scholarly journals Genotype Analysis of Patients with Hereditary Factor X Deficiency Enrolled in 2 Phase 3 Studies of Pdfx, a New High-Purity Factor X Concentrate

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3511-3511 ◽  
Author(s):  
Mike Mitchell ◽  
Kaan Kavakli ◽  
Miranda Norton ◽  
Steve Austin
Keyword(s):  
United States ◽  
United Kingdom ◽  
Board Member ◽  
Splice Site Mutation ◽  
Advisory Board ◽  
Compound Heterozygous ◽  
Factor X ◽  
Site Mutation ◽  
Educational Support ◽  
Compound Heterozygous Mutations

Abstract Introduction: Hereditary factor X (FX) deficiency is a rare, autosomal recessive bleeding disorder of variable severity, with an estimated prevalence of 1:500,000 to 1:1,000,000. Like hemophilia A and B, patients with severe FX deficiency commonly present with bleeding into joints, muscles, or mucous membranes. However, unlike the X-linked disorders of hemophilia A and B, hereditary FX deficiency occurs equally in both sexes due to the location of the FX gene (F10) on chromosome 13q34. A novel, high-purity, high-potency, plasma-derived FX concentrate (pdFX) has been developed for replacement therapy in patients with hereditary FX deficiency. This analysis examines the genotypic and phenotypic characteristics of subjects with hereditary FX deficiency enrolled in 2 prospective, open-label, multicenter phase 3 studies of pdFX. Methods: In study 1, subjects aged ≥12 years with moderate or severe FX deficiency (basal plasma FX activity [FX:C] of ≥1 and <5 IU/dL or <1 IU/dL, respectively) who required treatment with replacement therapy for ≥1 spontaneous or menorrhagic bleed in the past 12 months received pdFX as on-demand treatment or short-term preventative therapy for 6 months to 2 years. In study 2, subjects aged ≥12 years with mild to severe FX deficiency (basal plasma FX:C of <20 IU/dL) with a history of unusual bleeding received pdFX during and after surgery, until no longer at risk of postoperative bleeding. F10 genotyping was performed for each subject and, for study 1, F10 mutations were compared with bleed frequency to assess potential genotype-phenotype associations. Results: Study 1 enrolled 16 subjects (aged 12-58 years [mean 27.1 years], 62.5% female) from the United Kingdom (n=3), Spain (n=4), the United States (n=2), Turkey (n=6), and Germany (n=1); two patients had moderate and 14 had severe FX deficiency. Among the 16 subjects, 13 separate mutations were identified, of which 6 were novel. Nine mutations were missense mutations, 2 were deletions, 1 was a nonsense mutation, and 1 was a splice-site mutation. Consistent with the low FX:C of <5 IU/dL, all subjects either were homozygous for a single mutation (n=11) or had compound heterozygous mutations (n=5). Study 2 enrolled 2 male subjects (ages 55 years [United States] and 59 years [United Kingdom], respectively), both with mild FX deficiency (basal FX:C of 6 and 8 IU/dL, respectively) and compound heterozygous mutations. Of the 4 mutations identified in these 2 patients, 3 were novel. Of the subjects with moderate or severe FX deficiency (study 1), all 6 Turkish subjects had homozygous mutations resulting in an identical amino acid substitution (p.Gly262Asp). Two subjects in Spain and 1 each in the United States and Germany had mutations resulting in an identical amino acid substitution (p.Gly21Arg); one of these Spanish subjects was a compound heterozygote, with an additional missense mutation of p.Cys246Arg, while the other 3 subjects' mutations were homozygous. Two UK subjects were each homozygous for 2 different missense mutations (p.Phe71Ser and p.Ile451Phe, respectively), and the remaining 4 subjects each had unique compound heterozygous mutations (p.Val298Met and p.Tyr384Leufs*57 [United Kingdom], p.Glu350Lys and p.Gly450Arg [Spain], p.Cys57Phe and c.70+4A>G splice site mutation [Spain], and p.Gln411* and exon 2 deletion [United States], respectively). The basal level of expressed FX protein (FX:Ag) in 1 patient (87 U/dL) was within the normal range (73-127 U/dL), whereas FX:Ag levels in all other patients (range, <1-17 U/dL) were below normal. Due to the small numbers of each type of mutation, no conclusions could be drawn regarding the F10 genetic variants and bleed frequency. Each subject with mild FX deficiency (study 2) had unique compound heterozygous mutations (p.Tyr319His and c.71-1G>C splice site mutation [United Kingdom] and p.Cys90Arg and p.Gln416Leu [United States]). Basal FX:Ag levels in these patients (55 and 48 U/dL, respectively) were close to the normal range. Conclusions: In this analysis, 17 separate F10 mutations were identified in 18 subjects with mild to severe hereditary FX deficiency. Of the mutations identified, 9 are novel and have not previously been characterized. Support: Bio Products Laboratory Ltd. Disclosures Mitchell: Viapath: Employment, Other: employee of Viapath, which received funding from Bio Products Laboratory to perform genetic analysis. Kavakli:Baxter: Other: advisory board member and received educational and investigational support; Bayer: Other: advisory board member and received educational and investigational support; Novo Nordisk: Other: advisory board member and received educational and investigational support; Pfizer: Other: advisory board member and received educational and investigational support; Bio Products Laboratory: Other: received educational and investigational support; CSL Behring: Other: received educational and investigational support; Octapharma: Other: received educational and investigational support. Norton:Bio Products Laboratory: Employment. Austin:SOBI: Other: member of advisory board and received educational support; Pfizer: Other: member of advisory board and received educational support; Novo Nordisk: Other: member of advisory board and received educational support; CSL Behring: Other: member of advisory board and received educational support; Bio Products Laboratory: Other: member of advisory board and received educational support; Bayer: Other: member of advisory board and received educational support; Baxter: Other: member of advisory board and received educational support. Off Label Use: ALN-AT3 is an investigational drug for potential treatment of hemophilia. The data represent phase 1 data..

Novel compound heterozygous variants in the LHCGR gene identified in a subject with Leydig cell hypoplasia type 1

2018 ◽  
Vol 31 (2) ◽  
pp. 239-245 ◽  
Author(s):  
Yufei Xu ◽  
Yulin Chen ◽  
Niu Li ◽  
Xuyun Hu ◽  
Guoqiang Li ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Splice Site Mutation ◽  
Molecular Characteristics ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Family Pedigree ◽  
Correlation Spectrum ◽  
Compound Heterozygous Variants ◽  
Leydig Cell Hypoplasia

Abstract Background: Leydig cell hypoplasia (LCH) is a rare disease and one of the causes of male disorder of sexual differentiation (DSD). Inactivating mutations in the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) gene account for the underlying LCH pathogenicity. This study aimed to analyze the clinical presentation and diagnosis as well as highlight the molecular characteristics of a subject with LCH type 1. Case presentation: Clinical data were collected from the subject and analyzed. Next generation sequencing of the immediate family pedigree using peripheral blood genomic DNA was performed, and the relevant mutations were verified with Sanger sequencing. We describe the case of a 5-year-old patient with DSD, presenting with a lateral inguinal hernia accompanied by abnormal hormone tests. The genetic analysis revealed novel compound heterozygous variants in the LHCGR gene, including a splice site mutation (c.681-1 G>A) and a frameshift variant (c.1582_1585del ATAT, p.Ile528*). Conclusions: We identified novel compound heterozygous variants in the LHCGR gene, and expanded the genotype-phenotype correlation spectrum of LHCGR variants.

scholarly journals Cypriot Journal of Educational Sciences: Volume 10, Issue 3, September 2015

2016 ◽  
Vol 10 (3) ◽  
Author(s):  
Assist. Prof. Dr. Cigdem Hursen
Keyword(s):  
United States ◽  
United Kingdom ◽  
United Arab Emirates ◽  
Near East ◽  
Advisory Board ◽  
State University ◽  
Arizona State University ◽  
University Of Technology ◽  
Educational Sciences ◽  
International Advisory

<p>Editor-in-C hief Huseyin Uzunboylu, Near East University, Cyprus [email protected] Tel: +9 0392 6802000 - 110 <br />Executive Editor Cigdem Hursen, Near East University, Cyprus [email protected] Tel: +9 0392 6802000 - 111 <br />Editorial Board Ahmet Güneyli, Near East University, Cyprus Alevriadou Anastasia, University of Western Macedonia, Greece Canan Zeki, Eastern Mediterranean University, Cyprus Gokmen Daglı, Near East University, Cyprus Jesus Garcia Laborda, University of Alcala, Spain Milan Matijevic, University of Zagreb, Croatia Nerguz Bulut Serin, Lefke European University, Cyprus Özge Hacıfazlioglu, Kultur University, Turkey Kobus Maree, Pretoria University, South Africa Owner and Publisher SciencePark Science, Organization and Counseling LTD.</p><p><span>Publisher Contact</span></p><p>SciencePark Science, Organization and Counseling LTD.</p><p><span>13 Subat Street, No: 17, 99030 Kyrenia – Cyprus<span class="apple-converted-space"> </span><br /> E-mail: [email protected]</span></p><p><span>Tel: +90 5338366993 Fax: +90 3928157195</span></p><p><span>www.sproc.org</span></p><p><span>Editorial Contact</span></p><p><span>Cigdem Hursen</span></p><p><span>Near East University,</span></p><p>Faculty of Education Department of Educational Sciences Nicosia, Cyprus [email protected]</p><p><span>Tel. +90 392 6802000 - 111 </span>Sponsor Cypriot Journal of Educational Sciences is an academic journal which is sponsored by Near East University and Cyprus Educational Sciences Association. Frequency 4 issues (March 31, June 30, September 30, and December 31) per year (after May 2009). Technical Staff Meltem Haksiz Vasfi Tugun Basak Baglama Proofreading Academic Proofreading www.academicproofreading.com Cover Design Hasan Ozdal Azmiye Yinal Publishing Language All Manuscripts must be in English language. Abstracting/Indexing Academic Keys, DOAJ, PsycINFO, EBSCO, Ulrich's Educational Research Abstracts (ERA), Georgetown University Library, Asian Education Index, Turkish Education Index, Google Scholar and AWER Index Issue Publishing Date September 2015 International Advisory Board Abdullahi Fido, Kuwait University, Kuwait Ahmet Guneyli, Near East University, Cyprus Aijaz Ahmed Gujjar, Federal College of Education, Pakistan Alison Sheila Taysum, University of Leicester, United Kingdom Asuncion Lopez-Varela, Universidad Complutense, MADRID, Spain Baysen, Engin, Near East University, Cyprus Boaz Shulruf, University of Auckland, New Zealand Chia-Hao Yang, Chaoyang University of Technology, Taiwan Chong Ho Yu, Arizona State University, United States Christian Guetl, Graz University of Technology, Austria Christine E. Corcoran, University of Birmingham, United States Minor Outlying Islands Christine J. Briggs, University of Louisiana at Lafayette, United States Christopher Boyle, Charles Sturt University, Australia Çiğdem Hürsen, Near East University, Cyprus Colette Gray, Stranmillis University College, Ireland Cristina Daskagiani, Greece David Wyss Rudge, Western Michigan University, United States Donald Wilson Zimmerman, Carleton University, Canada Ellina Chernobilsky, Caldwell College, United States Evridiki Zachopoulou, Democritus University of Thrace, Greece Giuliana Dettori, ITD-CNR, Italy Helen Gunter, University of Manchester, United Kingdom Hüseyin Uzunboylu, Near East University, Cyprus Jafar Yaghoubi, Zanjan University, Iran, Islamic Republic Of Jere T. Humphreys, Arizona State University, United States John CK Wang, National Institute of Education, Singapore John Cowan, Edinburgh Napier University, United Kingdom Josie Maria Rodriguez Corral, University of Cádiz (Spain), Spain Kanji Akahori, Hakuoh University, Japan Madhumita Bhattacharya, Athabasca University &amp; Massey University, Canada Margaret Zeegers, University of Ballarat, Australia Marissa Silverman, Montclair State University, United States Muammer Caltik, Blacksea Techical University, Turkey Murat Tezer, Near East University, Cyprus Nadire Cavus, Near East University, Cyprus Othman Alsawaie, United Arab Emirates University, United Arab Emirates Ozge Hacifazlioglu, Bahcesehir University, Turkey Paulo Jorge Santos, Faculty of Arts, Porto University, Portugal Sirin Karadeniz, Bahcesehir University, Turkey Note: All members of international advisory board articles' indexed in SSCI. Important Information During review process we use iThenticate plagiarism software. So, it is recommended to the authors should scan with iThenticate plagiarism or other free plagiarism software of their manuscripts. © 2015 SciencePark Science, Organization and Counseling LTD. All rights reserved. The ideas published in the journal belong to the authors. Important Announcement We would like to announce that Cypriot Journal of Educational Sciences will only be published online from 1 September 2015. There will not be a printed version (ISSN: 1305-9076) of the journal.</p><p><br /><br /></p><p><span><br /></span></p><p> </p>

scholarly journals Cypriot Journal of Educational Sciences: Volume 10, Issue 4, December 2015

2016 ◽  
Vol 10 (4) ◽  
Author(s):  
Cigdem Hursen
Keyword(s):  
United States ◽  
United Kingdom ◽  
United Arab Emirates ◽  
Near East ◽  
Advisory Board ◽  
State University ◽  
Arizona State University ◽  
University Of Technology ◽  
Educational Sciences ◽  
International Advisory

<p>Editor-in-Chief Huseyin Uzunboylu, Near East University, Cyprus [email protected] Tel: +9 0392 6802000 - 110 Executive Editor Cigdem Hursen, Near East University, Cyprus [email protected] Tel: +9 0392 6802000 - 111 Editorial Board Ahmet Güneyli, Near East University, Cyprus Alevriadou Anastasia, University of Western Macedonia, Greece Canan Zeki, Eastern Mediterranean University, Cyprus Gokmen Daglı, Near East University, Cyprus Jesus Garcia Laborda, University of Alcala, Spain Milan Matijevic, University of Zagreb, Croatia Nerguz Bulut Serin, Lefke European University, Cyprus Özge Hacıfazlioglu, Kultur University, Turkey Kobus Maree, Pretoria University, South Africa Owner and Publisher SciencePark Science, Organization and Counseling LTD.<br />Publisher Contact<br />SciencePark Science, Organization and Counseling LTD.<br />13 Subat Street, No: 17, 99030<br />Kyrenia – Cyprus<br />E-mail: [email protected]<br />Tel: +90 5338366993<br />Fax: +90 3928157195 www.sproc.org<br />Editorial Contact<br />Cigdem Hursen<br />Near East University, Faculty of Education<br />Department of Educational Sciences<br />Nicosia, Cyprus<br />[email protected]<br />Tel. +90 392 6802000 - 111 Sponsor Cypriot Journal of Educational Sciences is an academic journal which is sponsored by Near East University and Cyprus Educational Sciences Association. Frequency 4 issues (March 31, June 30, September 30, and December 31) per year (after May 2009). Technical Staff Meltem Haksiz Vasfi Tugun Basak Baglama Proofreading Academic Proofreading www.academicproofreading.com Cover Design Hasan Ozdal Azmiye Yinal Publishing Language All Manuscripts must be in English language. Abstracting/Indexing Academic Keys, DOAJ, PsycINFO, EBSCO, Ulrich's Educational Research Abstracts (ERA), Georgetown University Library, Asian Education Index, Turkish Education Index, Google Scholar and AWER Index Issue Publishing Date 31 December 2015 International Advisory Board Abdullahi Fido, Kuwait University, Kuwait Ahmet Guneyli, Near East University, Cyprus Aijaz Ahmed Gujjar, Federal College of Education, Pakistan Alison Sheila Taysum, University of Leicester, United Kingdom Asuncion Lopez-Varela, Universidad Complutense, MADRID, Spain Baysen, Engin, Near East University, Cyprus Boaz Shulruf, University of Auckland, New Zealand Chia-Hao Yang, Chaoyang University of Technology, Taiwan Chong Ho Yu, Arizona State University, United States Christian Guetl, Graz University of Technology, Austria Christine E. Corcoran, University of Birmingham, United States Minor Outlying Islands Christine J. Briggs, University of Louisiana at Lafayette, United States Christopher Boyle, Charles Sturt University, Australia Çiğdem Hürsen, Near East University, Cyprus Colette Gray, Stranmillis University College, Ireland Cristina Daskagiani, Greece David Wyss Rudge, Western Michigan University, United States Donald Wilson Zimmerman, Carleton University, Canada Ellina Chernobilsky, Caldwell College, United States Evridiki Zachopoulou, Democritus University of Thrace, Greece Giuliana Dettori, ITD-CNR, Italy Helen Gunter, University of Manchester, United Kingdom Hüseyin Uzunboylu, Near East University, Cyprus Jafar Yaghoubi, Zanjan University, Iran, Islamic Republic Of Jere T. Humphreys, Arizona State University, United States John CK Wang, National Institute of Education, Singapore John Cowan, Edinburgh Napier University, United Kingdom Josie Maria Rodriguez Corral, University of Cádiz (Spain), Spain Kanji Akahori, Hakuoh University, Japan Madhumita Bhattacharya, Athabasca University &amp; Massey University, Canada Margaret Zeegers, University of Ballarat, Australia Marissa Silverman, Montclair State University, United States Muammer Caltik, Blacksea Techical University, Turkey Murat Tezer, Near East University, Cyprus Nadire Cavus, Near East University, Cyprus Othman Alsawaie, United Arab Emirates University, United Arab Emirates Ozge Hacifazlioglu, Bahcesehir University, Turkey Paulo Jorge Santos, Faculty of Arts, Porto University, Portugal, Portugal Sirin Karadeniz, Bahcesehir University, Turkey Note: All members of international advisory board articles' indexed in SSCI. Important Information During review process we use iThenticate plagiarism software. So, it is recommended to the authors should scan with iThenticate plagiarism or other free plagiarism software of their manuscripts. © 2015 SciencePark Science, Organization and Counseling LTD. All rights reserved. The ideas published in the journal belong to the authors. Important Announcement We would like to announce that Cypriot Journal of Educational Sciences will only be published online from 1 September 2015. There will not be a printed version (ISSN: 1305-9076) of the journal.</p>

scholarly journals Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany

2000 ◽  
Vol 85 (3) ◽  
pp. 1059-1065 ◽  
Author(s):  
Nils Krone ◽  
Andreas Braun ◽  
Adelbert Anton Roscher ◽  
Dietrich Knorr ◽  
Hans Peter Schwarz
Keyword(s):  
Splice Site ◽  
Splice Site Mutation ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Severe Mutation ◽  
Heterozygous Form ◽  
21 Hydroxylase Deficiency ◽  
Intron 2

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppvnull) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppvA to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppvB was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppvC was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.

A Common Splice Site Mutation Is Shared by Two Families with Different Type 2N von Willebrand Disease Mutations

1999 ◽  
Vol 82 (09) ◽  
pp. 1061-1064 ◽  
Author(s):  
Kingsley Hampton ◽  
F. Eric Preston ◽  
Ian Peake ◽  
Anne Goodeve ◽  
I. Mandy Nesbitt
Keyword(s):  
Splice Site ◽  
Direct Sequencing ◽  
Splice Site Mutation ◽  
Von Willebrand Disease ◽  
The Other ◽  
Compound Heterozygous ◽  
Site Mutation ◽  
Disease Mutations ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryUsing an ELISA-based method to detect type 2N von Willebrand disease (VWD), we found two individuals with absent FVIII binding. Direct sequencing of the FVIII binding region of the von Willebrand factor (VWF) gene showed that one individual had an R854Q substitution whilst the other had a T791M substitution. The very low FVIII binding and the VWF:Ag levels in both individuals suggested a second defect on the other VWF allele. Conformation sensitive gel electrophoresis of polymerase chain reaction amplified DNA was used to detect an additional change in the VWF gene of each patient. Direct sequencing confirmed a previously unreported G to A transition in the donor splice site in intron 25 of both individuals which should result in a null allele. This was confirmed by mRNA analysis. These two individuals therefore have compound heterozygous VWD in which the only expressed allele has a type 2N mutation. In our population, such compound heterozygosity appears to be a significant cause of type 2N VWD.

scholarly journals Novel mutations of the POLR3A gene caused POLR3-related leukodystrophy in a Chinese family: a case report

2019 ◽  
Author(s):  
Shuiyan Wu ◽  
Zhenjiang Bai ◽  
Xingqiang Dong ◽  
Daoping Yang ◽  
Hongmei Chen ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Rna Polymerase Iii ◽  
Onset Time ◽  
Splice Site Mutation ◽  
Female Child ◽  
Chinese Family ◽  
Compound Heterozygous ◽  
Heterozygous Carrier ◽  
Site Mutation ◽  
High Coverage

Abstract Background: POLR3-related leukodystrophy is an autosomal recessive neurodegenerative disorder characterized by onset time ranging from the neonatal period to late childhood, progressive motor decline that manifests as spasticity, ataxia, tremor, and cerebellar symptoms, as well as mild cognitive regression and hypodontia. POLR3-related leukodystrophy belongs to the family of RNA polymerase III-related leukodystrophy, which are caused by biallelic mutations in the POLR3A, POLR3B, POLRC1, or POLR3K genes. Case presentation: In this study, we report a female child with POLR3-related leukodystrophy manifesting as cognitive decline, moderate dysarthria, motor decline, cerebellar syndrome, short stature, dysphagia, hypodontia, and mild delayed myelination by brain imaging. Interestingly, polytrichia and bronchodysplasia were first observed in a POLR3-related leukodystrophy patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the POLR3A gene, c.1771-6C>G and c.2611del (p.M871Cfs*8), were detected. One of them is an uncommon splice site mutation, and this is the first report of this mutation in a Chinese family. The father was determined to be a heterozygous carrier of the c.2611del (p.M871Cfs*8) mutation and the mother a heterozygous carrier of the c.1771-6C>G mutation. Conclusion: The patient’s newly emerged clinical features and mutations provide useful information for further exploration of genotype-phenotype correlations of POLR3-related leukodystrophy.

scholarly journals Multiple neoplasia in a patient with Gitelman syndrome harboring germline monoallelic MUTYH mutation

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Jason Yongsheng Chan ◽  
Ming Ren Toh ◽  
Siao Ting Chong ◽  
Nur Diana Binte Ishak ◽  
Arun Mouli Kolinjivadi ◽  
...  
Keyword(s):  
Oxidative Dna Damage ◽  
Magnesium Deficiency ◽  
Splice Site Mutation ◽  
Gitelman Syndrome ◽  
Compound Heterozygous ◽  
Inherited Disease ◽  
Site Mutation ◽  
Colorectal Polyposis ◽  
Recurrent Breast

Abstract Gitelman syndrome is a rare, recessively inherited disease characterized by chronic hypokalemia and hypomagnesemia as a result of defective electrolyte co-transport at the level of the distal convoluted tubule of the kidney. Here, we present the first report of a patient with Gitelman syndrome who developed multiple neoplasia including colorectal polyposis, synchronous colorectal cancers, recurrent breast fibroadenomata and a desmoid tumor. Whole-exome sequencing confirmed germline compound heterozygous mutations of c.179C > T and c.1326C > G in SLC12A3, and in addition, identified a monoallelic germline c.934-2A > G splice site mutation in MUTYH. In vitro, magnesium deficiency potentiated oxidative DNA damage in lymphoblastoid cell lines derived from the same patient. We postulate that monoallelic MUTYH mutations may manifest in the presence of cooperative non-genetic mechanisms, in this case possibly magnesium deficiency from Gitelman syndrome.

Compound-Heterozygous Mutations in the Plasminogen Gene Predispose to the Development of Ligneous Conjunctivitis

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3457-3466 ◽  
Author(s):  
Volker Schuster ◽  
Silvia Seidenspinner ◽  
Petra Zeitler ◽  
Cornelia Escher ◽  
Uwe Pleyer ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Residual Activity ◽  
Compound Heterozygous ◽  
Type I ◽  
Activity Levels ◽  
Missense Mutations ◽  
Site Mutation ◽  
Ligneous Conjunctivitis ◽  
Compound Heterozygous Mutations ◽  
Compound Heterozygotes

Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 → Glu/Arg513 → His, Lys19 → Glu/Arg216 → His, and Lys19 → Glu/Leu128 → Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (&lt;0.4 mg/dL and &lt;5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity.

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