Medical Genetics Branch
Medical Genetics Branch
News Article | March 25, 2017
Ticked Off! Here's What You Need To Know About Lyme Disease Researchers have successfully employed a facial recognition software in the process of diagnosing a rare genetic disorder in Africans, Asians and Latin Americans. The disease is known as the DiGeorge syndrome and it affects 1 in 3,000 to 1 in 6,000 children. The research was carried out by scientists with the National Human Genome Research Institute, as part of the National Institutes of Health, along with their collaborators, and was published March 23 in the American Journal of Medical Genetics. Although the disease is popular by the name DiGeorge or velocadriofacial syndrome, its medical name is 22q11.2 deletion syndrome. The disorder causes multiple defects of the body, including heart problems, cleft palate, learning problems and a characteristic facial appearance. However, because of the very unusual symptoms, health specialists can't always pinpoint the disease, especially among very diverse populations. The main purpose of the study is to help specialists and health care providers to recognize and diagnose the syndrome more easily, in order to deliver medical interventions earlier and more efficiently. The software is all the more necessary as, according to Paul Kruszka, M.D., medical geneticist in NHRGI's Medical Genetics Branch, different syndromes appear differently depending on the part of the world, which makes it more difficult for specialists to promptly diagnose a series of diseases, especially among non-European populations. As part of the research, the scientists analyzed information from 106 participants, as well as photographs of 101 subjects who suffered from the disease. The subjects were chosen from 11 different countries in Africa, Latin America and Asia, as the appearance of different subjects suffering from the disease was very different inside this group. Then the team used facial analysis technology to address the disorder, comparing a group of 156 Caucasians, Latin Americans, Asians and Africans, who either suffered with the disease or who formed the control groups. The diagnoses were then made, comparing 126 facial features. The diagnoses were correct 96.6 percent of the time, which makes this software a success in addressing this syndrome. Additionally, this technology is very helpful when it comes to diagnosing Down syndrome. "[...] we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world," noted the research. Following this discovery, the researchers will focus on Noonan syndrome and Williams syndrome. Both of these diseases are rare. However, many clinicians reported having encountered them throughout their careers. DiGeorge syndrome and Down syndrome are both included in the Atlas of Human Malformations in Diverse Populations, a program launched in 2016. Upon its completion, this atlas will represent a comprehensive and exhaustive database of distinct inherited diseases worldwide. Additionally, the photos of these conditions will be accompanied by short descriptions of affected people. These descriptions would allow clinicians to search diseases based on a series of categories, from continental region to the phenotype or the syndrome. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.
News Article | August 23, 2016
National Institutes of Health researchers have discovered a rare and sometimes lethal inflammatory disease - otulipenia - that primarily affects young children. They have also identified anti-inflammatory treatments that ease some of the patients' symptoms: fever, skin rashes, diarrhea, joint pain and overall failure to grow or thrive. Otulipenia is caused by the malfunction of OTULIN, a single gene on chromosome 5. When functioning properly, OTULIN regulates the development of new blood vessels and mobilization of cells and proteins to fight infection. NIH researchers published their findings Aug. 22, 2016, in the early edition of the Proceedings of the National Academy of Sciences. Contributing to the work were researchers from the National Human Genome Research Institute (NHGRI), the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute and the NIH Clinical Center, all part of NIH, along with their colleagues in Turkey and the United Kingdom. "The results have been amazing and life changing for these children and their families," said Daniel Kastner, M.D., Ph.D., co-author, NHGRI scientific director and head of NHGRI's Inflammatory Disease Section. "We have achieved the important goal of helping these young patients and made progress in understanding the biological pathways and proteins that are important for the regulation of the immune system's responses." Cells use biological pathways to send and receive chemical cues in reaction to injury, infection or stress. Otulipenia is one of several inflammatory diseases that occur when the immune system attacks the host's own tissues. Inflammation is the body's natural response to invading bacteria or viruses. The body releases chemicals that cause blood vessels to leak and tissues to swell in order to isolate a foreign substance from further contact with the body's tissues. Inflammatory diseases affecting the whole body are caused by mutations in genes like OTULIN that are part of a person's innate immunity (the cells and proteins present at birth that fight infections). An international network of scientists studying inflammatory diseases identified four children from Pakistani and Turkish families with unexplained skin rashes and inflamed joints. NIH scientists then searched for disease-causing genes using next-generation DNA sequencing, technology that allows researchers to sequence DNA quickly and economically. Once they found that the OTULIN gene was abnormal in the sick children, they studied the immune pathway in order to understand the mechanisms of disease and to improve treatment of these patients. They discovered a problem in the processing of a small protein, ubiquitin, which is critical to the regulation of many other proteins in the body, including immune molecules. In the affected children, the inability to remove the ubiquitin proteins from various molecules resulted in an increased production of chemical messengers that lead to inflammation (inflammatory cytokines). The researchers determined that the children with otulipenia might respond to drugs that turned off tumor necrosis factor, a chemical messenger involved in systemic inflammation. Inflammation subsided in the children who had been treated with anti-tumor necrosis factor drugs (TNF inhibitors). TNF inhibitors are also used to treat chronic inflammatory diseases such as rheumatoid arthritis. "The malfunction in this protein has not been previously linked to clinical disorders of the human immune system," said Ivona Aksentijevich, M.D., staff scientist in NHGRI's Medical Genetics Branch and study co-author. "This discovery suggests a direction that can be explored for development of new therapies for patients with a wide range of inflammatory diseases." This study together with NIH's 2016 identification of haploinsufficiency of A20 (HA20), suggests a new category of human inflammatory diseases caused by impaired ubiquitination, according to the researchers.
Trimble A.,University of Virginia |
Gochuico B.R.,Medical Genetics Branch |
Markello T.C.,Medical Genetics Branch |
Markello T.C.,National Human Genome Research Institute |
And 8 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2014
Conclusions: CXCR41 fibrocyte concentration may be useful as a biomarker for outcome of ILD in subjects with HPS.Rationale: The rate of progression of most interstitial lung diseases (ILD) is unpredictable. Fibrocytes are circulating bone marrow-derived cells that have been implicated in the pathogenesis of lung fibrosis. Hermansky-Pudlak syndrome (HPS), a genetic cause of ILD in early adulthood, allows for study of biomarkers of ILD in a homogeneous population at near-certain risk of developing fibrotic lung disease.Objectives: To test the hypothesis that, in subjects with HPS, the number or phenotype of circulating fibrocytes predicts progression and outcome of ILD.Methods:We measured circulating fibrocyte counts and chemokine levels in a cohort of subjects with HPS and healthy control subjects and correlated the results to disease outcome. Measurements and Main Results: In a cross-sectional analysis, peripheral blood fibrocyte concentrations were markedly elevated in a subset of subjects with HPS who had ILD but not subjects without lung disease or normal control subjects. The blood concentration of fibrocytes expressing the chemokine receptor CXCR4 correlated significantly with the plasma concentration of the CXCR4 ligand, CXCL12. In a longitudinal study, we found marked episodic elevations in circulating fibrocyte counts over a median follow-up period of 614 days. Elevations in both maximal values and final values of peripheral blood CXCR41 fibrocyte concentration were strongly associated with death from ILD. Copyright © 2014 by the American Thoracic Society.
Solomon B.D.,Medical Genetics Branch |
Pineda-Alvarez D.E.,Medical Genetics Branch |
Gropman A.L.,Childrens National Medical Center |
Gropman A.L.,George Washington University |
And 4 more authors.
Molecular Syndromology | Year: 2012
Holoprosencephaly is the most common malformation of the forebrain and typically results in severe neurocognitive impairment with accompanying midline facial anomalies. Holoprosencephaly is heterogeneous and may be caused by chromosome aberrations or environmental factors, occur in the context of a syndrome or be due to heterozygous mutations in over 10 identified genes. The presence of these mutations may result in an extremely wide spectrum of severity, ranging from brain malformations incompatible with life to individuals with normal brain findings and subtle midline facial differences. Typically, clinicians regard intellectual disability as a sign that a parent or relative of a severely affected patient may be a mildly affected mutation 'carrier' with what is termed microform holoprosencephaly. Here we present 5 patients with clear phenotypic signs of microform holoprosencephaly, all of whom have evidence of above-average intellectual function. In 4 of these 5 individuals, the molecular cause of holoprosencephaly has been identified and includes mutations affecting SHH, SIX3, GLI2, and FGF8. This report expands the phenotypic spectrum of holoprosencephaly and is important in the counseling of patient and affected families. Copyright © 2012 S. Karger AG, Basel.
Keaton A.A.,Medical Genetics Branch |
Keaton A.A.,Howard Hughes Medical Institute |
Solomon B.D.,Medical Genetics Branch |
Kauvar E.F.,Medical Genetics Branch |
And 20 more authors.
Molecular Syndromology | Year: 2011
Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-β signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE.We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (χ2 (2) = 6.97, p permutated = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients. Copyright © 2011 S. Karger AG, Basel.