226 results on '"Obligate carrier"'
Search Results
2. Living Kidney Donation in a Type 1 Dent’s Disease Patient from His Mother
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Giovanni Gambaro, Alessandro Naticchia, Pietro Manuel Ferraro, Gionata Spagnoletti, Jacopo Romagnoli, Maria Paola Salerno, and Franco Citterio
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dent’s disease ,kidney transplantation ,living donation ,obligate carrier ,Dermatology ,RL1-803 ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Introduction: Dent’s disease is a rare X-linked recessive disorder that manifests in childhood or early adulthood and can lead to end-stage renal disease (ESRD). It occurs in males, who are hemizygous. In patients who develop ESRD, a deceased donor kidney transplant cures the disease. Females are obligate carriers of the mutated gene, and some show a mild Dent’s disease phenotype. There may be reason for concern when considering a female obligate carrier (i.e., the mother) for kidney donation because of the risk of kidney function deterioration. Case Presentation: We describe the first successful kidney transplantation involving a patient with type 1 Dent’s disease and ESRD given a kidney by an obligate carrier of the gene mutation, his mother. Conclusions: After careful assessment of the female obligate carriers, intrafamilial kidney donation in Dent’s disease type 1 is feasible. No deteriorating renal function in the donor was observed.
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- 2019
- Full Text
- View/download PDF
3. Living Kidney Donation in a Type 1 Dent's Disease Patient from His Mother.
- Author
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Gambaro, Giovanni, Naticchia, Alessandro, Ferraro, Pietro Manuel, Spagnoletti, Gionata, Romagnoli, Jacopo, Salerno, Maria Paola, and Citterio, Franco
- Subjects
- *
CHRONIC kidney failure , *KIDNEYS , *KIDNEY transplantation , *MOTHERS - Abstract
Introduction: Dent's disease is a rare X-linked recessive disorder that manifests in childhood or early adulthood and can lead to end-stage renal disease (ESRD). It occurs in males, who are hemizygous. In patients who develop ESRD, a deceased donor kidney transplant cures the disease. Females are obligate carriers of the mutated gene, and some show a mild Dent's disease phenotype. There may be reason for concern when considering a female obligate carrier (i.e., the mother) for kidney donation because of the risk of kidney function deterioration. Case Presentation: We describe the first successful kidney transplantation involving a patient with type 1 Dent's disease and ESRD given a kidney by an obligate carrier of the gene mutation, his mother. Conclusions: After careful assessment of the female obligate carriers, intrafamilial kidney donation in Dent's disease type 1 is feasible. No deteriorating renal function in the donor was observed. [ABSTRACT FROM AUTHOR]
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- 2019
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- View/download PDF
4. Whole-genome amplification/preimplantation genetic testing for propionic acidemia of successful pregnancy in an obligate carrier Mexican couple: A case report
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Miguel Angel Alcántara-Ortigoza, Nestor Alejandro Zarate Díaz, Leonardo M. Porchia, Adina Neumann, Esther López-Bayghen, Javier Sam Santana, and Ariadna González-del Angel
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Genetics ,Whole Genome Amplification ,congenital, hereditary, and neonatal diseases and abnormalities ,Preimplantation genetic testing ,medicine.diagnostic_test ,business.industry ,Autosomal recessive ,nutritional and metabolic diseases ,Case Report ,Embryo transfer ,General Medicine ,Propionic acidemia ,Successful pregnancy ,medicine.disease ,DNA sequencing ,Propionyl-CoA carboxylase alpha subunit (PCCA) gene ,Obligate carrier ,Next-generation sequencing ,medicine ,business ,Genetic testing - Abstract
BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities' current methodology for screening, which focuses on the detecting multiple genetic disorders at once. Here, we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects (PGT-M) approach for detecting propionic acidemia (PA) in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit (PCCA) couple. CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling. They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit (PCCB) genotype. Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant (c.2041-1G>T, ClinVar:RCV000802701.1; dbSNP:rs1367867218) in both parents. The couple requested in vitro fertilization (IVF) and PGT-M for PA. From IVF, 12 oocytes were collected and fertilized, of which two resulted in high-quality embryos. Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid. End-point polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo. Both embryos were transferred, resulting in a clinical pregnancy and the delivery of a healthy male newborn (38 wk, weight: 4080 g, length: 49 cm, APGAR 9/9). The absence of PA was confirmed by expanded newborn screening. CONCLUSION We show that using PGT-M with Whole Genome Amplification templates, coupled with IVF, can reduce the transmission of a pathogenic variant of the PCCA gene.
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- 2021
5. Genotypic Analysis of X-linked Retinoschisis in Western Australia
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Lamey, Tina, Laurin, Sarina, Chelva, Enid, De Roach, John, Anderson, Robert E., editor, Hollyfield, Joe G., editor, and LaVail, Matthew M., editor
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- 2010
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6. Clinical and Genetic Characterization of a Chinese Family with CSNB1
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Sui, Ruifang, Li, Fengrong, Zhao, Jialiang, Jiang, Ruxin, Back, Nathan, editor, Cohen, Irun R., editor, Abel Lajtha, N.S., editor, Lambris, John D., editor, Paoletti, Rodolfo, editor, Anderson, Robert E., editor, LaVail, Matthew M., editor, and Hollyfield, Joe G., editor
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- 2008
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7. Chromosome 17-linked Frontotemporal dementia with Ubiquitin-Positive, Tau-Negative Inclusions
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Rademakers, Rosa, van der Zee, Julie, Kumar-Singh, Samir, Dermaut, Bart, Cruts, Marc, Van Broeckhoven, Christine, Christen, Yves, editor, Agid, Yves, editor, Aguayo, Albert, editor, Anderton, Brian H., editor, Bartus, Raymond T., editor, Björklund, Anders, editor, Bloom, Floyd, editor, Boller, François, editor, Cotman, Carl, editor, Davies, Peter, editor, Delacourte, André, editor, Ferris, Steven, editor, Foncin, Jean-François, editor, Forette, Françoise, editor, Gage, Fred, editor, Goldgaber, Dmitry, editor, Hardy, John, editor, Hauw, Jean-Jacques, editor, Kordon, Claude, editor, Kosik, Kenneth S., editor, Mallet, Jacques, editor, Masters, Colin L., editor, Rapoport, Stanley I., editor, Reisberg, Barry, editor, Roses, Allen, editor, Selkoe, Dennis J., editor, Shelanski, Michael L., editor, Sinet, Pierre-Marie, editor, George-Hyslop, Peter St., editor, Terry, Robert, editor, Zarifian, Edouard, editor, Cummings, Jeffrey L., editor, and Poncet, Michel, editor
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- 2005
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8. Genetic liability, brain structure and symptoms of schizophrenia
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McIntosh, Andrew, Whalley, Heather, Job, Dominic, Johnstone, Eve, Lawrie, Stephen, Gattaz, Wagner F., editor, and Häfner, Heinz, editor
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- 2004
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9. Ultrasound Imaging and Colour Doppler Studies in Familial Nephropathy Associated with Hyperuricemia (FNAH)
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Prieto, Consuelo, Berrocal, Teresa, Sahota, Amrik, editor, and Taylor, Milton W., editor
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- 1994
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10. The Role of the XMD Dog in the Assessment of Myoblast Transfer Therapy
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Cooper, Barry J., Griggs, Robert C., editor, and Karpati, George, editor
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- 1990
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11. Living Kidney Donation in a Type 1 Dent’s Disease Patient from His Mother
- Author
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Franco Citterio, Alessandro Naticchia, Jacopo Romagnoli, Maria Paola Salerno, Pietro Manuel Ferraro, G. Spagnoletti, and Giovanni Gambaro
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Pediatrics ,medicine.medical_specialty ,lcsh:Diseases of the circulatory (Cardiovascular) system ,030232 urology & nephrology ,obligate carrier ,Renal function ,kidney transplantation ,Dent's disease ,Kidney transplantation ,Living donation ,Obligate carrier ,dent’s disease ,Disease ,Gene mutation ,lcsh:RC870-923 ,Dent’s disease ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Dermatology ,Medicine ,Settore MED/14 - NEFROLOGIA ,Kidney ,Obligate ,business.industry ,living donation ,General Medicine ,lcsh:RL1-803 ,medicine.disease ,lcsh:Diseases of the genitourinary system. Urology ,medicine.anatomical_structure ,Nephrology ,lcsh:RC666-701 ,Cardiology and Cardiovascular Medicine ,business - Abstract
Introduction: Dent’s disease is a rare X-linked recessive disorder that manifests in childhood or early adulthood and can lead to end-stage renal disease (ESRD). It occurs in males, who are hemizygous. In patients who develop ESRD, a deceased donor kidney transplant cures the disease. Females are obligate carriers of the mutated gene, and some show a mild Dent’s disease phenotype. There may be reason for concern when considering a female obligate carrier (i.e., the mother) for kidney donation because of the risk of kidney function deterioration. Case Presentation: We describe the first successful kidney transplantation involving a patient with type 1 Dent’s disease and ESRD given a kidney by an obligate carrier of the gene mutation, his mother. Conclusions: After careful assessment of the female obligate carriers, intrafamilial kidney donation in Dent’s disease type 1 is feasible. No deteriorating renal function in the donor was observed.
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- 2019
12. High cumulative risk of colorectal cancers and desmoid tumours and fibromatosis in South Asian APC mutation carriers
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Shivani Ashar, Anuja Lipsa, Rajiv Sarin, and Nikhat Khan
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genes, APC ,Colorectal cancer ,Adenomatous polyposis coli ,Genetic counseling ,Adenomatous Polyposis Coli Protein ,Fibroma ,030105 genetics & heredity ,Familial adenomatous polyposis ,03 medical and health sciences ,Internal medicine ,Obligate carrier ,Genetics ,Medicine ,Humans ,Codon ,Genetics (clinical) ,Genetic testing ,biology ,medicine.diagnostic_test ,business.industry ,Fibromatosis ,medicine.disease ,digestive system diseases ,Fibromatosis, Aggressive ,030104 developmental biology ,Adenomatous Polyposis Coli ,Aggressive fibromatosis ,Mutation ,biology.protein ,business - Abstract
Management of familial adenomatous polyposis (FAP) is guided by the cumulative risk of colorectal cancer (CRC) and aggressive fibromatosis/desmoid (AF/D). The first non-Caucasian FAP cohort with cumulative risk estimates for CRC and AF/D shows distinct differences with the Caucasian and other Asian cohorts. The strong correlation between the adenomatous polyposis coli (APC) mutation location with the FAP phenotype and the geoethnic differences in APC mutation spectrum, genetic constitution, lifestyle and sporadic CRC rates, mandates the use of population-specific cumulative risk estimates for CRC and desmoid for counselling and risk management. On genotype–phenotype correlation in 83 individuals with classical FAP and a confirmed pathogenic/likely Pathogenic (P/LP) APC variant (n=76) or obligate carrier of the family variant (n=7), we observed a high cumulative CRC risk of 40% and 85% by 40 and 60 years, respectively. The observed 30% cumulative risk by 50 years for desmoids was higher than previous European and Asian cohorts and was significantly associated with prophylactic surgery (OR: 4.58, 95% CI 1.06 to 19.78) and APC mutation 3′ of codon 1309 (OR: 13.07, 95% CI 3.58 to 47.56) and also 3′ of codon 1444 (OR: 8.0, 95% CI 1.83 to 34.94). Global cooperation is required to establish FAP genotype–phenotype associations and population-specific risk estimates to guide genetic counselling and risk management.
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- 2021
13. Analysis of complex structural variants in the DMD gene in one family
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Chiara Mazzanti, Liliana Francipane, Carlos Daniel de Brasi, Leonela Natalia Luce, Florencia Giliberto, Sebastián Menazzi, Pablo Lapunzina, Irene Szijan, Micaela Carcione, Liliana Carmen Rossetti, Julián Nevado, M. M. Abelleyro, and Pamela Radic
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0301 basic medicine ,Adult ,Male ,Adolescent ,Genetic counseling ,Duchenne muscular dystrophy ,Genetic Counseling ,Biology ,medicine.disease_cause ,Dystrophin ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Pregnancy ,Prenatal Diagnosis ,Gene duplication ,Obligate carrier ,medicine ,Humans ,Genetics (clinical) ,Whole genome sequencing ,Genetics ,Mutation ,Breakpoint ,Exons ,medicine.disease ,Muscular Dystrophy, Duchenne ,030104 developmental biology ,Neurology ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,Multiplex Polymerase Chain Reaction ,030217 neurology & neurosurgery ,Gene Deletion - Abstract
This work describes a family with Duchenne muscular dystrophy (DMD) with a rare case of a symptomatic pregnant woman. The main aim was to perform prenatal molecular diagnosis to provide genetic counseling. The secondary aim was to suggest the molecular mechanisms causing the complex structural variant (cxSV) identified. To accomplish this, we used a multi-technique algorithm including segregation analysis, Multiplex Ligation-dependent Probe Amplification, PCR, X-chromosome inactivation studies, microarrays, whole genome sequencing and bioinformatics. We identified a duplication of exons 38-43 in the DMD gene in all affected and obligate carrier members, proving that this was the DMD-causing mutation. We also observed a skewed X-chromosome inactivation in the symptomatic woman that explained her symptomatology. In addition, we identified a cxSV (duplication of exons 38-43 and deletion of exons 45-54) in the affected boy. The molecular characterization and bioinformatic analyses of the breakpoint junctions allowed us to identify Double Strand Breaks stimulator motifs and suggested the replication-dependent Fork Stalling and Template Switching as the most probable mechanisms leading to the duplication. In addition, the de novo deletion might have been the result of a germline inter-chromosome non-allelic recombination involving the Non-Homologous End Joining mechanism. In conclusion, the diagnostic strategy used allowed us to provide accurate molecular diagnosis and genetic counseling. In addition, the familial molecular diagnosis together with the in-depth characterization of the cxSV helped to determine the chronology of the molecular events, and propose and understand the molecular mechanisms involved in the generation of this complex rearrangement.
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- 2020
14. A deletion in GDF7 is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats
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Yoshihiko Yu, Erica K. Creighton, Leslie A. Lyons, and Reuben M. Buckley
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Sanger sequencing ,Whole genome sequencing ,Genetics ,0303 health sciences ,CATS ,040301 veterinary sciences ,Chromosome ,04 agricultural and veterinary sciences ,Biology ,Disease gene identification ,medicine.disease ,0403 veterinary science ,03 medical and health sciences ,symbols.namesake ,Obligate carrier ,symbols ,medicine ,030304 developmental biology ,Ventriculomegaly ,Genetic association - Abstract
An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test, a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing, and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. Obligate carrier cats were heterozygous. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasizes the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.
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- 2020
15. Next-Generation Sequencing in a Cohort of Asian Indian Patients with the Duchenne Muscular Dystrophy Phenotype: Diagnostic Yield and Mutation Spectrum
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Prajnya Ranganath, Sakthivel Murugan, and Gayatri Nerakh
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Proband ,Genetics ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,business.industry ,Duchenne muscular dystrophy ,medicine.disease ,Phenotype ,DNA sequencing ,Pediatrics, Perinatology and Child Health ,Obligate carrier ,medicine ,Multiplex ligation-dependent probe amplification ,business ,Gene ,Genetics (clinical) ,Exome sequencing - Abstract
Multiplex ligation-dependent probe amplification (MLPA) detects exonic deletions and duplications in the DMD gene in around 65 to 70% of patients with the Duchenne muscular dystrophy (DMD) phenotype. This study looks at the diagnostic yield of next-generation sequencing (NGS) and the mutation spectrum in an Asian Indian cohort of MLPA-negative cases with the DMD phenotype. NGS-based sequencing of DMD gene was done in 28 MLPA-negative cases (25 male probands with the DMD phenotype and 3 obligate carrier mothers of deceased affected male patients) and disease-causing variants were identified in 19 (67.9%) of these cases. Further molecular testing in four of the remaining nine cases revealed gene variants associated with limb girdle muscular dystrophies. Thus, NGS-based multigene panel testing for muscular dystrophy-associated genes or clinical exome sequencing rather than targeted DMD gene sequencing appears to be a more cost-effective testing modality with better diagnostic yield, for MLPA-negative patients with the DMD phenotype.
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- 2020
16. Mosaicism in carrier of Duchenne muscular dystrophy mutation – Implication for prenatal diagnosis
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Van Khanh Tran, Tuan Pham Le-Anh, Long Hoang Luong, Dat Quoc Tran, Thanh Van Ta, Thinh Huy Tran, The-Hung Bui, Linh Thuy Dinh, Phuong Thi Le, and Duc Hinh Nguyen
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musculoskeletal diseases ,0301 basic medicine ,Proband ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,Duchenne muscular dystrophy ,DNA Mutational Analysis ,Prenatal diagnosis ,Carrier testing ,lcsh:Gynecology and obstetrics ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Prenatal Diagnosis ,Obligate carrier ,Humans ,Medicine ,Child ,lcsh:RG1-991 ,Genetics ,biology ,Mosaicism ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Pedigree ,Muscular Dystrophy, Duchenne ,030104 developmental biology ,Mutation (genetic algorithm) ,Mutation testing ,biology.protein ,Female ,business ,Dystrophin ,030217 neurology & neurosurgery - Abstract
Objective: Duchenne muscular dystrophy (DMD) is a severe disorder caused by mutation in the X-linked dystrophin gene, therefor carrier testing is required for all female family members. However, there are cases mutation analysis cannot detect any mutation due to a phenomenon called mosaicism. The case report describes a case of mosaicism in a DMD carrier and discusses the approach in diagnosis and counseling of familial disorder. Case report: The proband was diagnosed with DMD at age six. Sequencing of Dystrophin gene identified a 2-nucleotide deletion c.2032_2033delCA, p.Q678DfsX41. Family investigation suggested that the mother was an obligate carrier of Dystrophin mutation. Sequencing of DNA sample from the mother's peripheral blood did not reveal any mutation, there for we take sample from hair follicle for analysis. The result indicated that the mother was a carrier but was masked from initial analysis by mosaicsism. Conclusion: We suggested that more care need to be taken in identifying cases when no mutation was detected in probable or obligate carrier and prenatal diagnosis should remain an option. Keywords: Duchenne muscular dystrophy, Dystrophin, Mosaicism, Counseling, Prenatal diagnosis
- Published
- 2018
17. A Multicentre Based Observation of a Screening tool to Differentiate Microcytosis and Hypochromia
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Hafizur Rahman, Tashmim Farhana Dipta, Amin Lutful Kabir, Nafisa Fatema, Ahmed Zahid Hossain, Shamima Ferdousi, and Gazi Sharmin Sultana
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medicine.medical_specialty ,Pediatrics ,education.field_of_study ,business.industry ,Microcytosis ,Population ,General Medicine ,Iron deficiency ,medicine.disease ,Gastroenterology ,Hypochromic microcytic anemia ,Iron-deficiency anemia ,hemic and lymphatic diseases ,Internal medicine ,Obligate carrier ,Hypochromia ,Medicine ,business ,education ,Mass screening - Abstract
Back ground: Iron deficiency anemia (IDA) and beta-thalassaemia trait (B-TT) are the most common causes of hypochromic microcytic anemia. Many indices have been defined to quickly discriminate these similar entities via parameters obtained from automated blood count analyzers.Methodology: The purpose of the study was to evaluate the predictive value of these indices in differential diagnosis of IDA and B-TT in adult cases. In this study we use auto-analyzer based formula of percentages of microcytic and hypochromic red cells (M/H ratio=% of Microcytosis/% of Hypochromia) as a screening tool for thalassaemia trait in Bangladeshi population.Results: A total of 150 subjects w ere included in this study with 50 known obligate carrier of beta-thalassaemia trait and 100 patients with hypochromia and microcytosis. Confirmatory tests for IDA were performed if serum ferritin level was 3.5% , on agarose gel Haemoglobin electrophoresis at an alkaline pH (8.6) where, in addition, MCV 3.5%, while the non- BTT group were those with HbA2
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- 2017
18. PHENOTYPING CHOROIDEREMIA AND ITS CARRIER STATE WITH MULTIMODAL IMAGING TECHNIQUES
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Kevin K Ma, Stephen H. Tsang, Katherine Boudreault, Royce W.S. Chen, and James Lin
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Retinal Disorder ,Retinal Pigment Epithelium ,Multimodal Imaging ,Article ,Choroideremia ,Nyctalopia ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Optical coherence tomography ,Ophthalmology ,Obligate carrier ,medicine ,Humans ,Fluorescein Angiography ,Retinal pigment epithelium ,medicine.diagnostic_test ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,eye diseases ,030104 developmental biology ,medicine.anatomical_structure ,Carrier State ,030221 ophthalmology & optometry ,Female ,sense organs ,Choroid ,medicine.symptom ,business ,Tomography, Optical Coherence - Abstract
PURPOSE To describe findings in a patient with choroideremia (CHM) and his mother, an obligate CHM carrier. METHODS Case report. RESULTS A 25-year-old man with nyctalopia and poor peripheral vision since childhood, as well as a family history consistent with an X-linked retinal disorder was diagnosed with CHM. His asymptomatic 50-year-old mother, an obligate carrier, was also examined. Fundus examination of the affected man showed significant atrophy of the choroid and retinal pigment epithelium, whereas the carrier woman showed patchy pigmentary mottling. Imaging of the affected man showed diffuse retinal pigment epithelium atrophy on optical coherence tomography and extensive areas of decreased choriocapillaris flow on optical coherence tomography angiography. By contrast, the carrier woman showed subtle retinal pigment epithelium changes on optical coherence tomography and mild flow alterations on optical coherence tomography angiography. CONCLUSION This case demonstrates the findings seen in CHM, and while CHM carrier women are often asymptomatic, they may exhibit a mosaic pattern of pigmentary change on fundus examination. Optical coherence tomography angiography may show mild choroidal flow abnormalities. This finding serves to further characterize the extent of dysfunction in CHM and its carrier state.
- Published
- 2017
19. A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly
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Yumiko Ondo, Haruo Shintaku, Toshiyuki Yamamoto, Toshiyuki Seto, Keiko Shimojima, Satoshi Kudo, Satsuki Nishigaki, and Takashi Hamazaki
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0301 basic medicine ,Genetics ,Microcephaly ,business.industry ,FG syndrome ,General Medicine ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Obligate carrier ,Intellectual disability ,Medicine ,Autism ,Abnormality ,CASK ,business ,Cerebellar hypoplasia ,030217 neurology & neurosurgery - Abstract
The calcium/calmodulin-dependent serine protein kinase gene (CASK) mutations are associated with various neurological disorders; a syndrome of intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID with/without nystagmus, epileptic encephalopathy, and autistic spectrum disorder (ASD). Next generation sequencing was performed to elucidate genetic causes in siblings exhibiting developmental disorders, and a novel CASK mutation, c.1424G>T (p.Ser475Ile), was detected in a male patient with ID, ASD, and microcephaly. Radiological examination of his brain showed no structural abnormality. The identified mutation was shared with the healthy mother and a younger sister exhibiting ASD. Although the mother showed a skewed X-chromosome inactivation (XCI) pattern, the sister showed a paradoxical XCI pattern. This would explain why this sister possessed a normal intellectual level, but showed the same ASD symptoms as the affected brother. A novel CASK mutation was identified in two siblings with ID and/or ASD, suggesting a relationship between the CASK mutation and ASD. Recently performed large molecular cohorts for patients with developmental disorders suggest that CASK is one of the genes related to developmental disorders. For better understanding of genotype-phenotype correlation in ASD cases with CASK mutations, more information should be accumulated.
- Published
- 2017
20. Calcyphosine-like (CAPSL) is regulated in multiple symmetric lipomatosis and is involved in adipogenesis
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Christine Ortner, Lukas Prantl, Stephan Schreml, Sebastian Tschernitz, Janine Altmüller, Mark Berneburg, Holger Thiele, Gunter Rappl, Angie Lindner, Felix Marbach, Oliver Felthaus, Min Jeong Kye, and Julia Schreml
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0301 basic medicine ,Male ,Candidate gene ,endocrine system ,Adipose tissue ,lcsh:Medicine ,Biology ,Article ,GTP Phosphohydrolases ,Mitochondrial Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Sirtuin 1 ,Adipocyte ,Obligate carrier ,Exome Sequencing ,Autophagy ,DNA metabolism ,Adipocytes ,Animals ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,lcsh:Science ,Gene ,Exome sequencing ,Genetics ,Multidisciplinary ,Adipogenesis ,lcsh:R ,fungi ,Cell Differentiation ,Pedigree ,030104 developmental biology ,Mechanisms of disease ,chemistry ,Adipose Tissue ,Gene Expression Regulation ,Mutation ,Lipomatosis, Multiple Symmetrical ,lcsh:Q ,Female ,Gene expression ,Technology Platforms ,030217 neurology & neurosurgery - Abstract
Little is known on the causes and pathogenesis of the adipose tissue disorder (familial) Multiple Symmetric Lipomatosis (MSL). In a four-generation MSL-family, we performed whole exome sequencing (WES) in 3 affected individuals and 1 obligate carrier and identified Calcyphosine-like (CAPSL) as the most promising candidate gene for this family. Screening of 21 independent patients excluded CAPSL coding sequence variants as a common monogenic cause, but using immunohistochemistry we found that CAPSL was down-regulated in adipose tissue not only from the index patient but also in 10 independent sporadic MSL-patients. This suggests that CAPSL is regulated in sporadic MSL irrespective of the underlying genetic/multifactorial cause. Furthermore, we cultivated pre-adipocytes from MSL-patients and generated 3T3-L1-based Capsl knockout and overexpressing cell models showing altered autophagy, adipogenesis, lipogenesis and Sirtuin-1 (SIRT1) expression. CAPSL seems to be involved in adipocyte biology and perturbation of autophagy is a potential mechanism in the pathogenesis of MSL. Downregulation of CAPSL and upregulation of UCP1 were common features in MSL fat while the known MSL genes MFN2 and LIPE did not show consistent alterations. CAPSL immunostainings could serve as first diagnostic tools in MSL clinical care with a potential to improve time to diagnosis and healthcare options.
- Published
- 2019
21. A de novo variant in the X-linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient
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Hans van Bokhoven, Daniel L. Polla, Bert B.A. de Vries, Arjan P.M. de Brouwer, and Harriet R Saunders
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0301 basic medicine ,de novo ,lcsh:QH426-470 ,media_common.quotation_subject ,Nonsense ,030105 genetics & heredity ,Clinical Reports ,Frameshift mutation ,03 medical and health sciences ,Epilepsy ,symbols.namesake ,Seizures ,X Chromosome Inactivation ,Genetic linkage ,Obligate carrier ,Genetics ,medicine ,Humans ,Child ,Molecular Biology ,Genetics (clinical) ,Exome sequencing ,Adaptor Proteins, Signal Transducing ,media_common ,Sanger sequencing ,Clinical Report ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,CNKSR2 ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,X‐linked ,lcsh:Genetics ,030104 developmental biology ,Codon, Nonsense ,intellectual disability ,symbols ,Female ,business ,exome sequencing - Abstract
Contains fulltext : 215374.pdf (Publisher’s version ) (Open Access) BACKGROUND: Eight different deletions and point variants of the X-chromosomal gene CNKSR2 have been reported in families with males presenting intellectual disability (ID) and epilepsy. Obligate carrier females with a frameshift variant in the N-terminal protein coding part of CNKSR2 or with a deletion of the complete gene are not affected. Only for one C-terminal nonsense variant, two carrier females were mildly affected by seizures without or with mild motor and language delay. METHODS: Exome sequencing was performed in one female child of a Dutch family, presenting seizures, mild ID, facial dysmorphisms, and abnormalities of the extremities. Potential causative variants were validated by Sanger sequencing. X-chromosome-inactivation (XCI) analysis was performed by methylation-sensitive PCR and fragment-length analysis of the androgen-receptor CAG repeat polymorphism. RESULTS: We identified a de novo variant, c.2304G>A (p.(Trp768*)), in the C-terminal protein coding part of the X-chromosomal gene CNKSR2 in a female patient with seizures and mild ID. Sanger sequencing confirmed the presence of this nonsense variant. XCI analysis showed a mild skewing of X inactivation (20:80) in the blood of our patient. Our variant is the second C-terminal-affecting CNKSR2 variant described in neurologically affected females. CONCLUSION: Our results indicate that CNKSR2 nonsense variants in the C-terminal coding part can result in ID with seizures in female variant carriers.
- Published
- 2019
22. Earlier Age of Breast Cancer Onset in Israeli BRCA Carriers-Is it a Real Phenomenon?
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David Margel, Shlomit Perry, Sivan Agranat, Rinat Yerushalmi, Shulamith Rizel, Aaron Sulkes, Inbal Kedar, Hagit N. Baris, and Mordechai Shochat
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Adult ,Heterozygote ,medicine.medical_specialty ,Breast Neoplasms ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Obligate carrier ,Internal Medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,030212 general & internal medicine ,Age of Onset ,Israel ,skin and connective tissue diseases ,Aged ,Aged, 80 and over ,BRCA2 Protein ,Gynecology ,BRCA1 Protein ,Obstetrics ,business.industry ,BRCA mutation ,Significant difference ,Cancer ,Mean age ,Middle Aged ,medicine.disease ,Oncology ,Jews ,030220 oncology & carcinogenesis ,Mutation ,Mutation (genetic algorithm) ,Anticipation (genetics) ,Female ,Surgery ,business - Abstract
Data on genetic anticipation in breast cancer are sparse. We sought to evaluate age at diagnosis of breast cancer in daughters with a BRCA mutation and their mothers. A review of all carriers of the BRCA mutation diagnosed with breast cancer at the Genetics Institute of a tertiary medical center in 2000-2013 yielded 80 women who could be paired with a mother with breast cancer who was either a carrier of the BRCA mutation or an obligate carrier according to pedigree analysis. Age at diagnosis, type of mutation (BRCA1, BRCA2), year of birth, and ethnicity were recorded. Paired t-test was used to analyze differences in age at cancer diagnosis between groups and subgroups. Mean age at diagnosis of breast cancer was 50.74 years (range 22-88) in the mothers and 43.85 years (range 24-75) in the daughters. The difference was statistically significant (p < 0.001). These findings were consistent regardless of type of BRCA mutation, ethnicity, or mother's year of birth. However, on separate analysis of pairs in which the mother was diagnosed before the age of 50 years, there was no significant difference in mean age at diagnosis between mothers and daughters (~42 years for both). Daughters who carry a BRCA mutation are diagnosed with breast cancer at an earlier age than their carrier mothers, with the exception of pairs in which the mother was diagnosed before the age of 50 years. Future breast-screening guidelines may need to target specific subpopulations of BRCA mutation carriers.
- Published
- 2016
23. A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1)
- Author
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Tosso Leeb, Vidhya Jagannathan, Daniela Gorgas, Michaela Drögemüller, Stephanie E Borer-Germann, G. Diane Shelton, Anna Oevermann, Michaela Wiedmer, and Diana Henke
- Subjects
0301 basic medicine ,Microcephaly ,Transcription, Genetic ,Genetic Linkage ,rab3 GTP-Binding Proteins ,QH426-470 ,Breeding ,Cornea ,0403 veterinary science ,610 Medicine & health ,Genetics (clinical) ,Genetics ,whole genome sequencing ,Genome ,630 Agriculture ,Chromosome Mapping ,High-Throughput Nucleotide Sequencing ,Exons ,Genomics ,04 agricultural and veterinary sciences ,Disease gene identification ,Immunohistochemistry ,Magnetic Resonance Imaging ,Phenotype ,dog ,590 Animals (Zoology) ,medicine.symptom ,linkage ,Polyneuropathy ,Ataxia ,Genotype ,040301 veterinary sciences ,Investigations ,Biology ,Polymorphism, Single Nucleotide ,Cataract ,canis familiaris ,03 medical and health sciences ,Dogs ,Genetic linkage ,Intellectual Disability ,Chromosome 19 ,Obligate carrier ,medicine ,Animals ,Humans ,Abnormalities, Multiple ,Molecular Biology ,Genetic Association Studies ,Hypogonadism ,animal model ,medicine.disease ,Mutagenesis, Insertional ,Optic Atrophy ,030104 developmental biology ,570 Life sciences ,biology ,homozygosity - Abstract
We observed a hereditary phenotype in Alaskan Huskies that was characterized by polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV). The affected dogs developed a progressive severe ataxia, which led to euthanasia between 8 and 16 months of age. The pedigrees were consistent with a monogenic autosomal recessive inheritance. We localized the causative genetic defect to a 4 Mb interval on chromosome 19 by a combined linkage and homozygosity mapping approach. Whole genome sequencing of one affected dog, an obligate carrier, and an unrelated control revealed a 218-bp SINE insertion into exon 7 of the RAB3GAP1 gene. The SINE insertion was perfectly associated with the disease phenotype in a cohort of 43 Alaskan Huskies, and it was absent from 541 control dogs of diverse other breeds. The SINE insertion induced aberrant splicing and led to a transcript with a greatly altered exon 7. RAB3GAP1 loss-of-function variants in humans cause Warburg Micro Syndrome 1 (WARBM1), which is characterized by additional developmental defects compared to canine POANV, whereas Rab3gap1-deficient mice have a much milder phenotype than either humans or dogs. Thus, the RAB3GAP1 mutant Alaskan Huskies provide an interesting intermediate phenotype that may help to better understand the function of RAB3GAP1 in development. Furthermore, the identification of the presumed causative genetic variant will enable genetic testing to avoid the nonintentional breeding of affected dogs.
- Published
- 2016
24. A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer's disease
- Author
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Patricio Chrem-Méndez, Ricardo F. Allegri, Matías Niikado, Micaela Barbieri-Kennedy, Gustavo Sevlever, Tatiana Itzcovich, Silvia Vazquez, Horacio Martinetto, and Ezequiel Surace
- Subjects
Male ,0301 basic medicine ,Proband ,congenital, hereditary, and neonatal diseases and abnormalities ,Aging ,Cousin ,Argentina ,03 medical and health sciences ,0302 clinical medicine ,Mutation Carrier ,Alzheimer Disease ,PSEN2 ,Obligate carrier ,Presenilin-1 ,PSEN1 ,Humans ,Medicine ,Family ,Age of Onset ,Exome sequencing ,Aged ,Genetics ,business.industry ,General Neuroscience ,Middle Aged ,030104 developmental biology ,Positron-Emission Tomography ,Mutation ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Age of onset ,business ,Biomarkers ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Mutations in PSEN1 are the most common cause of early-onset Alzheimer's disease (AD). In this article, we present an Argentine family with autosomal dominant early- and late-onset AD. The proband and 6 family members were available for genetic testing and clinical and neuropsychological assessments. Cerebrospinal fluid biomarkers were analyzed in the proband and a cousin (mutation carrier), who also underwent positron emission tomography using F-18-2-fluoro-2-deoxy-D-glucose and Pittsburgh compound B. Exon sequencing of PSEN1, PSEN2, and APP revealed a novel heterozygous variant in PSEN1 (c.356C>T; p.T119I). Median age of onset in the family was 56 years. However, the proband's uncle showed initial symptoms at age 71. Although no DNA was available, he was an obligate carrier because his daughter (proband's cousin) carried the mutation. Both the proband and his cousin exhibited biomarker evidence (cerebrospinal fluid or imaging) of underlying Alzheimer's pathology. Overall, our results support that the PSEN1 p.T119I variant is likely pathogenic.
- Published
- 2020
25. HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients
- Author
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Rolph Pfundt, Sarju G. Mehta, Amy Lawson Yuen, Gunnar Houge, Marie-Cécile Nassogne, Nicola S. Cooper, Bjørn Ivar Haukanes, Ingvild Aukrust, Siren Berland, Pradeep Vasudevan, Mónica Roselló, Stéphanie Moortgat, Nina Powell-Hamilton, Charlotte von der Lippe, Barbara van Loon, Ruth Newbury-Ecob, Alain Verloes, Laura A. Baker, Trine Prescott, Andrew O.M. Wilkie, Emma Wakeling, Ddd Study, Isabelle Maystadt, Francisco Martínez, Laurence Faivre, Alfonso Caro-Llopis, Karen J. Low, Emma Kivuva, François-Guillaume Debray, Thatjana Gardeitchik, Louise C. Wilson, Christine Verellen-Dumoulin, Valérie Benoit, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,X-linked intellectual disability ,Ubiquitin-Protein Ligases ,Mutation, Missense ,Short stature ,Article ,Craniosynostosis ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Intellectual Disability ,Intellectual disability ,Obligate carrier ,Genetics ,medicine ,Missense mutation ,Humans ,Child ,Genetics (clinical) ,X chromosome ,Genes, Dominant ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,Tumor Suppressor Proteins ,Genetic Diseases, X-Linked ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Syndrome ,medicine.disease ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Dermatology ,030104 developmental biology ,Speech delay ,Female ,medicine.symptom ,business - Abstract
Whole-gene duplications and missense variants in the HUWE1 gene (NM_031407.6) have been reported in association with intellectual disability (ID). Increased gene dosage has been observed in males with non-syndromic mild to moderate ID with speech delay. Missense variants reported previously appear to be associated with severe ID in males and mild or no ID in obligate carrier females. Here, we report the largest cohort of patients with HUWE1 variants, consisting of 14 females and 7 males, with 15 different missense variants and one splice site variant. Clinical assessment identified common clinical features consisting of moderate to profound ID, delayed or absent speech, short stature with small hands and feet and facial dysmorphism consisting of a broad nasal tip, deep set eyes, epicanthic folds, short palpebral fissures, and a short philtrum. We describe for the first time that females can be severely affected, despite preferential inactivation of the affected X chromosome. Three females with the c.329 G > A p.Arg110Gln variant, present with a phenotype of mild ID, specific facial features, scoliosis and craniosynostosis, as reported previously in a single patient. In these females, the X inactivation pattern appeared skewed in favour of the affected transcript. In summary, HUWE1 missense variants may cause syndromic ID in both males and females.
- Published
- 2018
26. Increased incidence of Parkinson disease among relatives of patients with Gaucher disease
- Author
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Halperin, Assaf, Elstein, Deborah, and Zimran, Ari
- Subjects
- *
PARKINSON'S disease , *GENETIC mutation , *CARRIER state (Communicable diseases) - Abstract
Abstract: In a previous study of 99 Ashkenazi Jewish patients with Parkinson disease from Israel who were tested for the six most common mutations for Gaucher disease, 31.3% had at least one Gaucher disease mutation, implying that carrier status per se my be a risk for Parkinson disease. The purpose of this survey was to ascertain the presence of Parkinson disease among Ashkenazi Jewish obligate carriers of Gaucher disease relative to its incidence in a comparable cohort of Ashkenazi Jews who are putatively non-carriers. There was no statistically significant difference in gender or age between the groups (n >100). Among patients, 27.3% reported having a relative with Parkinson disease while among the controls there was a reported 12.3% which was statistically significant (P =0.05). While based completely on subjective reports in a paper-base questionnaire, the results of this survey implicate a high rate of Parkinson disease among individuals with Gaucher disease mutations. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
27. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles
- Author
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Meghan Deforest, Colleen Notley, Jayne Leggo, Victor S. Blanchette, Angie Tuttle, M. Bowman, Christine Brown, David Lillicrap, Paula D. James, and Shawn Tinlin
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Hematology ,Biology ,medicine.disease ,Compound heterozygosity ,Article ,Frameshift mutation ,Von Willebrand factor ,hemic and lymphatic diseases ,Genotype ,Obligate carrier ,biology.protein ,Von Willebrand disease ,medicine ,Missense mutation ,Allele - Abstract
Summary Background Type 3 von Willebrand disease (VWD) is the most severe form of the disease and is classically inherited in an autosomal recessive fashion. Objectives The aim of the current study was to investigate the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Patients and methods Thirty-four families comprised of 100 individuals were investigated. Phenotypic data, including bleeding scores (BS), von Willebrand factor (VWF) laboratory values and anti-VWF inhibitor status were included as well as sequence analysis. Results We identified 31 different mutations (20 novel): 8 frameshift, 5 splice site, 9 nonsense, 1 gene conversion, 6 missense and 2 partial gene deletion mutations. The majority of mutations identified were in the propeptide (42%); index cases (IC) with these mutations exhibited more severe bleeding (BS = 22) than those with mutations elsewhere in VWF (BS = 13). Sixty-two out of 68 (91%) mutant alleles were identified. Twenty-nine IC (85%) had a VWF null genotype identified; 17 homozygous, 12 compound heterozygous. In five IC (15%), two mutant VWF alleles were not identified to explain the type 3 VWD phenotype. In four ICs only one mutant VWF allele was identified and in one IC no mutant VWF alleles were identified. Conclusions We have investigated the molecular pathogenesis of a Canadian cohort of type 3 VWD patients. Obligate carriers are not phenotypically silent in the Canadian population; 48% have been diagnosed with type 1 VWD. In approximately 50% of families in this study the inheritance pattern for type 3 VWD is co-dominant and not recessive.
- Published
- 2013
28. Factor VIIIC — immunology and activity
- Author
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Peake, I., Forbes, Charles D., editor, and Lowe, Gordon D. O., editor
- Published
- 1982
- Full Text
- View/download PDF
29. Mapping the gene causing X-linked recessive idiopathic hypoparathyroidism to Xq26-Xq27 by linkage studies
- Author
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Michael P. Whyte, J. L. H. O'Riordan, Kay E. Davies, Rajesh V. Thakker, and C Wooding
- Subjects
Genetics ,medicine.medical_specialty ,X Chromosome ,Genetic Linkage ,Hypoparathyroidism ,Chromosome Mapping ,Genes, Recessive ,Locus (genetics) ,General Medicine ,Biology ,medicine.disease ,Pedigree ,Endocrinology ,Genetic linkage ,Internal medicine ,Obligate carrier ,medicine ,Humans ,Restriction fragment length polymorphism ,Gene ,Polymorphism, Restriction Fragment Length ,X chromosome ,X-linked recessive inheritance ,Research Article - Abstract
Idiopathic hypoparathyroidism has been reported to occur as an X-linked recessive disorder in two multigeneration kindreds. Affected individuals, who are males, suffer from infantile onset of epilepsy and hypocalcemia, which appears to be due to an isolated congenital defect of parathyroid gland development; females are not affected and are normocalcemic. We have performed linkage studies in these two kindreds (5 affected males, 11 obligate carrier females, and 44 unaffected members) and have used cloned human X chromosome sequences identifying restriction fragment length polymorphisms to localize the mutant gene causing this disorder. Our studies established linkage between the X-linked recessive idiopathic hypoparathyroid gene (HPT) and the DXS98 (4D.8) locus, peak LOD score = 3.82 (theta = 0.05), thereby mapping HPT to the distal long arm of the X chromosome (Xq26-Xq27). Multilocus analysis indicated that HPT is proximal to the DXS98 (4D.8) locus but distal to the F9 (Factor IX) locus, thereby revealing bridging markers for the disease. The results of this study will improve genetic counseling of affected families, and further characterization of this gene locus will open the way for elucidating the factors controlling the development and activity of the parathyroid glands.
- Published
- 2016
30. The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature
- Author
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Joyce So, Deborah Verbaan, and Pierre Sinajon
- Subjects
0301 basic medicine ,Male ,Microcephaly ,Heterozygote ,Sodium-Hydrogen Exchangers ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Ocular Motility Disorders ,Angelman syndrome ,Intellectual Disability ,Intellectual disability ,Obligate carrier ,Genetics ,medicine ,Humans ,Global developmental delay ,Genetics (clinical) ,Epilepsy ,Learning Disabilities ,Genetic Diseases, X-Linked ,medicine.disease ,Human genetics ,Pedigree ,030104 developmental biology ,Codon, Nonsense ,Mutation (genetic algorithm) ,Mutation ,Ataxia ,Female ,Angelman Syndrome ,Developmental regression ,030217 neurology & neurosurgery - Abstract
Christianson syndrome (OMIM 300243), caused by mutations in the X-linked SLC9A6 gene, is characterized by severe global developmental delay and intellectual disability, developmental regression, epilepsy, microcephaly and impaired ocular movements. It shares many common features with Angelman syndrome. Carrier females have been described as having learning difficulties with mild to moderate intellectual disability, behavioural issues and psychiatric illnesses. There is little literature on the carrier female phenotype of Christianson syndrome. We describe a large extended family with three affected males, four carrier females, one presumed carrier female and one obligate carrier female with a c.190G>T, p.E64X mutation known to cause a premature stop codon in SLC9A6. We characterize and expand the clinical phenotype of female SLC9A6 mutation carriers by comparing our described family with female carriers previously discussed in the literature. In particular, we highlight the neurodevelopmental and psychiatric phenotypes observed in our family and previous reports.
- Published
- 2016
31. Identification of 123 previously unreported mutations in the F8 gene of Iranian patients with Haemophilia A
- Author
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F. Ala, Said Enayat, S. Ravanbod, G. Rastegar-Lari, M. Rassoulzadegan, and Mohammad Jazebi
- Subjects
Genetics ,Mutation ,Haemophilia A ,Hematology ,General Medicine ,Biology ,Haemophilia ,medicine.disease ,medicine.disease_cause ,DNA sequencing ,Obligate carrier ,medicine ,Missense mutation ,Multiplex ligation-dependent probe amplification ,Gene ,Genetics (clinical) - Abstract
In Haemophilia A (HA), the deficiency in coagulation factor VIII is caused by mutations in the F8 gene. In the past, HA carrier detection in Iran used to be carried out by tracking polymorphic DNA markers - a technical strategy with poor efficacy and accuracy. For some 10 years, however, mutations have been identified by direct DNA sequencing at the Iranian Comprehensive Haemophilia Care Centre (ICHCC), resulting in the detection of 580 different mutations and accurate carrier detection. The aim of this study was to characterize and report the unreported mutations not recorded in the F8 HAMSTeRS database and HGMD, which we have detected amongst all the mutations hitherto identified. After excluding introns 1 and 22 inversions, direct DNA sequencing was used to detect mutations among our patients. These were then confirmed in another affected relative or obligate carrier. Severe cases of HA, where no mutation could be identified, were further investigated by the MLPA method. The new, unreported mutations identified include: 51 missense, 15 nonsense, 45 frame-shifts, 11 splice-site, 1 duplications. We report a large spectrum of mutations identified in the course of the past 10 years at the ICHCC, which offers this service to all patients from regions throughout Iran. Aside from the common introns 1 and 22 inversions, this work demonstrates a high degree of heterogeneity in F8 mutations. The establishment of a comprehensive Iranian HA database will improve the care and genetic counselling of Iranian HA families.
- Published
- 2011
32. Investigation of the 15q13.3 CNV as a genetic modifier for familial epilepsies with variable phenotypes
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Tarishi Desai, Marta A. Bayly, Bronwyn E. Grinton, Danya F. Vears, Samuel F. Berkovic, Leanne M. Dibbens, Ingrid E. Scheffer, and John C. Mulley
- Subjects
Genetics ,Genetic heterogeneity ,Seizure types ,Locus (genetics) ,Biology ,medicine.disease ,Penetrance ,Idiopathic generalized epilepsy ,Epilepsy ,Neurology ,Obligate carrier ,medicine ,Neurology (clinical) ,Copy-number variation - Abstract
Incomplete penetrance and variable phenotypic expression are characteristic of a number of syndromes of familial epilepsy. The purpose of the present investigation is to determine if the 15q13.3 copy number deletion functions as a locus modifying the epilepsy phenotype caused by other known or presumed pathogenic mutations segregating in families with epilepsies. No 15q13.3 microdeletions were detected in 756 affected or definite obligate carrier individuals across 151 families selected on the basis of having multiple members affected with epilepsy and showing a range of seizure types. Therefore, the 15q13.3 microdeletion does not act as a genetic modifier in this cohort of families and is not responsible for any of the genetic heterogeneity hypothesized to account for failure to detect linkage in previous genome-wide scans in five of the larger families included in this study.
- Published
- 2011
33. Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene
- Author
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Beatrice Husson, Diana Rodriguez, Lydie Burglen, Pierre Labauge, Ghaidaa Nasser, Laurent Chevret, Christian Denier, and Laurent Balu
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Pathology ,Encephalopathy ,Asymptomatic ,Central nervous system disease ,Obligate carrier ,medicine ,Humans ,Family Health ,Coma ,business.industry ,Multiple sclerosis ,Brain ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Leukoencephalitis, Acute Hemorrhagic ,Nuclear Pore Complex Proteins ,Neurology ,Child, Preschool ,Mutation ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Asymptomatic carrier ,Molecular Chaperones ,Familial acute necrotizing encephalopathy - Abstract
Background Acute necrotizing encephalopathy (ANE) is a rare and severe parainfectious central nervous system disease in which previously healthy children develop rapidly progressive coma following viral illness. While most ANE are sporadic, familial autosomal dominant ANE due to mutations in the RANBP2 gene has been recently reported (ANE1 or infection-induced acute encephalopathy-3 (IIAE3)). To date, only few IIAE3 families with ADANE episodes have been described. Objective To report a new family with ADANE, describe clinical and radiological features and discuss differential diagnosis including Leigh syndrome or multiple sclerosis. Observation The family included 3 symptomatic individuals and one 59 year-old asymptomatic obligate carrier. Patients presented acute episodes of encephalopathy few days after common viral infection. Ages of onset ranged from 6 months to 5 years. Episodes not only occurred in childhood but also recurred in adulthood. Initial neurological signs included coma, focal neurological deficits and seizures. MRI showed typical necrotizing lesions primarily in the thalamus and brainstem, and in the temporal lobes and insula. CSF cell count and cultures were normal during episodes. RANBP2 gene screening identified pathogenic heterozygous c.1754C>T mutation (p.Thr585Met). Episodes led to cognitive or physical handicap in 2 patients and were fatal in one child. Conclusion IIAE3 or ADANE due to RANBP2 mutations has a large clinical heterogeneity. Our family illustrates the associated phenotypes from asymptomatic carrier to severe episodes of encephalopathy. Based on MRI features, the genetic IIAE3 diagnosis is important since prophylaxis and symptomatic management of infections may be beneficial, possibly in association with steroid or gammaglobulins.
- Published
- 2014
34. Familial Simpson-Golabi-Behmel syndrome: studies of X-chromosome inactivation and clinical phenotypes in two female individuals with GPC3 mutations
- Author
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A Bagheri, Yoriko Watanabe, Naomichi Matsumoto, Berivan Baskin, PN Ray, Kathryn Moseley, Shoji Yano, and Akira Nishimura
- Subjects
Heart Defects, Congenital ,Male ,Pathology ,medicine.medical_specialty ,Buccal swab ,Biology ,medicine.disease_cause ,Gigantism ,X-inactivation ,Glypicans ,X Chromosome Inactivation ,Intellectual Disability ,Obligate carrier ,Genetics ,Macroglossia ,medicine ,Humans ,Abnormalities, Multiple ,Skewed X-inactivation ,Genetics (clinical) ,Mutation ,Macrocephaly ,Arrhythmias, Cardiac ,Genetic Diseases, X-Linked ,Simpson–Golabi–Behmel syndrome ,medicine.disease ,Phenotype ,Receptors, Androgen ,Fragile X Syndrome ,Female ,medicine.symptom - Abstract
Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth/multiple congenital anomalies syndrome with an X-linked inheritance. Most cases of SGBS are attributed to mutations in the glypican 3-gene (GPC3), which is highly expressed in the mesodermal embryonic tissues and involves in a local growth regulation. Typical clinical features include pre/postnatal overgrowth, developmental delay, macrocephaly, characteristic facies with prominent eyes and macroglossia, diaphragmatic hernia, congenital heart defects, kidney anomalies, and skeletal anomalies. Obligate carrier females with GPC3 mutations are usually asymptomatic or with mild symptoms. It is thought that skewed X-inactivation is the underlining mechanism for the female patients to present with findings of SGBS. We identified three siblings with typical SGBS (two male and one female cases) and their mother with very mild symptoms in a family carrying c.256C>T (p.Arg86X) mutation in GPC3. X-inactivation studies on the androgen-receptor gene (AR) and the Fragile XE (FRAXE) gene were performed with blood, buccal swabs, and fibroblasts in the carrier females. The studies with blood showed moderately skewed X-inactivation with paternal X-chromosome being preferentially inactivated (71-80% inactivated) in the female patient with SGBS and no skewing was shown in the mother with very mild symptoms. The X-inactivation studies in the mother showed inactivation of the X-chromosome with the mutation by 57%. This suggests that loss of the functional GPC3 protein by 43% is closed to the threshold to develop the SGBS phenotype. Studies with buccal swabs and fibroblasts failed to show different X-inactivation patterns between the two female individuals.
- Published
- 2010
35. A novel X-linked four-repeat tauopathy with Parkinsonism and spasticity
- Author
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Cyrus P. Zabetian, Ellen J. Steinbart, John G. Nutt, Dora Yearout, Parvoneh Poorkaj, Mark Matsushita, Wendy H. Raskind, John Wolff, James B. Leverenz, Thomas D. Bird, Sophia Kim, Ali Samii, Nayiry Gazi, and J. Lynne Greenup
- Subjects
Genetics ,Candidate gene ,Pathology ,medicine.medical_specialty ,Parkinsonism ,Haplotype ,Locus (genetics) ,medicine.disease ,nervous system diseases ,Neurology ,Genetic linkage ,Obligate carrier ,medicine ,Neurology (clinical) ,Tauopathy ,Psychology ,X chromosome - Abstract
The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LOD(max) score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an approximately 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false-positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and four-repeat tau pathology, and defined a novel candidate gene locus spanning approximately 28 Mb from Xp11.2-Xq13.3.
- Published
- 2010
36. A novel missense mutation in the EDA gene associated with X-linked recessive isolated hypodontia
- Author
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Muhammad Aslam, Miriam Entesarian, Amjad Ali, Shahid Mahmood Baig, Niklas Dahl, Mahmood Rasool, Muhammad Tariq, Ilyas Ahmad, and Jens Schuster
- Subjects
Male ,Models, Molecular ,Protein Folding ,Molecular Sequence Data ,Mutation, Missense ,Genes, Recessive ,Biology ,Anodontia ,Obligate carrier ,Genetics ,medicine ,Humans ,Missense mutation ,Amino Acid Sequence ,Gene ,Genetics (clinical) ,X-linked recessive inheritance ,Recombination, Genetic ,Chromosomes, Human, X ,Sequence Homology, Amino Acid ,Ectodysplasins ,medicine.disease ,Pedigree ,Hypodontia ,Phenotype ,Amino Acid Substitution ,Female ,Ectodysplasin A - Abstract
Isolated hypodontia, or congenital absence of one to six permanent teeth (OMIM 300606), is a common condition that affects about 20% of individuals worldwide. We identified two extended Pakistani pedigrees segregating X-linked hypodontia with variable expressivity. Affected males show no other associated anomalies, and obligate carrier females have normal dentition. We analyzed the families with polymorphic markers in the ectodysplasin A (EDA) gene region and obtained significant linkage to the phenotype in each pedigree (Z(max) 3.29 and 2.65, respectively, at theta = 0.00). Sequence analysis of the coding regions of EDA revealed a novel missense mutation c.1091TC resulting in a methionine to threonine substitution (p.M364T) in the tumor necrosis factor (TNF) homology domain. Met364 is a highly conserved residue located on the outer surface of the EDA protein. From our findings, we suggest that the mutation disturbs but does not destroy the EDA structure, resulting in the partial and unusually mild ED phenotype restricted to hypodontia.
- Published
- 2008
37. A novel mutation (967−970+2)delAAAGGT in the choroideremia gene found in a Japanese family and related clinical findings
- Author
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Takuro Fujimaki, Akira Murakami, Yutaka Iino, and Keiko Fujiki
- Subjects
Adult ,Male ,Heterozygote ,DNA Mutational Analysis ,Visual Acuity ,Biology ,Polymerase Chain Reaction ,Choroideremia ,Frameshift mutation ,Exon ,Night Blindness ,Obligate carrier ,Electroretinography ,medicine ,Humans ,Frameshift Mutation ,Gene ,X-linked recessive inheritance ,Adaptor Proteins, Signal Transducing ,Aged ,DNA Primers ,Sequence Deletion ,Genetics ,Base Sequence ,Exons ,General Medicine ,medicine.disease ,eye diseases ,Pedigree ,Ophthalmology ,rab GTP-Binding Proteins ,Mutation (genetic algorithm) ,Female ,sense organs ,Visual Fields ,Novel mutation - Abstract
To investigate the choroideremia (CHM) gene of one affected male and one obligate carrier in a Japanese family with choroideremia, and to characterize the related clinical features.We examined one affected man and one carrier woman from a Japanese family. Genomic DNA was extracted from leukocytes of peripheral blood collected from the affected man and his daughter, who is an obligate carrier of choroideremia. Exons 1-15 of the CHM gene were amplified by polymerase chain reaction (PCR) and directly sequenced. We performed ophthalmic examinations including best-corrected visual acuity, slit-lamp examination, fundus examination, electroretinography, and Goldmann perimetry.A novel (967-970+2)delAAAGGT mutation was detected in the CHM gene. The affected man was hemizygous and had night-blindness, chorioretinal atrophy spreading from the posterior pole to the mid-periphery, and bareness of the sclera. His daughter was a heterozygous carrier who had chorioretinal atrophy and mottled appearance of the retinal pigment epithelium.A novel (967-970+2)delAAAGGT mutation existed in the CHM gene of a Japanese family with choroideremia.
- Published
- 2008
38. X-linked lymphoproliferative disease: prenatal detection of an unaffected histocompatible male
- Author
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T. H. M. Huang, David H. Ledbetter, D. T. Purtilo, V. A. Berdoukas, John C. Mulley, Agi K. Gedeon, Anne M. Turner, and H. Grierson
- Subjects
Genetic Markers ,Male ,X Chromosome ,Genotype ,Genetic Linkage ,Prenatal diagnosis ,Human leukocyte antigen ,Biology ,Polymerase Chain Reaction ,Pregnancy ,Genetic linkage ,Obligate carrier ,Genetics ,Humans ,Sex Chromosome Aberrations ,Genetics (clinical) ,Recombination, Genetic ,Fetus ,Molecular biology ,Lymphoproliferative Disorders ,Pedigree ,Histocompatibility ,Transplantation ,Chorionic Villi Sampling ,Child, Preschool ,Female ,Restriction fragment length polymorphism ,Polymorphism, Restriction Fragment Length - Abstract
Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25–q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC. Transplantation has been carried out utilising cord and placental blood.
- Published
- 2008
39. The Fragile-X syndrome in twin sisters
- Author
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J.M. Bird, R. Wheater, K. Rameshwari Singh, and V. A. Cowie
- Subjects
Adult ,Heterozygote ,medicine.medical_specialty ,Psychosis ,Dizygotic twin ,Intelligence ,Lesion ,Arts and Humanities (miscellaneous) ,Obligate carrier ,Diseases in Twins ,Twins, Dizygotic ,medicine ,Humans ,Psychiatry ,Sex Chromosome Aberrations ,Cognitive deficit ,Rehabilitation ,Cognition ,medicine.disease ,Fragile X syndrome ,Psychiatry and Mental health ,Neurology ,Fragile X Syndrome ,Female ,Neurology (clinical) ,medicine.symptom ,Psychology - Abstract
Two mentally handicapped dizygotic twin sisters were found to possess the Fragile-X lesion. They showed different levels of cognitive deficit. The hypothesis that the level of cognitive function in female carriers of the Fragile-X lesion may be influenced by Lyonization is discussed. The mother of the twins was schizophrenic. Although she was an obligate carrier her psychosis was thought not to be causally connected with the Fragile-X status.
- Published
- 2008
40. Correlation of Ophthalmic Examination with Carrier Status in Females Potentially Harboring a Severe Norrie Disease Gene Mutation
- Author
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Mohammed A. Aldahmesh, Arif O. Khan, and Brian F. Meyer
- Subjects
Male ,Heterozygote ,Pathology ,medicine.medical_specialty ,Hearing Loss, Sensorineural ,Phenylalanine ,Genes, Recessive ,Nerve Tissue Proteins ,Diagnostic Techniques, Ophthalmological ,Gene mutation ,Severity of Illness Index ,Asymptomatic ,chemistry.chemical_compound ,Retinal Diseases ,Retinal Examination ,Intellectual Disability ,Molecular genetics ,Obligate carrier ,medicine ,Humans ,Cysteine ,Prospective Studies ,Eye Proteins ,Molecular Biology ,business.industry ,Vitreoretinopathy, Proliferative ,Genetic Diseases, X-Linked ,Retinal ,medicine.disease ,Pedigree ,Ophthalmology ,chemistry ,Mutation ,Female ,Norrie disease ,medicine.symptom ,business ,Retinopathy - Abstract
Purpose To correlate ophthalmic findings with carrier status for a severe Norrie disease (ND) gene mutation (C95F). Design Prospective interventional case series. Participants Six potential carriers and 1 obligate carrier from a family harboring the mutation. Methods An ophthalmologist blind to the pedigree performed a full ophthalmic examination for the 7 asymptomatic family members. A peripheral blood sample was collected from each for ND gene sequencing. Main Outcome Measures Ophthalmic examination findings (with attention to the presence or absence of retinal findings) and results of ND gene sequencing. Results Three carriers were identified by molecular genetics, and all 3 of them had peripheral retinal abnormality. However, 3 of the 4 genetically identified noncarriers also exhibited peripheral retinal abnormality. Two of these noncarriers with retinal findings were the offspring of a confirmed noncarrier. The genetically identified noncarrier with a normal peripheral retinal examination was the daughter of an obligate carrier. Conclusions The presence of peripheral retinal changes was not useful for carrier prediction in a family harboring ND. There are likely additional loci responsible for phenotypic expression.
- Published
- 2008
41. Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7
- Author
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S. L. Jain, Rebecca Jane McLean, E.O. Roberts, Susanne Lindner, S. Thomas, Frank A Proudlock, Chris Degg, Geoffrey Woodruff, M. Surendran, Richard P. Gale, Irene Gottlob, Anil Kumar, Patrick S. Tarpey, N. Sarvananthan, S.J. Farooq, M. Awan, Andrea Langmann, Robert D. Reinecke, and F. Lucy Raymond
- Subjects
Adult ,Male ,Heterozygote ,medicine.medical_specialty ,Visual acuity ,Adolescent ,genetic structures ,Eye disease ,Posture ,Visual Acuity ,Nystagmus ,Nystagmus, Pathologic ,Pendular nystagmus ,Ophthalmology ,Obligate carrier ,medicine ,Humans ,Child ,Strabismus ,Aged ,Aged, 80 and over ,Chromosomes, Human, X ,Depth Perception ,business.industry ,Membrane Proteins ,Eye Diseases, Hereditary ,Genetic Diseases, X-Linked ,Optokinetic reflex ,Middle Aged ,medicine.disease ,eye diseases ,Pedigree ,Surgery ,Cytoskeletal Proteins ,El Niño ,Child, Preschool ,Mutation ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Head ,Nystagmus, Congenital ,Color Perception - Abstract
Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene ( FRMD7 group) to 48 subjects without mutations but with clinical IIN (non- FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar ( FRMD7 : 7.8%, non- FRMD7 : 10%). The presence of anomalous head posture (AHP) was significantly higher in the non- FRMD7 group ( P < 0.0001). The amplitude of nystagmus was more strongly dependant on the direction of gaze in the FRMD7 group being lower at primary position ( P < 0.0001), compared to non- FRMD7 group ( P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group ( P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males ( P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non- FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.
- Published
- 2008
42. Mapping the Mutation Causing Lens Luxation in Several Terrier Breeds
- Author
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David R. Sargan, Cathryn S. Mellersh, Louise Pettitt, David J. Withers, David J. Gould, and Michael Squire
- Subjects
Genetic Markers ,Genetics ,Lens luxation ,Chromosome Mapping ,Membrane Proteins ,Lens Subluxation ,Biology ,Phosphoproteins ,Dogs ,Species Specificity ,Chromosome 3 ,Genetic marker ,Lens, Crystalline ,Mutation ,Mutation (genetic algorithm) ,Obligate carrier ,Animals ,Microsatellite ,Genetic Predisposition to Disease ,Allele ,Molecular Biology ,Genetics (clinical) ,Biotechnology ,Genetic association - Abstract
Primary lens luxation (PLL), a painful and blinding inherited condition, is common in several breeds of terrier. Here we have examined the Veterinary Medical Database of patient encounters and Canine Eye Registration Foundation (CERF) cases records for the last 10 years and found the diagnosis recorded in 85 breeds. We have performed association analysis using a genome-wide microsatellite screen to map mutations underlying the condition in miniature bull terriers and Lancashire heelers. These studies show microsatellite alleles in disequilibrium with disease status with highest support in a 6.3-Mbp region in the central part of chromosome 3 (-log P(max) = 6.4). The same region also shows an association to the disease in Tibetan terriers. Tight junction protein-1 (TJP1) is a positional candidate to contain the PLL mutation. All recognized exons and splice junctions of TJP1 have been sequenced from affected, obligate carrier and control Lancashire heeler dogs. Several polymorphisms have been found, but these are not likely to cause the disease.
- Published
- 2007
43. Analysis of the AluI polymorphism in intron 1 of the human coagulation factor VIII gene: A new marker for the hemophilia a carrier detection
- Author
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V. L. Surin, A V Luk'ianenko, and Yu. A. Luchinina
- Subjects
Genetics ,Restriction enzyme ,Exon ,biology ,Polymorphism (computer science) ,HpaII ,Obligate carrier ,biology.protein ,Intron ,SNP ,HindIII ,Molecular biology - Abstract
Frequencies of the C/T SNP alleles at position 2403 of the human coagulation factor VIII gene intron 1, containing the AluI restriction endonuclease recognition site, were examined. Genomic DNA samples for the analysis were obtained from the consulted women and their relatives from the families with hemophilia A. A total of 221 unrelated X chromosomes were studied. The two allelic variants were found with similar frequencies of T(Alu+), 0.53 and C(Alu−), 0.47. The heterozygosity index evaluated as equal to 0.50 was correlated with the experimental heterozygote number. The absence of a tight linkage between the AluI SNP and the widely used in the hemophilia A gene diagnostics HindIII polymorphism (C/T SNP at position 103 of intron 19) was demonstrated. Summarized informativity of these two markers for obligate carriers and for those detected in this study constituted 68% (32 out of 47). At the same time using one of the markers, only 40% (HindIII) and 51% (AluI) of the consulted women were informative. The new marker was used in 13 prenatal DNA diagnostics of hemophilia A. A new deletion polymorphism (del TGA, position 2281–2283 of intron 1) was described in close proximity of the AluI SNP with the frequency of about 0.05. among the five other SNP of the factor VIII gene examined (Bme18I, intron 1; HpaII, intron 13; MnlI, exon 14; Bst4CI, exon 25; and MseI, exon 26) no effective diagnostic markers were found. Only the MnlI polymorphism could be recommended for limited usage.
- Published
- 2007
44. Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease
- Author
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Inga Peter, Dermot P.B. McGovern, Lei Huang, Steven R. Brant, Stacy A. Kahn, Riyue Bao, Barbara S. Kirschner, Judy H. Cho, Eric A. Hungate, Kenan Onel, Andrew D. Skol, Mark S. Silverberg, Mark M. Sasaki, and James M. Allan
- Subjects
0301 basic medicine ,Adult ,Male ,Adolescent ,Population ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Young Adult ,Obligate carrier ,medicine ,Immunology and Allergy ,Humans ,Exome ,Genetic Predisposition to Disease ,Family history ,education ,Exome sequencing ,Genetic testing ,Aged ,Genetics ,education.field_of_study ,Receptors, Interleukin-17 ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,High-Throughput Nucleotide Sequencing ,Odds ratio ,Middle Aged ,Inflammatory Bowel Diseases ,Prognosis ,Pedigree ,Minor allele frequency ,030104 developmental biology ,Phenotype ,Case-Control Studies ,Female ,business - Abstract
BACKGROUND Rare variants (
- Published
- 2015
45. A distinct X-linked syndrome involving joint contractures, keloids, large optic cup-to-disc ratio, and renal stones results from a filamin A (FLNA) mutation
- Author
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Charles E. Schwartz, Melissa Lah, Tejasvi Niranjan, Lynda Holloway, Tao Wang, Sujata Srikanth, and David D. Weaver
- Subjects
0301 basic medicine ,Adult ,Male ,Adolescent ,Genotype ,Genetic Linkage ,Filamins ,030105 genetics & heredity ,Biology ,medicine.disease_cause ,Filamin ,Article ,03 medical and health sciences ,Exon ,Young Adult ,Genetic linkage ,X Chromosome Inactivation ,Putative gene ,Obligate carrier ,Genetics ,medicine ,FLNA ,Humans ,Abnormalities, Multiple ,Exome ,Allele ,Child ,Genetics (clinical) ,Genetic Association Studies ,Mutation ,High-Throughput Nucleotide Sequencing ,Genetic Diseases, X-Linked ,Syndrome ,Middle Aged ,Pedigree ,Phenotype ,Human medicine - Abstract
We further evaluated a previously reported family with an apparently undescribed X‐linked syndrome involving joint contractures, keloids, an increased optic cup‐to‐disc ratio, and renal stones to elucidate the genetic cause. To do this, we obtained medical histories and performed physical examination on 14 individuals in the family, five of whom are affected males and three are obligate carrier females. Linkage analysis was performed on all but one individual and chromosome X‐exome sequencing was done on two affected males. The analysis localized the putative gene to Xq27‐qter and chromosome X‐exome sequencing revealed a mutation in exon 28 (c.4726G>A) of the filamin A (FLNA) gene, predicting that a conserved glycine had been replaced by arginine at amino acid 1576 (p.G1576R). Segregation analysis demonstrated that all known carrier females tested were heterozygous (G/A), all affected males were hemizygous for the mutation (A allele) and all normal males were hemizygous for the normal G allele. The data and the bioinformatic analysis indicate that the G1576R mutation in the FLNA gene is very likely pathogenic in this family. The syndrome affecting the family shares phenotypic overlap with other syndromes caused by FLNA mutations, but appears to be a distinct phenotype, likely representing a unique genetic syndrome.
- Published
- 2015
46. Dandy-Walker malformation, genitourinary abnormalities, and intellectual disability in two families
- Author
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Joseph G. Gleeson, Maha S. Zaki, Anne Gregor, Amira Masri, and Rasim Ozgur Rosti
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Consanguinity ,Article ,Dandy–Walker syndrome ,Intellectual Disability ,Obligate carrier ,Intellectual disability ,Genetics ,medicine ,Humans ,Family ,Pathological ,Genetics (clinical) ,Genitourinary system ,business.industry ,Infant ,medicine.disease ,Phenotype ,Pedigree ,Child, Preschool ,Urogenital Abnormalities ,Female ,business ,Dandy-Walker Syndrome ,Dandy-Walker malformation - Abstract
We report on two families, each with documented consanguinity and two affected with overlapping features of Dandy-Walker malformation, genitourinary abnormalities, intellectual disability, and hearing deficit. This phenotype shares similar findings with many well-known syndromes. However, the clinical findings of this syndrome categorize this as a new syndrome as compared with the phenotype of already established syndromes. Due to parental consanguinity, occurrence in siblings of both genders and the absence of manifestations in obligate carrier parents, an autosomal recessive pattern of inheritance is more likely. The authors believe that these families suggest a novel autosomal recessive cerebello-genital syndrome. Array CGH analyses of an affected did not show pathological deletions or duplications.
- Published
- 2015
47. Predisposition to atypical teratoid/rhabdoid tumor due to an inheritedINI1 mutation
- Author
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John W. Walsh, Marshall A. Schorin, Alexander R. Judkins, Jaclyn A. Biegel, Gabriella Pridjian, Kristin Janson, Odile David, Lucien A. Nedzi, Meena B. Bhattacharjee, and Lu Tan
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Chromosomal Proteins, Non-Histone ,DNA Mutational Analysis ,Brain tumor ,Context (language use) ,Sensitivity and Specificity ,Germline ,Rhabdoid Tumor Predisposition Syndrome ,Germline mutation ,Risk Factors ,Antineoplastic Combined Chemotherapy Protocols ,Obligate carrier ,medicine ,Humans ,Genetic Predisposition to Disease ,SMARCB1 ,Germ-Line Mutation ,Rhabdoid Tumor ,business.industry ,Teratoma ,Infant ,SMARCB1 Protein ,Hematology ,medicine.disease ,Immunohistochemistry ,Magnetic Resonance Imaging ,Pedigree ,DNA-Binding Proteins ,Treatment Outcome ,Oncology ,Pediatrics, Perinatology and Child Health ,Atypical teratoid rhabdoid tumor ,business ,Transcription Factors - Abstract
Background Germline mutations of the INI1 gene predispose children to the development of rhabdoid tumors. Reports of familial cases, however, are extremely rare. Procedure We have identified a three-generation family in which two half-brothers were diagnosed with central nervous system atypical teratoid/rhabdoid tumors (AT/RT). The two boys, diagnosed at 2 months and 17 months of age, had a germline insertion mutation in exon 4 of the INI1 gene that was inherited from their healthy mother. A maternal uncle died in childhood from a brain tumor and a malignant rhabdoid tumor of the kidney, and presumably carried the same germline mutation. As the mother and uncle had different fathers, the grandmother is also an obligate carrier of the mutation. Conclusion The identification of two unaffected carriers in a family segregating a germline mutation and rhabdoid tumor supports the hypothesis that there may be variable risks of development of rhabdoid tumor in the context of a germline mutation. There may be a developmental window in which most rhabdoid tumors occur. This family highlights the importance of mutation analysis in all patients with a suspected rhabdoid tumor. Pediatr Blood Cancer 2006;47:279–284. © 2005 Wiley-Liss, Inc.
- Published
- 2006
48. Subtelomeric chromosome aberrations: still a lot to learn
- Author
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Yvonne Arens, P E A Huijts, Eric Smeets, J. J. M. Engelen, J.C.M. van Lent-Albrechts, Ute Moog, and Ctrm Schrander-Stumpel
- Subjects
Genetics ,Pathology ,medicine.medical_specialty ,Monosomy ,medicine.diagnostic_test ,Aneuploidy ,Biology ,medicine.disease ,Subtelomere ,Gene duplication ,Obligate carrier ,medicine ,Family history ,Trisomy ,Genetics (clinical) ,Fluorescence in situ hybridization - Abstract
Subtelomeric chromosome aberrations: still a lot to learn.Cryptic subtelomeric chromosome aberrations are a significant cause of mental retardation (MR). More than 4000 patients have been investigated, and the mean overall prevalence of subtelomeric rearrangements has been found to be 5.2%. In order to contribute to knowledge on the clinical presentation of subtelomeric rearrangements, we retrospectively studied patients with unexplained MR who had been evaluated for subtelomeric abnormalities by different fluorescence in situ hybridization (FISH) techniques. Hundred and two patients had an unexplained combination of MR with dysmorphism, congenital anomalies, and/or a positive family history and were investigated by total subtelomeric (TS) FISH (89/102), or by total painting (TP) in an obligate carrier in the case of familial MR (13/102). In 59 additional patients, a sequence-specific FISH was performed on clinical indication. In the 102 patients studied by TS or TP, six pathogenic aberrations (5.9%) were found in addition to one polymorphism. In total, eight clinically significant subtelomeric aberrations were found in the 161 index patients; four of these eight aberrations were familial. We report on the clinical presentation of all patients with an aberration and review the relevant literature. Factors complicating the interpretation of subtelomeric rearrangements are discussed, such as the occurrence of variants, clinical variability, and limited knowledge of the phenotype.
- Published
- 2005
49. Audiometric evaluation of carriers of the connexin 26 mutation 35delG
- Author
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Francesca Di Leva, Annamaria Franzè, Laura Esposito, Elio Marciano, Antonella Caravelli, Paolo Gasparini, Claudio Saulino, Massimo Carella, Federica D'Aulos, Gennaro Auletta, Franze, A, Caravelli, A, DI LEVA, F, Marciano, E, Auletta, G, D'Aulos, F, Saulino, C, Esposito, L, Carella, M, Gasparini, Paolo, Franze', Annamaria, DI LEVA, Francesca, Marciano, Elio, Auletta, Gennaro, Saulino, Claudio, and Gasparini, P.
- Subjects
Adult ,Male ,Heterozygote ,obligate carriers ,medicine.medical_specialty ,Genotype ,Hearing loss ,Connexin ,Recessive deafne ,connexin 26 ,Deafness ,Audiology ,Severity of Illness Index ,Connexins ,Loss of heterozygosity ,Audiometry ,Hearing ,otorhinolaryngologic diseases ,medicine ,Humans ,Point Mutation ,recessive deafness ,Genetics ,Obligate carrier ,medicine.diagnostic_test ,business.industry ,Point mutation ,Auditory Threshold ,Heterozygote advantage ,General Medicine ,Middle Aged ,Phenotype ,Otorhinolaryngology ,audiometric test ,Mutation (genetic algorithm) ,Female ,medicine.symptom ,business ,heterozygotes - Abstract
Mutation in a gap junction protein gene (GJB2 also named connexin 26) is a major cause of autosomal recessive congenital deafness, which is responsible for about 80% of the cases in Mediterranean families, but actually little is known about the influence of GJB2 mutations on the hearing of obligate carriers. We examined GJB2 35delG mutation carrier individuals to test the possible presence and incidence of audiometric abnormalities among carriers of 35delG mutations. Tonal audiometric analysis was performed on a 35delG mutation carrier group (H) and on a non-carrier control group (N). Audiometric evaluations in the control group showed the presence of thresholds within normal limits at all frequencies, while carriers of 35delG mutations presented a decrease of hearing principally at 6,000 and 8,000 Hz. The difference at 6,000 and 8,000 Hz between groups H and N is statistically significant.
- Published
- 2005
50. Cosegregation of a Factor VIII Microsatellite Marker with Mild Hemophilia A in Golden Retriever Dogs
- Author
-
Jharna Ray, Jennifer L. Barnas, Jacqueline Fremont, and Marjory B. Brooks
- Subjects
Genetics ,General Veterinary ,Cosegregation ,hemic and lymphatic diseases ,Obligate carrier ,Microsatellite ,Population study ,Locus (genetics) ,Golden Retriever ,Allele ,Biology ,Phenotype - Abstract
Mild hemophilia A (factor VIII deficiency) was diagnosed in Golden Retrievers and pedigree studies were undertaken to test the cosegregation of an intragenic factor VIII marker with the disease phenotype. The study population consisted of 30 client-owned dogs (22 males and 8 females). Hemophilic males (n = 12) typically demonstrated prolonged bleeding after trauma or surgery rather than spontaneous hemorrhagic events. The affected males had a proportionate reduction in factor VIII coagulant activity (mean FVIII:C = 4%) and factor VIII protein concentration (mean FVIII:Ag = 3%). Twenty-five dogs (10 affected males, 8 clear males, 2 obligate carrier dams, and 5 suspect carrier daughters) were genotyped for a factor VIII microsatellite marker, with allele size assigned by an automated capillary electrophoresis system. Five distinct marker alleles were present in the study pedigree and a 300-base pair allele was found to segregate with the hemophilia A phenotype. The inheritance of the hemophilia-associated allele defined carrier status for 5 suspect daughters of obligate carrier dams. The limitations inherent to linkage analyses (ie, lack of access to key family members and homozygosity at the marker locus) did not preclude carrier detection in this pedigree. We conclude that genotype analysis for the intragenic factor VIII marker can aid in control of canine hemophilia A through enhanced carrier detection.
- Published
- 2005
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