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24-h ambulatory blood pressure is linked to chromosome 18q21-22 and genetic variation of NEDD4L associates with cross-sectional and longitudinal blood pressure in Swedes.

https://arctichealth.org/en/permalink/ahliterature81774
Source
Kidney Int. 2006 Aug;70(3):562-9
Publication Type
Article
Date
Aug-2006
Author
Fava C.
von Wowern F.
Berglund G.
Carlson J.
Hedblad B.
Rosberg L.
Burri P.
Almgren P.
Melander O.
Author Affiliation
Department of Clinical Sciences, University Hospital MAS, Malmö, Sweden.
Source
Kidney Int. 2006 Aug;70(3):562-9
Date
Aug-2006
Language
English
Publication Type
Article
Keywords
Adult
Alternative Splicing
Antihypertensive Agents - therapeutic use
Blood Pressure - genetics
Blood Pressure Monitoring, Ambulatory
Chromosomes, Human, Pair 18
Circadian Rhythm
Cross-Sectional Studies
Female
Genetic Predisposition to Disease - epidemiology
Genotype
Humans
Hypertension - drug therapy - epidemiology - genetics
Insulin - blood
Linkage (Genetics)
Longitudinal Studies
Male
Middle Aged
Phenotype
Polymorphism, Single Nucleotide
Risk factors
Sweden - epidemiology
Ubiquitin-Protein Ligases - genetics
Variation (Genetics)
Abstract
Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
PubMed ID
16788695 View in PubMed
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Analysis of PARK2 gene exon rearrangements in Russian patients with sporadic Parkinson's disease.

https://arctichealth.org/en/permalink/ahliterature131315
Source
Mov Disord. 2012 Jan;27(1):139-42
Publication Type
Article
Date
Jan-2012
Author
Elena V Semenova
Maria I Shadrina
Pyotr A Slominsky
Irina A Ivanova-Smolenskaya
Gulbakhar Bagyeva
Sergei N Illarioshkin
Svetlana A Limborska
Author Affiliation
Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia.
Source
Mov Disord. 2012 Jan;27(1):139-42
Date
Jan-2012
Language
English
Publication Type
Article
Keywords
Adult
Aged
Exons - genetics
Female
Gene Rearrangement - genetics
Humans
Male
Middle Aged
Parkinson Disease - classification - epidemiology - genetics
Russia - epidemiology
Ubiquitin-Protein Ligases - genetics
Young Adult
Abstract
Deletions and duplications of single exons or exon groups account for a large proportion of the PARK2 gene mutations described in juvenile autosomal recessive Parkinson's disease (PD).
We analyzed rearrangements in exons 1 to 12 of the PARK2 gene in Russian sporadic patients with early-onset PD (EOPD) and late-onset PD (LOPD).
The frequency of EOPD and LOPD patients carrying these mutations was 12.4% and 3.8%, respectively. The most frequent rearrangements were detected in exons 3 and 4. The odds ratio for EOPD in individuals carrying PARK2 exon deletions and duplications was 13.95 (95% confidence interval [CI], 1.846-105.46; P = .0022). In addition, we found a correlation between exon rearrangements in PARK2 and the age at onset of PD, presence of dystonia, and symmetrical course of the disease.
Exon rearrangements in the PARK2 gene play a significant role in the pathogenesis of sporadic PD in Russian patients.
PubMed ID
21915905 View in PubMed
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The BARD1 Cys557Ser variant and breast cancer risk in Iceland.

https://arctichealth.org/en/permalink/ahliterature81881
Source
PLoS Med. 2006 Jul;3(7):e217
Publication Type
Article
Date
Jul-2006
Author
Stacey Simon N
Sulem Patrick
Johannsson Oskar T
Helgason Agnar
Gudmundsson Julius
Kostic Jelena P
Kristjansson Kristleifur
Jonsdottir Thora
Sigurdsson Helgi
Hrafnkelsson Jon
Johannsson Jakob
Sveinsson Thorarinn
Myrdal Gardar
Grimsson Hlynur Niels
Bergthorsson Jon T
Amundadottir Laufey T
Gulcher Jeffrey R
Thorsteinsdottir Unnur
Kong Augustine
Stefansson Kari
Author Affiliation
deCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.is
Source
PLoS Med. 2006 Jul;3(7):e217
Date
Jul-2006
Language
English
Publication Type
Article
Keywords
Adult
Age of Onset
Aged
Alleles
Amino Acid Substitution
Breast Neoplasms - ethnology - genetics
Carcinoma in Situ - ethnology - genetics
Carcinoma, Ductal, Breast - ethnology - genetics
Carcinoma, Intraductal, Noninfiltrating - ethnology - genetics
Carcinoma, Lobular - ethnology - genetics
Carcinoma, Medullary - ethnology - genetics
Case-Control Studies
Cluster analysis
Cohort Studies
Female
Founder Effect
Gene Frequency
Genes, BRCA2
Genetic Predisposition to Disease
Genotype
Haplotypes
Humans
Iceland - epidemiology
Middle Aged
Mutation, Missense
Neoplastic Syndromes, Hereditary - ethnology - genetics
Odds Ratio
Point Mutation
Polymorphism, Single Nucleotide
Risk
Sequence Deletion
Tumor Suppressor Proteins - genetics - physiology
Ubiquitin-Protein Ligases - genetics - physiology
Abstract
BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
PubMed ID
16768547 View in PubMed
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BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition.

https://arctichealth.org/en/permalink/ahliterature171664
Source
Eur J Hum Genet. 2006 Feb;14(2):167-72
Publication Type
Article
Date
Feb-2006
Author
Pia Vahteristo
Kirsi Syrjäkoski
Tuomas Heikkinen
Hannaleena Eerola
Kristiina Aittomäki
Karl von Smitten
Kaija Holli
Carl Blomqvist
Olli-Pekka Kallioniemi
Heli Nevanlinna
Author Affiliation
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. pia.vahteristo@helsinki.fi
Source
Eur J Hum Genet. 2006 Feb;14(2):167-72
Date
Feb-2006
Language
English
Publication Type
Article
Keywords
Breast Neoplasms - genetics
DNA Mutational Analysis
Female
Finland
Gene Frequency
Genetic Predisposition to Disease
Genotype
Humans
Mutation, Missense - genetics
Tumor Suppressor Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Abstract
BARD1 (BRCA1-associated RING-domain 1) is a tumor suppressor whose protein product interacts with BRCA1, and in which rare somatic and germline mutations have been reported in breast, uterine, and endometrial cancers. We aimed to evaluate whether there are BARD1 genetic variants that contribute to breast cancer risk by screening the gene for germline alterations in 45 Finnish familial breast cancer patients and in seven patients with both breast and ovarian cancer. Two of the missense alterations identified (Cys557Ser and Val507Met) were recently suggested to associate with an increased breast cancer risk. We also analyzed these variants in large and independent series of familial and unselected breast cancer patients and healthy controls. No clearly deleterious mutations were detected in the initial mutation screening. No association of the Cys557Ser and breast cancer risk was observed as the variant was found altogether in 1.4% (16/1181) of familial and 2.2% (34/1565) of unselected breast cancer patients, and in 2.5% (27/1083) of healthy controls. The frequency of the Val-allele of the Val507Met variant was modestly higher among breast cancer patients than among healthy controls, although the difference did not reach statistical significance. No statistically significant association of the Cys557Ser or Val507Met variants with any clinicopathologic parameters was observed. These results suggest that the contribution of the BARD1 germline variants to breast cancer predisposition is very limited, and that neither Cys557Ser nor Val507Met have an effect on familial breast cancer susceptibility.
PubMed ID
16333312 View in PubMed
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Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.

https://arctichealth.org/en/permalink/ahliterature181962
Source
Blood. 2004 May 15;103(10):3924-32
Publication Type
Article
Date
May-15-2004
Author
Victor R Gordeuk
Adelina I Sergueeva
Galina Y Miasnikova
Daniel Okhotin
Yaroslav Voloshin
Peter L Choyke
John A Butman
Katerina Jedlickova
Josef T Prchal
Lydia A Polyakova
Author Affiliation
Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, DC 20059, USA. vgordeuk@howard.edu
Source
Blood. 2004 May 15;103(10):3924-32
Date
May-15-2004
Language
English
Publication Type
Article
Keywords
Adaptation, Physiological - genetics
Adolescent
Adult
Anoxia - congenital - genetics
Child
Cross-Sectional Studies
Female
Homozygote
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Male
Mutation
Neoplasms - genetics
Polycythemia - complications - epidemiology - genetics - mortality
Retrospective Studies
Russia - epidemiology
Survival Rate
Syndrome
Thrombosis - etiology - genetics
Transcription Factors - blood
Tumor Suppressor Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Vascular Diseases - etiology - genetics
Vascular Endothelial Growth Factor A - blood
Von Hippel-Lindau Tumor Suppressor Protein
Abstract
Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C>T) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C>T homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1alpha (HIF-1alpha), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, VHL 598C>T homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P T homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.
PubMed ID
14726398 View in PubMed
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Danish retinoblastoma patients 1943-2013 - genetic testing and clinical implications.

https://arctichealth.org/en/permalink/ahliterature278508
Source
Acta Oncol. 2016;55(4):412-7
Publication Type
Article
Date
2016
Author
Pernille A Gregersen
Steen F Urbak
Mikkel Funding
Jens Overgaard
Uffe B Jensen
Jan Alsner
Source
Acta Oncol. 2016;55(4):412-7
Date
2016
Language
English
Publication Type
Article
Keywords
Child
Child, Preschool
Denmark - epidemiology
Genetic Counseling
Genetic Testing - statistics & numerical data
Humans
Infant
Mutation
Retinal Neoplasms - epidemiology - genetics
Retinoblastoma - epidemiology - genetics
Retinoblastoma Binding Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Abstract
In heritable retinoblastoma there is a 50% risk of transmitting the RB1 mutation, and offspring carriers have more than 90% risk of developing retinoblastoma. Today, all newly diagnosed retinoblastoma patients in Denmark are screened for mutations in RB1, as opposed to only a minority of patients diagnosed before DNA testing was offered. Knowledge of heredity increases the chance of early diagnosis in offspring, leading to improved prognosis. We present data from the Danish retinoblastoma patients that emphasize the need for genetic counseling and RB1 screening in all untested retinoblastoma survivors.
Data are extracted from The Danish Ocular Oncology Group Database, a national population database containing data on all Danish retinoblastoma patients since 1943.
In total 323 retinoblastoma patients have been diagnosed between 1943 and 2013. Since 1963, the rate has been stable around 1 per 14 000 live births with 95% of the patients surviving their retinoblastoma. Stratifying data on the time of diagnosis and status of genetic testing, the number of screened patients gradually increased from 5% in the beginning of the period to 96% in the last five-year period. A cohort of 181 retinoblastoma survivors with sporadic disease (15% heritable) did not receive genetic testing. Since the introduction of routine testing, one of 14 sporadic unilateral patients tested (7%) has been identified with a germline mutation. Before routine testing, five additional sporadic unilateral patients have been identified as heritable.
Only a minority of Danish retinoblastoma patients diagnosed before routine genetic testing was offered have been RB1 screened. To counsel the remaining untested patients and their families sufficiently regarding the risk to offspring and elevated risk of second primary cancers, we recommend information and access to genetic counseling and RB1 screening. This has ethical, psychological and possible economic consequences, and should be handled with caution.
PubMed ID
26494512 View in PubMed
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Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.

https://arctichealth.org/en/permalink/ahliterature107038
Source
PLoS Genet. 2013;9(9):e1003723
Publication Type
Article
Date
2013
Author
Mélissa Beaudoin
Philippe Goyette
Gabrielle Boucher
Ken Sin Lo
Manuel A Rivas
Christine Stevens
Azadeh Alikashani
Martin Ladouceur
David Ellinghaus
Leif Törkvist
Gautam Goel
Caroline Lagacé
Vito Annese
Alain Bitton
Jakob Begun
Steve R Brant
Francesca Bresso
Judy H Cho
Richard H Duerr
Jonas Halfvarson
Dermot P B McGovern
Graham Radford-Smith
Stefan Schreiber
Philip L Schumm
Yashoda Sharma
Mark S Silverberg
Rinse K Weersma
Mauro D'Amato
Severine Vermeire
Andre Franke
Guillaume Lettre
Ramnik J Xavier
Mark J Daly
John D Rioux
Author Affiliation
Montreal Heart Institute, Research Center, Montreal, Quebec, Canada.
Source
PLoS Genet. 2013;9(9):e1003723
Date
2013
Language
English
Publication Type
Article
Keywords
CARD Signaling Adaptor Proteins - genetics
Canada
Colitis, Ulcerative - genetics - pathology
Crohn Disease - genetics - pathology
Ethnic Groups
Genetic Predisposition to Disease
Genome-Wide Association Study
High-Throughput Nucleotide Sequencing
Humans
Polymorphism, Single Nucleotide
Receptors, Interleukin - genetics
Ubiquitin-Protein Ligases - genetics
Abstract
Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.
Notes
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PubMed ID
24068945 View in PubMed
Less detail
Source
Mov Disord. 2007 Mar 15;22(4):585-7
Publication Type
Article
Date
Mar-15-2007
Author
Haugarvoll Kristoffer
Toft Mathias
Ross Owen A
Stone Jeremy T
Heckman Michael G
White Linda R
Lynch Timothy
Gibson John Mark
Wszolek Zbigniew K
Uitti Ryan J
Aasly Jan O
Farrer Matthew J
Author Affiliation
Department of Neuroscience and Neurology, Mayo Clinic College of Medicine, Jacksonville, Florida, USA. haugarvoll.kristoffer@mayo.edu
Source
Mov Disord. 2007 Mar 15;22(4):585-7
Date
Mar-15-2007
Language
English
Publication Type
Article
Keywords
Adult
Age Factors
Aged
Aged, 80 and over
Alleles
Female
Genetic markers
Genetic Predisposition to Disease
Hu Paraneoplastic Encephalomyelitis Antigens - genetics
Humans
Linkage (Genetics) - genetics
Male
Middle Aged
Norway - ethnology
Parkinson Disease - ethnology - genetics
Point Mutation - genetics
Protein-Serine-Threonine Kinases - genetics
Ubiquitin-Protein Ligases - genetics
United States
Abstract
Genetic variability in ELAVL4 located in the PARK10 locus was recently associated with age-at-onset (AAO) in a series of Parkinson's disease (PD) patients originating from the United States. We examined five markers spanning ELAVL4 in Norwegian, United States, and Irish PD case-control samples. No association was found between the examined markers and AAO or PD in Norwegian or US samples. However, ELAVL4 markers (rs967582 and rs3902720) were significantly associated with susceptibility to PD in our Irish series. Our data suggest that the association between ELAVL4 and PD previously observed might be explained by a Celtic-founder effect.
PubMed ID
17230446 View in PubMed
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Epilepsy and cataplexy in Angelman syndrome. Genotype-phenotype correlations.

https://arctichealth.org/en/permalink/ahliterature281183
Source
Res Dev Disabil. 2016 Sep;56:177-82
Publication Type
Article
Date
Sep-2016
Author
Line Granild Bie Mertz
Rikke Christensen
Ida Vogel
Jens Michael Hertz
John R Østergaard
Source
Res Dev Disabil. 2016 Sep;56:177-82
Date
Sep-2016
Language
English
Publication Type
Article
Keywords
Age of Onset
Angelman Syndrome - complications - genetics
Base Sequence
Cataplexy - complications - genetics
Child
Chromosomes, Human, Pair 15 - genetics
Comparative Genomic Hybridization
Denmark
Epilepsy - complications - genetics
Female
Genotype
Humans
Male
Mutation
Phenotype
Sequence Deletion
Ubiquitin-Protein Ligases - genetics
Uniparental Disomy - genetics
Abstract
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, epilepsy, and low threshold for laughter.
We investigated the occurrence and severity of epilepsy and laughter-induced loss of postural muscle tone determined by the different genetic subtypes.
This study included 39 children with AS. Deletion breakpoints were determined by high resolution CGH microarray (1×1M Agilent). Clinical data were based on a parent interview and medical record review.
All patients with AS based on a deletion had epilepsy. Epilepsy was present in 3/4 children with UBE3A mutation, and 4/5 with pUPD. Onset of epilepsy occurred earlier in deletion cases compared to pUPD or UBE3A mutations cases. Laughter-induced postural muscle tone loss occurred only among deletion cases. We found no differences in severity of epilepsy between children with a larger Class I or a smaller Class II deletions, or between the total group with a deletion compared to children with pUPD or a UBE3A mutation. The drugs most frequently prescribed were benzodiazepines in monotherapy, or a combination of benzodiazepines and valproic acid.
Epilepsy is very common in patients with AS, especially in patients with a deletion. Postural muscle tone loss and collapsing during outbursts of laughter were seen in patients with a deletion only.
PubMed ID
27323320 View in PubMed
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Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families.

https://arctichealth.org/en/permalink/ahliterature108069
Source
BMC Med Genet. 2013;14:82
Publication Type
Article
Date
2013
Author
Maria Haanpää
Katri Pylkäs
Jukka S Moilanen
Robert Winqvist
Author Affiliation
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, Institute of Diagnostics, University of Oulu, P,O, Box 5000, 90014 Oulu, Finland.
Source
BMC Med Genet. 2013;14:82
Date
2013
Language
English
Publication Type
Article
Keywords
Adult
Alleles
BRCA2 Protein - genetics
Breast Neoplasms - diagnosis - epidemiology - genetics
Cohort Studies
European Continental Ancestry Group - genetics
Female
Finland - epidemiology
Genetic Predisposition to Disease
Genetic Testing
Germ-Line Mutation
Heterozygote
Humans
Middle Aged
Nuclear Proteins - genetics
Pedigree
Risk factors
Tumor Suppressor Proteins - genetics
Ubiquitin-Protein Ligases - genetics
Abstract
Testing for mutations in the BRCA1 and BRCA2 genes among high-risk breast cancer patients has become a routine practice among clinical geneticists. Unfortunately, however, the genetic background of a majority of the cases coming to the clinics remains currently unexplained, making genetic counseling rather challenging. In recent years it has become evident world-wide that also women carrying a heterozygous germline mutation in PALB2 are at significantly increased risk of getting breast cancer. We have previously studied the clinical as well as biological impact of the PALB2 c.1592delT founder mutation occurring in about 1% of Finnish breast cancer patients unselected for their family history of disease, and our results demonstrated a 40% increased breast cancer risk by age 70 for female mutation carriers. Thus, this relatively common mutation in PALB2 is associated with a high risk of developing breast cancer. The aim of the current study was to analyze whether female index individuals of breast cancer families who had tested negative for germline mutations in BRCA1/BRCA2 as part of genetic counseling services should be offered mutation testing for PALB2 c.1592delT.
The study cohort consisted of altogether 223 individuals who had contacted the Department of Clinical Genetics at the Oulu University Hospital in Finland between the years 1997 and 2011 for counseling on hereditary breast and/or ovarian cancer risk. 101 of them met our inclusion criteria. Of these, 10 persons were now deceased, but 6 of them had participated in one of our previous studies on PALB2. Seventy (77%) of the remaining 91 persons responded positively to our study invitation. Chart review of updated pedigree data led to the exclusion of 14 further individuals not meeting the selection criteria.
Of the 56 alive affected female individuals screened for PALB2 c.1592delT, altogether two (3.6%) tested positive for this mutation. In addition, of the previously tested but now deceased 6 persons eligible for the current study, one more mutation carrier was observed. Therefore, overall 4.8% (3/62) of the tested individuals belonging to the Northern Finnish 1997-2011 study cohort turned out to be carriers of the PALB2 c.1592delT allele.
Given the potential benefits versus harms of this testing, the result of our study suggest that PALB2 c.1592delT should be a routine part of the genetic counseling protocol for Finnish high-risk breast cancer cases tested negative for mutations in BRCA1/BRCA2.
Notes
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PubMed ID
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