DOCSLIB.ORG

Expanded Genetic Screening Panel for the Ashkenazi Jewish Population

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Expanded Genetic Screening Panel for the Ashkenazi Jewish Population ORIGINAL RESEARCH ARTICLE © American College of Medical Genetics and Genomics Expanded genetic screening panel for the Ashkenazi Jewish population Brett Baskovich, MD1, Susan Hiraki, MS, MPH2, Kinnari Upadhyay, MS2, Philip Meyer2, Shai Carmi, PhD3, Nir Barzilai, MD2, Ariel Darvasi, PhD4, Laurie Ozelius, PhD5, Inga Peter, PhD5, Judy H. Cho, MD5, Gil Atzmon, PhD2,6, Lorraine Clark, PhD7, Jin Yu, PhD8, Todd Lencz, PhD8, Itsik Pe’er, PhD9, Harry Ostrer, MD1,2, and Carole Oddoux, PhD1,2 Purpose: Carrier screening programs that identify the presence of American College of Medical Genetics and Genomics scoring known mutations have been effective for reducing the incidence of (ACMG) system. Other known mutations were identified through autosomal recessive conditions in the Ashkenazi Jewish (AJ) popu- literature review. lation and other populations. Yet, these programs have not realized Results: A panel of 163 mutations was identified for 76 autosomal their full potential. Furthermore, many known autosomal recessive recessive, 24 autosomal dominant, and 3 X-linked disorders. and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is Conclusion: Screening for a broader range of disorders not only unknown. could further reduce the incidence of autosomal recessive disorders Methods: Through literature review and annotation of full but also could offer the benefits of early or presymptomatic diagnosis. sequenced genomes from healthy individuals, we expanded the list Genet Med advance online publication 3 September 2015 of mutations. Mutations were identified in a sample of 128 fully sequenced AJ genomes that were filtered through clinical data- Key Words: Ashkenazi Jews; carrier screening; genetic testing; vari- bases and curated manually for clinical validity and utility using the ant annotation; whole genome sequencing INTRODUCTION prevalent in the Ashkenazi Jewish (AJ) population. Ethnicity- Population-based genetic screening is a valuable application of based carrier screening programs in this and other populations genomic technology that can have significant clinical and pub- have been successful in decreasing the incidence of autosomal lic health benefits. Presymptomatic detection of disease and recessive conditions.1 The best-known example is Tay-Sachs dis- identification of increased disease risk provide the opportunity ease, a severe, progressive neurodegenerative disorder caused for early diagnosis, intervention, or prevention. Identification by a defect in hexosaminidase A enzyme activity. Beginning of genetic carrier status provides the opportunity for reproduc- in 1970, Tay-Sachs carrier screening in AJ individuals was the tive counseling and family planning, allowing for the preven- first population-based public health initiative aimed at decreas- tion of the birth of an affected child or for early diagnosis and ing the incidence of a lethal genetic disease. This coordinated intervention.1 Many population-based screening programs tar- effort, which included education, genetic counseling, and vol- get specific populations, such as newborns, particular ethnic untary screening, was adopted throughout the United States as groups, or those deemed to be at increased risk for certain dis- well as internationally. Within 30 years of its inception, the pro- eases. With the advancement of genetic technologies, such as gram was successful in decreasing the incidence of Tay-Sachs multiplex testing to conduct high-throughput genotyping of a disease by more than 90% in the AJ populations of the United multitude of variants, there has been an expansion in the num- States and Canada.1 In addition to Tay-Sachs disease, there are ber of diseases that can be screened for in the predisposition, many other recessive disorders that occur more commonly in presymptomatic, and carrier states. Selecting conditions to the AJ population, and many laboratories now offer genetic include on a population-based screening panel and even select- carrier panels aimed at those of AJ ethnicity. The American ing the criteria to make this decision are still active questions. College of Medical Genetics and Genomics (ACMG) and the Founder effects, in combination with endogamy and pos- American College of Obstetricians and Gynecologists have set sible selection, have made some Mendelian conditions more forth recommendations for conditions that should be included B.B. is the first author. S.H. and K.U. are co-first authors. 1Department of Pathology, Montefiore Medical Center, New York, New York, USA; 2Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, New York, New York, USA; 3The Faculty of Medicine, Braun School of Public Health, Hebrew University of Jerusalem, Jerusalem, Israel; 4Department of Genetics, Hebrew University of Jerusalem, Givat Ram, Jerusalem; 5Department of Genetics, Icahn School of Medicine at Mount Sinai School of Medicine, New York, New York, USA; 6Faculty of Natural Science, University of Haifa, Haifa, Israel; 7Department of Pathology, Columbia University, New York, New York, USA; 8The Feinstein Institute for Medical Research, Manhasset, New York, USA; 9Department of Computer Science, Columbia University, New York, New York, USA. Correspondence: Harry Ostrer ([email protected]) Submitted 10 December 2014; accepted 22 July 2015; advance online publication 3 September 2015. doi:10.1038/gim.2015.123 522 Volume 18 | Number 5 | May 2016 | GeneticS in medicine Expanded Ashkenazi panel | BASKOVICH et al ORIGINAL RESEARCH ARTICLE on an AJ panel.2 Despite these recommendations, there are dif- studies (Supplementary Figure S1 online). A recent study that ferences between what is recommended and what is offered by performed whole-exome sequencing on 6,517 European and laboratories, as well as differences among the various labora- African Americans suggested that 45% of individuals carry at tories. In a multi-ethnic study of screening 23,000 individuals least one mutation in genes included on newborn screens.9 for 400+ Mendelian variants, including variants found among We recently sequenced 128 AJ individuals (The Ashkenazi AJ, this ethnic group was the most likely to have carriers of Genome Consortium data set, or “TAGC dataset”) and estab- serious recessive disorders. Many of these disorders were not lished a list of previously known and new mutations.10 Here we included on the ACMG or American College of Obstetricians address the pathogenicity of the newly identified mutations and and Gynecologists lists of recommendations.2 In addition, the the clinical utility of screening for them. AJ community has generally been supportive of carrier screen- ing for severe disorders and expansion beyond what is currently MATERIALS AND METHODS recommended. Therefore, expanding current AJ screening DNA samples were collected from 128 individuals who were panels to include more conditions appears justified. disease-free and were verified by principal component analysis In addition to carrier screening panels, there are a growing to have AJ origin, as we recently described.10 DNA sequenc- number of predisposition genetic screening panels that identify ing was performed by complete genomics (CG) and annotated those at increased risk for future disease. Currently, the targeted using the reference genome version hg19.10 population tends to be those already deemed to be at increased ClinVar and OMIM, publicly available genetic databases that risk due to their family history of disease. Cancer risk assess- catalog genotypes and phenotypes, were scanned via a custom ment represents an application of predisposition screening that web crawler to identify variants associated with phenotypes.11 provides the opportunity for prevention and early diagnosis to Of the 2,434 variants that were identified from sequencing 128 decrease risk.3 One such example is BRCA1/2 screening, which AJ individuals, 80 variants were reported by ClinVar or OMIM serves as a paradigm for high-risk, population-based screening. as “pathogenic” or “possibly pathogenic.” These variants were With an increasing number of disease risk variants being dis- curated manually by at least two independent reviewers through covered, genetic risk assessment for adult-onset conditions will literature review and assigned a score based on the ACMG scor- continue to grow.4 Some who might benefit from genetic risk ing system. An additional 56 variants were scored as “patho- assessment may escape attention due to incomplete penetrance, genic, very strong” using the ACMG system. Factors considered sex-limited expression, and lack of or limited personal and/ were number of patients, number of controls, association with or family history.5 Extending predisposition screening beyond other mutations, and functional studies (Supplementary those who meet standard high-risk criteria should have clinical Table S1 online).8 Those determined to be pathogenic or likely utility, especially when offered in multiplex format. pathogenic were further reviewed for individual clinical utility As the number of disease variants grows and technological and frequency of the variant and then confirmed for their pres- advances improve ease and efficiency of detection, criteria are ence in the AJ population using orthogonal whole genome (315 needed against which to judge the merits of adding new genetic subjects) or whole exome Illumina sequencing (640 subjects). tests. In 1968, Wilson and Jungner delineated the principles of Calculations
Load more

Recommended publications
  • Mishpacha-Article-February-2011.Pdf
    HANGING ON BY A FRINGCOLONE:EL MORDECHAI FRIZIS’S MEMBERS COURAG THEEOUS LA SRESPONSET ACT OF THE TRIBE? FOR HIS COUNTRY OPEN MIKE FOR HUCKABEE SWEET SONG OF EMPATHY THE PRESIDENTIAL HOPEFUL ON WHAT FUELED HIS FIFTEENTH TRIP TO ISRAEL A CANDID CONVERSATION WITH SHLOIME DACHS, CHILD OF A “BROKEN HOME” LIFEGUARD AT THE GENE POOL HIS SCREENING PROGRAM HAS SPARED THOUSANDS FROM THE HORROR OF HIS PERSONAL LOSSES. NOW DOR YESHORIM’S RABBI YOSEF EKSTEIN BRAVES THE STEM CELL FRONTIER ON-SITE REPORT RAMALLAHEDUCATOR AND INNOVATOR IN RREALABBI YAAKOV TIME SPITZER CAN THES P.TILLA. FORM LIVA FISCESALLY RSOUNDAV STATE?WEI SSMANDEL’S WORDS familyfirst ISSUE 346 I 5 Adar I 5771 I February 9, 2011 PRICE: NY/NJ $3.99 Out of NY/NJ $4.99 Canada CAD $5.50 Israel NIS 11.90 UK £3.20 INSIDE The Gene Marker's Rabbi Yosef Ekstein of Dor Yeshorim Vowed that No Couple Would Know His Pain Bride When Rabbi Yosef Ekstein’s fourth Tay-Sachs baby was born, he knew he had two options – to fall into crushing despair, or take action. “The Ribono Shel Olam knew I would bury four children before I could take my self-pity and turn it outward,” Rabbi Ekstein says. But he knew nothing about genetics or biology, couldn’t speak English, and didn’t even have a high school diploma. How did this Satmar chassid, a shochet and kashrus supervisor from Argentina, evolve into a leading expert in the field of preventative genetic research, creating an Bride international screening program used by most people in shidduchim today? 34 5 Adar I 5771 2.9.11 35 QUOTES %%% Rachel Ginsberg His father, Rabbi Kalman Eliezer disease and its devastating progression, as Photos: Meir Haltovsky, Ouria Tadmor Ekstein, used to tell him, “You survived by the infant seemed perfect for the first half- a miracle.
    [Show full text]
  • Open Full Page
    CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders.
    [Show full text]
  • The Role of Z-Disc Proteins in Myopathy and Cardiomyopathy
    International Journal of Molecular Sciences Review The Role of Z-disc Proteins in Myopathy and Cardiomyopathy Kirsty Wadmore 1,†, Amar J. Azad 1,† and Katja Gehmlich 1,2,* 1 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; [email protected] (K.W.); [email protected] (A.J.A.) 2 Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford, Oxford OX3 9DU, UK * Correspondence: [email protected]; Tel.: +44-121-414-8259 † These authors contributed equally. Abstract: The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.
    [Show full text]
  • Oxalate Loading Test: a Screening Test for Steatorrhoea
    Gut: first published as 10.1136/gut.20.12.1089 on 1 December 1979. Downloaded from Gut, 1979, 20, 1089-1094 Oxalate loading test: a screening test for steatorrhoea D. S. RAMPTON', G. P. KASIDAS, G. ALAN ROSE, AND MARTIN SARNER2 From University College Hospital, London, St. Peter's Hospitals and Institute of Urology, London SUMMARY To investigate the possibility of measuring urinary oxalate output instead of faecal fat excretion as an outpatient screening test for steatorrhoea, we determined 24 hour urinary oxalate and five day faecal fat excretion before and during an oral load of sodium oxalate 600 mg daily (oxalate 4-44 mmol), in 32 patients with suspected malabsorption on a diet containing oxalate 30 mg (0-33 mmol), fat 50 g (180 mmol), and calcium 1 g (25 mmol). Nineteen patients proved to have steatorrhoea (mean faecal fat 62 mmol/24 h, range 19-186 mmol) of varying aetiologies. On the diet alone, urinary oxalate was raised in only nine of these patients (mean 0 25 mmol/24 h, range 0-08-059 mmol) (normal <0 20). By contrast, when the diet was supplemented with oral sodium oxalate, all 19 patients with steatorrhoea had hyperoxaluria (mean 0-91 mmol/24 h, range 046- 1P44 mmol) (normal <0-44). There was a significant positive linear relationship between urinary oxalate and faecal fat when the 32 patients were on the high oxalate intake (r=0*73, P <0.001), but not when they were on the low oxalate intake. Mean percentage absorption of orally administered oxalate was 58+09% (±1 SD) in normal subjects and 14-7+6-0% (P <0.002) in patients with steatorrhoea.
    [Show full text]
  • CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions Christopher C
    CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions Christopher C. Porter1, Todd E. Druley2, Ayelet Erez3, Roland P. Kuiper4, Kenan Onel5, Joshua D. Schiffman6, Kami Wolfe Schneider7, Sarah R. Scollon8, Hamish S. Scott9, Louise C. Strong10, Michael F. Walsh11, and Kim E. Nichols12 Abstract Leukemia, the most common childhood cancer, has long been patients. The panel recognized that for several conditions, recognized to occasionally run in families. The first clues about routine monitoring with complete blood counts and bone the genetic mechanisms underlying familial leukemia emerged marrow evaluations is essential to identify disease evolution in 1990 when Li-Fraumeni syndrome was linked to TP53 muta- and enable early intervention with allogeneic hematopoietic tions. Since this discovery, many other genes associated with stem cell transplantation. However, for others, less intensive hereditary predisposition to leukemia have been identified. surveillance may be considered. Because few reports describ- Although several of these disorders also predispose individuals ing the efficacy of surveillance exist, the recommendations to solid tumors, certain conditions exist in which individuals are derived by this panel are based on opinion, and local expe- specifically at increased risk to develop myelodysplastic syn- rience and will need to be revised over time. The development drome (MDS) and/or acute leukemia. The increasing identifica- of registries and clinical trials is urgently needed to enhance tion of affected individuals and families has raised questions understanding of the natural history of the leukemia-predis- around the efficacy, timing, and optimal methods of surveil- posing conditions, such that these surveillance recommenda- lance.
    [Show full text]
  • Novel Association of Hypertrophic Cardiomyopathy, Sensorineural Deafness, and a Mutation in Unconventional Myosin VI (MYO6)
    309 LETTER TO JMG J Med Genet: first published as 10.1136/jmg.2003.011973 on 1 April 2004. Downloaded from Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6) S A Mohiddin, Z M Ahmed, A J Griffith, D Tripodi, T B Friedman, L Fananapazir, R J Morell ............................................................................................................................... J Med Genet 2004;41:309–314. doi: 10.1136/jmg.2003.011973 amilial hypertrophic cardiomyopathy (FHC) is typically Key points characterised by left ventricular hypertrophy, diastolic Fdysfunction, and hypercontractility, and is often asso- ciated with disabling symptoms, arrhythmias, and sudden N Familial hypertrophic cardiomyopathy (FHC) is typi- death.1 FHC shows both non-allelic and allelic genetic cally confined to a cardiac phenotype and is caused by heterogeneity, and results from any one of more than 100 mutations in genes encoding sarcomeric proteins. mutations in genes encoding sarcomeric proteins.2 Identified Occasionally FHC may be one component of a genes include those encoding b myosin heavy chain, the hereditary multisystem disorder. myosin regulatory and essential light chains, myosin bind- N Sensorineural hearing loss is genetically heteroge- ing protein C, troponin I, troponin C, a cardiac actin, and neous. Mutations in the MYO6 gene, encoding 23 titin. The FHC phenotype is characterised by hypertrophy, unconventional myosin VI, have been found to cause myocyte disarray and fibrosis, and results from the dominant non-syndromic sensorineural hearing loss—that is, negative expression of one of these (mainly missense) sensorineural hearing loss in the absence of any other mutations. The resulting sarcomeric dysfunction leads related clinical features. ultimately, through mechanisms that remain obscure, to pathological left ventricular remodelling.
    [Show full text]
  • Towards Mutation-Specific Precision Medicine in Atypical Clinical
    International Journal of Molecular Sciences Review Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes Tadashi Nakajima * , Shuntaro Tamura, Masahiko Kurabayashi and Yoshiaki Kaneko Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan; [email protected] (S.T.); [email protected] (M.K.); [email protected] (Y.K.) * Correspondence: [email protected]; Tel.: +81-27-220-8145; Fax: +81-27-220-8158 Abstract: Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel- related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterol- ogous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the patho- physiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and Citation: Nakajima, T.; Tamura, S.; paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a Kurabayashi, M.; Kaneko, Y.
    [Show full text]
  • Congenital Chloride Diarrhea in a Bartter Syndrome Misdiagnosed
    Case Report iMedPub Journals Journal of Rare Disorders: Diagnosis & Therapy 2019 www.imedpub.com ISSN 2380-7245 Vol.5 No.2:4 DOI: 10.36648/2380-7245.5.2.196 Congenital Chloride Diarrhea in a Bartter Maria Helena Vaisbich*, Juliana Caires de Oliveira Syndrome Misdiagnosed Brazilian Patient Achili Ferreira, Ana Carola Hebbia Lobo Messa and Abstract Fernando Kok The differential diagnosis in children with hypokalemic hypochloremic alkalosis Department of Pediatric Nephrology, include a group of an inherited tubulopathies, such as Bartter Syndrome (BS) Instituto da Criança, University of São Paulo, and Gitelman Syndrome (GS). However, some of the clinically diagnosed São Paulo, Brasil patients present no pathogenic mutation in BS/GS known genes. Therefore, one can conclude that a similar clinical picture may be caused by PseudoBartter Syndrome (PBS) conditions. PBS include acquired renal problems (ex.: use of diuretics) as well as genetic or acquired extrarenal problems such as cystic *Corresponding author: fibrosis or cyclic vomiting, respectively. The accurate diagnosis of BS/GS needs Maria Helena Vaisbich a rational investigation. First step is to rule out PBS and confirm the primary renal tubular defect. However, it is not easy in some situations. In this sense, Department of Pediatric Nephrology, we reported a patient that was referred to our service with the diagnosis Instituto da Criança, University of São Paulo, of BS, but presented no mutation in BS/GS known genes. The whole-exome São Paulo, Brasil. sequencing detected a SCL26A3 likely pathogenic mutation leading to the final diagnosis of Congenital Chloride Diarrhea (CCD). Reviewing the records, the [email protected] authors noticed that liquid stools were mistaken for urine.
    [Show full text]
  • Clinical Genetics and the Hutterite Brethren
    Clinical Genetics and the Hutterite Brethren: What have we learned in the new millenium? Or: A Micheil Innes MD FRCPC FCCMG Adapted from: Medical Genetics Grand Rounds January 2013 History and Population Hutterite Population Today >40 000 in AB, 30000 MB, ND, SD 1593-1770 1874-1879 25000 Transylvania 1256 migrated to American Prairies 20000 15000 World War I 10000 1565-1592 1770 - 1870 Migration to Canada Moravia5000 Ukraine 0 1500s 1520 1540 1550 1570 1580 1590 1610 1620 1680 1750 1760 1840 1860 1890 1900 1950 1975 1990 Tyrolean Alps Why Identify Genes in this Population? • Direct Benefits to • Benefit to Larger Patients/Families population – Non-invasive – Most of these disorders diagnostic test are not confined to this – Carrier test (*marriage population restrictions) – May allow for diagnosis – ?Prenatal testing of atypical cases – Enhanced understanding of – Expand basic science disease may facilitate and clinical knowledge management or treatment Initial Presentations May be Non-Specific Highlighting Importance of Careful Syndrome Delineation and Early Genetic Diagnosis • Hearing Loss – Autosomal recessive non-syndromic hearing loss (> 2loci) – Usher syndrome (> 2loci) – HDR syndrome • Cerebellar Ataxia – Joubert syndrome – DES syndrome – DCMA syndrome – CASS syndrome • Muscular Dystrophy/ High CK – LGMD2H – LGDM2I – AR EDMD – Myopathy with CPEO – Microcephaly with Chorea Genetic services and the Hutterites Religion/Culture • Has posed little barrier overall • Very accepting of medical care and technology • Although they believe that God plays a day to day role in guiding their lives, most couples accept genetic explanations for their children’s disorders • Some leuts and individual colonies are more conservative than others • Colony leader is clearly the Minister • Who speaks for the overall community when it comes to community wide issues? – e.g.
    [Show full text]
  • Pseudo-Bartter Syndrome As the Initial Presentation of Cystic Fibrosis in Infants: a Paediatrics Section Paediatrics Series of Three Cases and Review of Literature
    DOI: 10.7860/JCDR/2018/36189.11965 Case Series Pseudo-bartter Syndrome as the Initial Presentation of Cystic Fibrosis in Infants: A Paediatrics Section Paediatrics Series of Three cases and Review of Literature PRAWIN KUMAR1, NEERAJ GUPTA2, DAISY KHERA3, KULDEEP SINGH4 ABSTRACT Cystic Fibrosis (CF) is predominantly a disease of Caucasians, but it is increasingly being recognised in India. The typical presentations of CF are recurrent pneumonia and malabsorption. Atypical presentations are also increasingly being reported from India due to the differences in genotype and environmental factors. Pseudo-Bartter syndrome (PBS) is one of these atypical presentations which can present at any time after the diagnosis of CF but its presentation as an initial manifestation is rare. We hereby report three infants who presented with dehydration without obvious external losses. The investigations revealed metabolic alkalosis with hypochloraemia. A stepwise approach towards metabolic alkalosis revealed possibility of cystic fibrosis which was confirmed by sweat chloride test. All infants completely recovered with initial fluid and electrolyte therapy, following which supportive therapy for CF was started and subsequently they were discharged from the hospital. Keywords: Hypochloraemia, Metabolic alkalosis, Pseudo-Bartter Syndrome CASE SERIES sweat chloride test was not available at our centre so they were sent In this case series, we have described three infants in the age group to paediatric pulmonology division, AIIMS, New Delhi where sweat of 5-10 months from western Rajasthan, India, who presented with chloride test was performed (pilocarpine iontophoresis method), features of dehydration, without any evidence of obvious external which turned out to be positive (sweat chloride >60 mEq/L) in all fluid loss.
    [Show full text]
  • Blueprint Genetics Primary Hyperoxaluria Panel
    Primary Hyperoxaluria Panel Test code: KI0801 Is a 3 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of hyperoxaluria. About Primary Hyperoxaluria The primary hyperoxalurias are rare disorders of glyoxylate metabolism, which result in markedly increased endogenous oxalate synthesis by the liver. They are characterized by an excess of oxalate resulting in manifestations ranging from occasional renal stones, recurrent nephrolithiasis and nephrocalcinosis to end-stage renal disease (ESRD) and systemic oxalosis. Presenting ranges from the neonatal period to adulthood. Among disorders causing hyperoxaluria, the primary hyperoxalurias are the most severe, ultimately leading to ESRD and if untreated, death in most patients. Type I primary hyperoxaluria (PH1), is caused by deficient or absent activity of liver-specific peroxisomal alanine glyoxylate aminotransferase (AGT). In some patients with PH1 type disease, the enzyme is present but mistargeted to mitochondria where it is metabolically inactive. The severe infantile form is characterized by a failure to thrive, nephrocalcinosis with or without nephrolithiasis and early ESRD. Onset in childhood and adolescence is often characterized by recurrent urolithiasis (with or without nephrocalcinosis) and progressive renal failure. The late onset form is characterized by occasional renal stones with onset in adulthood, but acute renal failure caused by bilateral obstruction of the kidneys by oxalate stones may occur. Other manifestations include urinary tract infections, dysuria and hematuria. The ongoing systemic oxalosis also may lead to other clinical manifestations such as cardiac conduction defects, vascular calcification with distal gangrene, disturbed vision, specific brown colored retinal deposits, skin nodules, joint involvement and bone disease leading to fractures in long-term dialysis-dependent patients.
    [Show full text]
  • Hypokalemic Periodic Paralysis - an Owner's Manual
    Hypokalemic periodic paralysis - an owner's manual Michael M. Segal MD PhD1, Karin Jurkat-Rott MD PhD2, Jacob Levitt MD3, Frank Lehmann-Horn MD PhD2 1 SimulConsult Inc., USA 2 University of Ulm, Germany 3 Mt. Sinai Medical Center, New York, USA 5 June 2009 This article focuses on questions that arise about diagnosis and treatment for people with hypokalemic periodic paralysis. We will focus on the familial form of hypokalemic periodic paralysis that is due to mutations in one of various genes for ion channels. We will only briefly mention other �secondary� forms such as those due to hormone abnormalities or due to kidney disorders that result in chronically low potassium levels in the blood. One can be the only one in a family known to have familial hypokalemic periodic paralysis if there has been a new mutation or if others in the family are not aware of their illness. For more general background about hypokalemic periodic paralysis, a variety of descriptions of the disease are available, aimed at physicians or patients. Diagnosis What tests are used to diagnose hypokalemic periodic paralysis? The best tests to diagnose hypokalemic periodic paralysis are measuring the blood potassium level during an attack of paralysis and checking for known gene mutations. Other tests sometimes used in diagnosing periodic paralysis patients are the Compound Muscle Action Potential (CMAP) and Exercise EMG; further details are here. The most definitive way to make the diagnosis is to identify one of the calcium channel gene mutations or sodium channel gene mutations known to cause the disease. However, known mutations are found in only 70% of people with hypokalemic periodic paralysis (60% have known calcium channel mutations and 10% have known sodium channel mutations).
    [Show full text]