Should we 'open the kimono' to release the results of rare autosomal aneuploidies following noninvasive prenatal whole genome sequencing?

Prenat Diagn. 2017 Feb;37(2):123-125

Authors: Bianchi DW

Abstract
The metaphor 'open kimono' has been applied in the business world to connote transparency via the release of all available data to an external party. Here, the author uses this term to discuss the relative advantages and disadvantages of reporting on the presence of rare autosomal aneuploidies detected by massively parallel sequencing of placental cell-free DNA in the plasma of pregnant women. Newly presented data sets from multiple laboratories suggest that autosomal aneuploidies such as trisomies 7, 15, 16, 22, and 8 are easily detectable and are potentially associated with fetal growth restriction, pregnancy loss, and maternal preeclampsia. Furthermore, they may explain false positive results for the common autosomal trisomies (13, 18, and 21) as well as test failures. Thus, release of this information may result in improved clinical utility. At the present time, however, professional societies in various parts of the world differ in their recommendations as to whether or not to release expanded autosomal aneuploidy results beyond the common trisomies. © 2016 John Wiley & Sons, Ltd.

PMID: 28010042 [PubMed - indexed for MEDLINE]

A case of multiple gastrointestinal stromal tumors caused by a germline KIT gene mutation (p.Leu576Pro).

Fam Cancer. 2017 Apr;16(2):267-270

Authors: Vale Rodrigues R, Santos F, Pereira da Silva J, Francisco I, Claro I, Albuquerque C, Lemos MM, Limbert M, Dias Pereira A

Abstract
Multiple gastrointestinal stromal tumors (GISTs) caused by germline KIT gene mutations are an extremely rare autosomal dominant disorder. We report a case of a 21-year-old woman who presented to the emergency department with a 2-week history of asthenia, palpitations and upper gastrointestinal bleeding. After further clinical evaluation one gastric and two small bowel GISTs were diagnosed, which were surgically resected after neoadjuvant therapy with Imatinib. Diffuse hyperplasia of the interstitial cells of Cajal was also seen in the background gastric and small intestinal walls. Somatic mutational analysis of the KIT gene revealed a substitution at codon 576 in exon 11 (p.Leu576Pro) in all tumors and normal ileal mucosa. The germline nature of this mutation was confirmed by mutation analysis in peripheral blood leukocytes. However, she had no familial history of GISTs and her parents did not carry the respective germline mutation.

PMID: 27771813 [PubMed - indexed for MEDLINE]

Alveolar Rhabdomyosarcoma of the foot metastasizing to the Iris: report of a rare case.

BMC Cancer. 2016 Jul 11;16:447

Authors: Fabian ID, Hildebrand GD, Wilson S, Foord T, Sagoo MS

Abstract
BACKGROUND: Intraocular iris rhabdomyosarcoma is extremely rare, and in the 3 cases reported to date occurred as the primary site of tumour growth. We report a case of rhabdomyosarcoma of the foot metastasizing to the iris.
CASE PRESENTATION: An 18-year-old white female was referred to the London Ocular Oncology Service for management of a metastatic rhabdomyosarcomatous deposit in the iris, a metastasis from alveolar rhabdomyosarcoma of the foot. She was diagnosed nearly 2 years earlier with the primary sarcoma with extensive systemic spread and treated by resection of the foot lesion and chemotherapy, and achieved a partial remission. The left iris deposit was noted while she was receiving systemic chemotherapy, heralding a relapse. However, anterior uveitis and raised intraocular pressure developed and she was referred to our service for further management. A left iris secondary rhabdomyosarcoma deposit was noticed and in addition a lacrimal gland mass, as indicated by ultrasound B scan of the eye and orbit. The patient was treated with external beam radiotherapy to the globe and orbit, but died 2 months after treatment completion.
CONCLUSION: Rhabdomyosarcoma of the iris is very rare and was previously documented only as a primary malignancy in this location. We report that secondary spread to the iris can also occur, in this case as the first sign of widely disseminated systemic relapse.

PMID: 27401166 [PubMed - indexed for MEDLINE]

Controversies and research agenda in nephropathic cystinosis: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

Kidney Int. 2016 Jun;89(6):1192-203

Authors: Langman CB, Barshop BA, Deschênes G, Emma F, Goodyer P, Lipkin G, Midgley JP, Ottolenghi C, Servais A, Soliman NA, Thoene JG, Levtchenko EN, Conference Participants

Abstract
Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

PMID: 27181776 [PubMed - indexed for MEDLINE]

Implementing the single institutional review board model in the undiagnosed diseases network.

Clin Transl Sci. 2017 Sep 25;:

Authors: Splinter K, Hull SC, Holm IA, McDonough TL, Wise AL, Ramoni RB, Members of the Undiagnosed Diseases Network

PMID: 28945957 [PubMed - as supplied by publisher]

Monogenic Hashimoto thyroiditis associated with a variant in the thyroglobulin (TG) gene.

J Autoimmun. 2017 Sep 21;:

Authors: Lo MS, Towne M, VanNoy GE, Brownstein CA, Lane AA, Chatila TA, Agrawal PB

Abstract
BACKGROUND: Risk of autoimmune thyroid disease (AITD) is strongly heritable. Multiple genes confer increased risk for AITD, but a monogenic origin has not yet been described. We studied a family with apparent autosomal dominant, early onset Hashimoto thyroiditis.
METHODS: The family was enrolled in an IRB-approved protocol. Whole exome sequencing was used to study the proband and an affected sibling. The identified variant was studied in other family members by Sanger sequencing.
RESULTS: We identified a previously unreported splice site variant in the thyroglobulin gene (TG c.1076-1G > C). This variant was confirmed in all affected family members who underwent testing, and also noted in one unaffected child. The variant is associated with exon 9 skipping, resulting in a novel in-frame variant transcript of TG.
CONCLUSION: We discovered a monogenic form of AITD associated with a splice site variant in the thyroglobulin gene. This finding raises questions about the origins of thyroid autoimmunity; possible explanations include increased immunogenicity of the mutated protein or thyroid toxicity with secondary development of anti-thyroid antibodies. Further study into the effects of this variant on thyroid function and thyroid autoimmunity are warranted.

PMID: 28942902 [PubMed - as supplied by publisher]