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Laboratory, United States

Zanke B.,Ottawa Health Research Institute | Hawken S.,University of Ottawa | Carter R.,Laboratory Genetics | Chow D.,St. Michaels Hospital
Canadian Journal of Ophthalmology | Year: 2010

The genetic determinants of age-related macular degeneration (AMD) are reviewed and a novel approach to risk determination based upon inherited genetic polymorphisms and smoking history is presented. Although AMD was long thought to have primarily an environmental etiology, genetic variation is now known to account for the majority of the disease risk, with variations in the genes of the complement pathways playing a prominent role. Independent and validated clinical studies have implicated the C3 gene and its regulator, complement factor H (1q31.1), complement component 2 (6q21.33), and complement factor B (6q21.33). Subtle variations in complement activity increase the risk of symptomatic macular inflammation with age. A second group of AMD-associated genetic markers may aggravate complementmediated inflammation by permitting retinal oxidative damage. Variation within the chromosomal site (10q26) coding a mitochondrial-associated protein (age-related maculopathy susceptibility 2) and an independent variation within the mitochondrial genome itself (A4917G) suggest a contributing pathophysiological role of retinal oxidative stress. A genetic panel of disease-susceptibility markers and smoking history can identify a group of individuals with greater than 65% lifetime risk of AMD. The introduction of genetic marker testing into clinical practice may identify patients with early disease who may be aided by presymptomatic monitoring or inclusion into trials of newer prophylactic agents. Source


McGowan R.,West of Scotland Clinical Genetics Service | Tydeman G.,Victoria Hospital | Shapiro D.,Royal Infirmary | Craig T.,Laboratory Genetics | And 7 more authors.
Fertility and Sterility | Year: 2015

Objective: To clinically and genetically investigate women with müllerian disorders, including Mayer-Rokitanksy-Kuster-Hauser (MRKH) syndrome. Design: Two-year prospective clinical and laboratory study. Setting: Not applicable. Patient(s): Thirty-five women over 16years of age with a müllerian disorder, including MRKH. Intervention(s): Women were recruited from specialist gynecology clinics or identified from the Scottish Disorders of Sex Development Register (www.sdsd.scot.nhs.uk/index.html). Associated abnormalities were detected by clinical examination, imaging studies, and biochemical analyses. Chromosomal microduplications and microdeletions were detected by array comparative genomic hybridization (CGH) and validated by fluorescence in situ hydridization. Main Outcome Measure(s): Identification of associated congenital and biochemical abnormalities and identification of regions of genomic imbalance using array CGH. Result(s): Associated congenital anomalies were common, present in 25/35 (71%) of affected women, particularly renal and skeletal abnormalities, which were present in 15/35 (43%) and 17/35 (49%) women, respectively. Using array CGH, novel or recurrent regions of genomic imbalance were identified in 4/11 (36%) women with MRKH and in 5/24 (21%) women with other müllerian abnormalities. Conclusion(s): Additional congenital abnormalities and regions of genomic imbalance are common in women with müllerian disorders, including MRKH. Recurrent microdeletions and microduplications associated with MRKH implicate specific possibly causative genes. The investigation of women with müllerian disorders should be thorough, and array CGH should be considered, given the potential highly significant familial implications of a chromosomal abnormality. © 2015 American Society for Reproductive Medicine. Source


Cicek M.S.,Divisions of Experimental Pathology | Cicek M.S.,Laboratory Genetics | Lindor N.M.,Mayo Medical School | Gallinger S.,Samuel Lunenfeld Research Institute | And 15 more authors.
Journal of Molecular Diagnostics | Year: 2011

The detection of defective mismatch repair (MMR), as assessed by the presence of tumor microsatellite instability (MSI) and/or loss of MMR protein expression by IHC, has been useful for risk assessment, prognosis, and prediction of treatment in patients with colorectal cancer. We analyzed tumors for the presence of defective MMR from 5927 Colorectal Cancer Family Registry patients recruited at six international consortium sites. We evaluated the appropriate percentage instability cutoff used to distinguish the three MSI phenotypes [ie, stable (MSS), low instability (MSI-L), and high instability (MSIH)]; the sensitivity, specificity, and performance characteristics of individual markers; and the concordance between MSI and IHC phenotypes. Guided by the results of the IHC testing, our findings indicate that the distinction between an MSI-H phenotype from a low-instability or MSS phenotype can best be accomplished by using a cutoff of 30% or greater of the markers showing instability. The sensitivity and specificity of the mononucleotide markers were higher than those of the dinucleotide markers. Specifically, BAT26 and BAT25 had the highest sensitivity (94%) and specificity (98%), and the use of mononucleotide markers alone identified 97% of the MSI-H cases correctly. As expected, the presence of MSI-H correlated with an older age of diagnosis, the presence of tumor in the proximal colon, and female sex. Source


McGowan R.,Laboratory Medicine Building | Tydeman G.,Victoria Hospital | Shapiro D.,Royal Infirmary | Craig T.,Laboratory Genetics | And 7 more authors.
Fertility and Sterility | Year: 2015

Objective: To clinically and genetically investigate women with müllerian disorders, including Mayer-Rokitanksy-Kuster-Hauser (MRKH) syndrome. Design: Two-year prospective clinical and laboratory study. Setting: Not applicable. Patient(s): Thirty-five women over 16 years of age with a müllerian disorder, including MRKH. Intervention(s): Women were recruited from specialist gynecology clinics or identified from the Scottish Disorders of Sex Development Register (www.sdsd.scot.nhs.uk/index.html). Associated abnormalities were detected by clinical examination, imaging studies, and biochemical analyses. Chromosomal microduplications and microdeletions were detected by array comparative genomic hybridization (CGH) and validated by fluorescence in situ hydridization. Main Outcome Measure(s): Identification of associated congenital and biochemical abnormalities and identification of regions of genomic imbalance using array CGH. Result(s): Associated congenital anomalies were common, present in 25/35 (71%) of affected women, particularly renal and skeletal abnormalities, which were present in 15/35 (43%) and 17/35 (49%) women, respectively. Using array CGH, novel or recurrent regions of genomic imbalance were identified in 4/11 (36%) women with MRKH and in 5/24 (21%) women with other müllerian abnormalities. Conclusion(s): Additional congenital abnormalities and regions of genomic imbalance are common in women with müllerian disorders, including MRKH. Recurrent microdeletions and microduplications associated with MRKH implicate specific possibly causative genes. The investigation of women with müllerian disorders should be thorough, and array CGH should be considered, given the potential highly significant familial implications of a chromosomal abnormality. Source

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