| 1. |
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| 2. |
- Langbehn, D, et al.
(författare)
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A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length.
- 2004
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 65:4, s. 267-277
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a neurodegenerative disorder caused by an unstable CAG repeat. For patients at risk, participating in predictive testing and learning of having CAG expansion, a major unanswered question shifts from "Will I get HD?" to "When will it manifest?" Using the largest cohort of HD patients analyzed to date (2913 individuals from 40 centers worldwide), we developed a parametric survival model based on CAG repeat length to predict the probability of neurological disease onset (based on motor neurological symptoms rather than psychiatric onset) at different ages for individual patients. We provide estimated probabilities of onset associated with CAG repeats between 36 and 56 for individuals of any age with narrow confidence intervals. For example, our model predicts a 91% chance that a 40-year-old individual with 42 repeats will have onset by the age of 65, with a 95% confidence interval from 90 to 93%. This model also defines the variability in HD onset that is not attributable to CAG length and provides information concerning CAG-related penetrance rates.
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| 3. |
- Ljung, R, et al.
(författare)
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Fanconi's anaemia associated with haemophilia A
- 1979
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 16:5, s. 8-364
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Tidskriftsartikel (refereegranskat)abstract
- Fanconi's anaemia and haemophilia A are born inherited diseases creating haemostatic defects. The association of these two rare diseases in one patient is described. The patient's haemophilia was studied with a newly developed immunological technique determining the plasma antigen associated with Factor VIII activity, and was found to be a genetic variant of moderately severe haemophilia A. It was not possible to demonstrate a common bone marrow defect or a common immunological or genetical background of the two diseases. The double haemostatic defect created, i.e. Factor VIII deficiency and thrombocytopenia, resulted in only a slight increase in bleeding tendency. A favourable result was obtained with corticosteroid and androgenic treatment.
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| 4. |
- Ljung, R, et al.
(författare)
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Haemophilia A and B--two years experience of genetic counselling and prenatal diagnosis
- 1982
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 22:2, s. 70-75
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Tidskriftsartikel (refereegranskat)abstract
- Haemophilia A. Thirty-one pregnant women, obligate or probable carriers of haemophilia A, requested prenatal diagnosis if sex determination showed the foetus to be a male. In 11 of the 31 cases the foetuses were females; in two, the genetic variant of the disease rendered prenatal diagnosis impossible; and in two, the mother aborted spontaneously. From the remaining 16 male foetuses, blood samples were obtained in utero in the 17th to 20th week of gestation. Examination of the samples showed that 11 of the foetuses were unaffected and five affected. Haemophilia B. Three carriers of haemophilia B had male foetuses. Examination of foetal blood obtained in utero showed that these three foetuses were affected. Confirmation. All women with an affected foetus requested termination of pregnancy. In one of the cases of abortion, no blood was obtained for confirmative examination. In the remaining cases, the prenatal prediction was confirmed in the abortus or in the child after birth; three women are still pregnant.
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| 5. |
- Ljung, R, et al.
(författare)
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How do carriers of hemophilia experience prenatal diagnosis by fetal blood sampling?
- 1987
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 31:5, s. 297-302
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Tidskriftsartikel (refereegranskat)abstract
- A semistructured personal interview was performed with 29 carriers of hemophilia A or B, 1-4 years after a pregnancy in which prenatal diagnosis (PND) of hemophilia was performed by fetal blood sampling. The carriers had received different recommendations regarding future pregnancies, and 14/29 did not know before they became pregnant that PND by fetal blood sampling was possible. One third of the women felt that important information was lacking in the consultations that preceded the PND. The conclusions regarding future genetic counselling are that more attention should be paid to improving education of all female carriers before a pregnancy, to motivating fathers-to-be to attend counselling sessions with the carriers, and to emphasizing the importance of the emotional support given by the family doctor and by other females who have experienced PND.
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| 6. |
- Peacock, Rachel E, et al.
(författare)
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Associations of genotypes at the apolipoprotein AI-CIII-AIV, apolipoprotein B and lipoprotein lipase gene loci with coronary atherosclerosis and high density lipoprotein subclasses
- 1994
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 46:4, s. 273-282
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Tidskriftsartikel (refereegranskat)abstract
- Association studies were carried out in a sample of 86 patients from Sweden who had survived a myocardial infarction (MI) at a young age and 93 age-matched healthy individuals, to compare the impact of polymorphisms at the apolipoprotein (apo) AI-CIII-AIV gene cluster on among-individual differences in plasma lipid and lipoprotein traits, the five high density lipoprotein (HDL) subclasses (2b to 3c), lipoprotein lipase (LPL) activity and presence and progression of atherosclerosis. Individuals were genotyped for four polymorphisms; 5'apoAI (G/A-75), 3'apoAI (PstI; P +/-), apoCIII (C/T1100) and apoCIII (PvuII; V +/-), using PCR-based techniques. Allele frequencies were similar in healthy individuals and patients (frequencies of alleles in combined population: 5'apoAI-A-75 = 0.14, 3'apoAI-P- = 0.05, apoCIII-T1100 = 0.27 and apoCIII-V- = 0.18). In the healthy individuals, levels of low density lipoprotein (LDL) triglycerides were significantly associated with genotypes of the apoCIII-PvuII polymorphism (p = 0.02), but no other associations were found between lipids or HDL subclasses and single polymorphisms in the apoAI-CIII-AIV gene cluster. Levels of triglycerides and very low density lipoprotein (VLDL) triglycerides were significantly higher in the presence of the haplotype defined by the presence of apoCIII-T1100 and common alleles of the other three polymorphisms, explaining 5.8% and 7.8% (p = 0.03 and 0.01), respectively, of sample variance. In the patients, no associations were found between lipids or HDL subclasses and variation at the apoAI-CIII-AIV gene cluster. Associations were also examined between levels of HDL subclasses and variation at the apoE (common isoforms), apoB (signal peptide and XbaI polymorphisms) and lipoprotein lipase (PvuII, HindIII and Serine447/Stop polymorphisms) gene loci. In the patient group only, levels of protein in HDL2b, HDL2a and HDL3b subclasses were significantly associated with genotypes of the LPL-HindIII polymorphism (22.1, 19.3 and 11.4%, respectively, of sample variance; p < 0.05). Finally, associations were examined between genotypes at the apoAI-CIII-AIV gene cluster and the extent of coronary atherosclerosis. Global severity of atherosclerosis at the first angiography was weakly associated with genotypes of the apoCIII-C/T1100 polymorphism, presence of the T1100 allele being associated with 53% lower median score (1.6 vs 0.75; p = 0.09).(ABSTRACT TRUNCATED AT 400 WORDS)
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| 7. |
- Wincent, J, et al.
(författare)
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CHD7 mutation spectrum in 28 Swedish patients diagnosed with CHARGE syndrome
- 2008
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 74:1, s. 31-38
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Tidskriftsartikel (refereegranskat)abstract
- CHARGE syndrome is a disorder characterized by Coloboma, Heart defect, Atresia choanae, Retarded growth and/or development, Genital hypoplasia and Ear anomalies. Heterozygous mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene have been identified in about 60% of individuals diagnosed with CHARGE syndrome. We performed a CHD7 mutation screening by direct exon sequencing in 28 index patients (26 sporadic cases, 1 familial case consisting of a brother and sister and 1 case consisting of monozygotic twins) diagnosed with CHARGE syndrome in order to determine the mutations in a cohort of Swedish CHARGE syndrome patients. The patients without a detectable CHD7 mutation, or with a missense mutation, were further investigated by multiplex ligation-dependent probe amplification (MLPA) in order to search for intragenic deletions or duplications. Thirteen novel mutations and five previously reported mutations were detected. The mutations were scattered throughout the gene and included nonsense, frameshift and missense mutations as well as intragenic deletions. In conclusion, CHD7 mutations were detected in a large proportion (64%) of cases diagnosed with CHARGE syndrome. Screening for intragenic deletions with MLPA is recommended in cases where mutations are not found by sequencing. In addition, a CDH7 mutation was found in an individual without temporal bone malformation.
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| 8. |
- Halgren, Christina, et al.
(författare)
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Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B
- 2012
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Ingår i: Clinical Genetics. - : John Wiley & Sons. - 0009-9163 .- 1399-0004. ; 82:3, s. 248-255
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.
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| 9. |
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| 10. |
- Almqvist, E W, et al.
(författare)
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Psychological consequences and predictors of adverse events in the first 5 years after predictive testing for Huntington's disease.
- 2003
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 64:4, s. 300-9
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Tidskriftsartikel (refereegranskat)abstract
- The promise of genetic medicine is to provide information, based on genotype, to persons not yet sick about their risk of future illness. However, little is known of the long-term psychological effects for asymptomatic persons learning their risk of having a serious disease. Predictive genetic testing for Huntington's disease (HD) has been offered for the longest time for any disease. In the present study, the psychological consequences of predictive testing were assessed prospectively in individuals at risk for HD during seven visits over 5 years. Questionnaires of standard measures of psychological distress (the General Severity Index of the Symptom Check List-90-Revised), depression (the Beck Depression Inventory), and general well-being (the General Well-Being Scale) were administered to the participants. A significant reduction in psychological distress was observed for both result groups throughout 2 years (p < 0.001) and at 5 years (p = 0.002). Despite the overall improvement of the psychological well-being, 6.9% (14 of 202) of the participants experienced an adverse event during the first 2 years after predictive testing that was clinically significant. The frequency of all defined adverse events in the participants was 21.8%, with higher frequency in the increased risk group (p = 0.03) and most occurring within 12 months of receiving results.
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| 11. |
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| 12. |
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| 14. |
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| 15. |
- Cario, Holger, et al.
(författare)
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A microdeletion syndrome due to a 3-Mb deletion on 19q13.2--Diamond-Blackfan anemia associated with macrocephaly, hypotonia, and psychomotor retardation
- 1999
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 55:6, s. 487-92
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Tidskriftsartikel (refereegranskat)abstract
- We report on a boy with congenital pure red blood cell aplasia [Diamond Blackfan anemia (DBA)] and severe congenital hypotonia, macrocephaly, hypertelorism, a broad and tall forehead, medial epicanthus, and facial hypotonia with mouth-breathing and drooling, an affable and out-going personality, and a general psychomotor retardation. These features show similarity to the phenotype of the X-linked FG syndrome. DBA was diagnosed at the age of 4 months, and the boy underwent treatment with transfusion and with prednisolone. He had a normal 46, XY karyotype, but fluorescence in situ hybridization (FISH) analysis to metaphase chromosomes revealed a 3-Mb deletion on 19q13.2. This chromosomal region has previously been linked to the DBA phenotype and one 19q13 microdeletion has been identified in a patient with DBA. This deletion coincides with the deletion reported here. We suggest that the complex phenotype of our patient, including both DBA and the associated features, represent a microdeletion syndrome.
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| 16. |
- Cederquist, Kristina, et al.
(författare)
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Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.
- 2005
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 68:6, s. 533-541
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Tidskriftsartikel (refereegranskat)abstract
- Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.
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| 17. |
- Hu, F.Z., et al.
(författare)
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Mapping of an autosomal dominant gene for Dupuytren's contracture to chromosome 16q in a Swedish family
- 2005
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Ingår i: Clinical Genetics. - Oxford : Wiley. - 0009-9163 .- 1399-0004. ; 68:5, s. 424-429
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Tidskriftsartikel (refereegranskat)abstract
- Dupuytren's contracture (DC) (OMIM 126900) is the most common connective tissue disease of mankind and has both heritable and sporadic forms. The inherited form is most frequently observed among the xanthochroi peoples of Northern Europe where its most common manifestations are thickening of the palmar fascia and contracture of the fingers. We ascertained a five-generation Swedish family in which DC is inherited in an autosomal dominant manner with high, but incomplete, penetrance by the end of the fifth decade. Blood was collected from all affected and informative unaffected family members for the performance of a genome-wide scan at a resolution of approximately 8 cM for all autosomes. Linkage was established to a single 6 cM region between markers D 16S419 and D 16S3032 on chromosome 16. A maximal two-point logarithm of odds (LOD) score of 3.18 was achieved at microsatellite marker D16S415 with four other markers in the region producing LODs of > 1.5. © Blackwell Munksgaard, 2005.
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| 18. |
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| 20. |
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| 21. |
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| 22. |
- Nyström, Anna-Maja, et al.
(författare)
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Noonan syndrome and Neurofibromatosis type I in a family with a novel mutation in NF1
- 2009
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 76:6, s. 524-534
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Tidskriftsartikel (refereegranskat)abstract
- Noonan Syndrome (NS) and Neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, while skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 - a condition known as Neurofibromatosis-Noonan Syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.
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| 23. |
- Olsson, Malin, 1972-, et al.
(författare)
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Mitochondrial haplogroup is associated with the phenotype of familial amyloidosis with polyneuropathy in Swedish and French patients
- 2009
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 75:2, s. 163-168
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Tidskriftsartikel (refereegranskat)abstract
- Familial amyloidotic polyneuropathy (FAP) is a monogenic disease caused by mutations in the transthyretin (TTR) gene. The phenotype of the most common TTR mutation, V30M, varies within and between populations. Oxidative stress and protein misfolding are cellular processes involved in the development of FAP. Because the mitochondria are important for both these processes, we investigated if mitochondrial haplogroups are related to age at onset of the disease in Swedish and French FAP patients. Mitochondrial haplogroup analysis was performed on 25 early-onset (below 40 years) and 29 late-onset (above 51 years) Swedish FAP patients. DNA from 249 Swedish individuals served as controls. In addition, 6 early-onset and 17 late-onset French FAP patients were examined with 25 French controls. The haplogroup distribution among late-onset Swedish and French cases was similar to that found in the general populations, whereas among early-onset cases a different haplogroup distribution was seen. The relatively rare haplogroup K was significantly more common among early-onset cases. Our findings substantiate the suggestion that a genetic component, still to be found, affecting mitochondrial function has an impact on the amyloid generating process in transthyretin amyloidosis.
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| 24. |
- Rafiq, M. A., et al.
(författare)
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Mapping of three novel loci for non-syndromic autosomal recessive mental retardation (NS-ARMR) in consanguineous families from Pakistan
- 2010
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 78:5, s. 478-483
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Tidskriftsartikel (refereegranskat)abstract
- To date, of 13 loci with linkage to non-syndromic autosomal recessive mental retardation (NS-ARMR), only six genes have been established with associated mutations. Here we present our study on NS-ARMR among the Pakistani population, where people are traditionally bound to marry within the family or the wider clan. In an exceptional, far-reaching genetic survey we have collected more than 50 consanguineous families exhibiting clinical symptoms/phenotypes of NS-ARMR. In the first step, nine families (MR2-9 and MR11) with multiple affected individuals were selected for molecular genetic studies. Two families (MR3, MR4) showed linkage to already know NS-ARMR loci. Fifteen affected and 10 unaffected individuals from six (MR2, MR6, MR7, MR8, MR9 and MR11) families were genotyped by using Affymetrix 5.0 or 6.0 single-nucleotide polymorphism (SNP) microarrays. SNP microarray data was visually inspected by dChip and genome-wide homozygosity analysis was performed by HomozygosityMapper. Additional mapping was performed (to exclude false-positive regions of homozygosity called by HomozygosityMapper and dChip) on all available affected and unaffected members in seven NS-ARMR families, using microsatellite markers. In this manner we were able to map three novel loci in seven different families originating from different areas of Pakistan. Two families (MR2, MR5) showed linkage on chromosome 2p25.3-p25.2. Three families (MR7, MR8, and MR9) that have been collected from the same village and belong to the same clan were mapped on chromosome 9q34.3. MR11 maps to a locus on 9p23-p13.3. Analysis of MR6 showed two positive loci, on chromosome 1q23.2-q23.3 and 8q24.21-q24.23. Genotyping in additional family members has so far narrowed, but not excluded the 1q locus. In summary, through this study we have identified three new loci for NS-ARMR, namely MRT14, 15 and 16.
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| 25. |
- Shen, M. H., et al.
(författare)
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Detection of copy number changes at the NF1 locus with improved high-resolution array CGH
- 2007
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 72:3, s. 238-244
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Tidskriftsartikel (refereegranskat)abstract
- Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease caused by various types of mutations in the NF1 gene. We have previously developed a locus-specific DNA microarray for detection of copy number changes at the NF1 locus by comparative genomic hybridization (CGH) analysis. The original array contains 183 probes pooled from 444 polymerase chain reaction (PCR) products. In the current work, we have used 493 probes derived from single PCR products (200-998 bp in size) to construct a higher resolution array with a smaller average probe size for molecular diagnosis of NF1. This has improved the average resolution from 12.6 kb in the previous array to 4.5 kb in the current version. The performance of the newly constructed microarray was validated with 14 well-characterized NF1 mutations for CGH analysis. These mutations represent deletions from ∼7 kb to over 2 Mb in size. Using this array, we examined a total of 55 NF1 patients for copy number changes at the NF1 locus, detecting deletions in four of them. These results demonstrate that a locus-specific microarray constructed from single PCR products can efficiently detect copy number changes at the NF1 locus, providing a simple method for the molecular diagnosis of NF1.
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