| 1. |
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| 2. |
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| 3. |
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| 4. |
- Almqvist, E W, et al.
(författare)
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High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia.
- 2001
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 60:3, s. 198-205
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Tidskriftsartikel (refereegranskat)abstract
- The advent of the direct mutation test for Huntington disease (HD) has made it possible to identify a previously unrecognized symptomatic population of HD, including those with an atypical presentation or patients without a family history of HD. The present study investigated the uptake of this test in the province of British Columbia (BC), Canada and assessed the incidence rate and rate of identification of new mutations for HD. All symptomatic individuals residing in BC who were referred for the genetic test for HD between 1993 and 2000 (n=205) were analyzed for CAG expansion, baseline demographics and clinical data, and a family history of HD. A total of 141 (or 68.8%) had a CAG expansion > or =36. Of these, almost one-quarter (24.1%) did not have a family history of HD. An extensive chart review revealed that 11 patients (or 7.8%) had reliable information on both parents (who lived well into old age) and therefore possibly could represent new mutations for HD. This indicates a three to four times higher new mutation rate than previously reported. Our findings also show that the yearly incidence rate for HD was 6.9 per million, which is two times higher than previous incidence studies performed prior to the identification of the HD mutation. We also identified five persons with a clinical presentation of HD but without CAG expansion (genocopies) (2.4%).
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| 5. |
- 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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| 8. |
- Andrew, S, et al.
(författare)
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DNA analysis of distinct populations suggests multiple origins for the mutation causing Huntington disease.
- 1993
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 43:6, s. 286-94
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Tidskriftsartikel (refereegranskat)abstract
- Results of association studies can be significantly biased if the ancestry of the control population is not similar to that of the affected population. One approach to overcome such a bias is to use distinct populations where controls and affected individuals are likely to be of similar descent. We have examined homogeneous populations of French, Danish and Swedish ancestry for nonrandom allelic association between Huntington disease (HD) and several markers previously shown to be in association with HD. No evidence for nonrandom allelic association between HD and these markers was shown in these populations. The demonstration of association in a United Kingdom (UK) sample of similar size, and lack of significant differences in allele frequencies between the French, Danish, Swedish and UK populations suggested that the absence of association was not predominantly a consequence of allele frequencies or sample size. To investigate further the number of potential HD chromosomes, DNA haplotypes were constructed for the Danish, French, Swedish and UK populations. The minimum of two HD haplotypes observed in each of the French, Danish and Swedish populations, compared to the one haplotype in the UK population of a similar size, is an important factor accounting for the absence of association between HD and the DNA markers in these populations. Furthermore, these data are in favour of multiple independent origins for the mutation causing HD.
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| 9. |
- Angius, Andrea, et al.
(författare)
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Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses
- 2019
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Ingår i: Clinical Genetics. - : WILEY. - 0009-9163 .- 1399-0004. ; 95:5, s. 607-614
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Tidskriftsartikel (refereegranskat)abstract
- Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.
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| 10. |
- Apostolou, P., et al.
(författare)
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Haplotype analysis reveals that the recurrent BRCA1 deletion of exons 23 and 24 is a Greek founder mutation
- 2017
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 91:3, s. 482-487
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Tidskriftsartikel (refereegranskat)abstract
- A recurrent large genomic rearrangement (LGR) encompassing exons 23 and 24 of the BRCA1 gene has been identified in breast-ovarian cancer families of Greek origin. Its breakpoints have been determined as c.5406+664_*8273del11052 (RefSeq: NM_007294.3) and a diagnostic polymerase chain reaction (PCR) has been set up for rapid screening. In a series of 2,092 high-risk families completely screened for BRCA1 and BRCA2 germline mutations, we have found the deletion in 35 families (1.68%), representing 7.83% of the mutations identified in both genes and 10.3% of the total BRCA1 mutations. In order to characterize this deletion as a founder mutation, haplotype analysis was conducted in 60 carriers from 35 families, using three BRCA1 intragenic microsatellite markers and four markers surrounding the BRCA1 locus. Our results demonstrate a common shared core disease-associated haplotype of 2.89Mb. Our calculations estimate that the deletion has originated from a common ancestor 1450years ago, which most probably inhabited the Asia Minor area. The particular (LGR) is the third mutation of such type that is proven to have a Greek founder effect in the Greek population, illustrating the necessity for LGRs testing in individuals of Greek descent.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Bi, D., et al.
(författare)
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Association of COL4A1 gene polymorphisms with cerebral palsy in a Chinese Han population
- 2016
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 90:2, s. 149-155
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Tidskriftsartikel (refereegranskat)abstract
- The basement membrane (BM) is an extracellular matrix associated with overlying cells and is important for proper tissue development, stability, and physiology. COL4A1 is the most abundant component of type IV collagen in the BM, and COL4A1 variants can present with variable phenotypes that might be related to cerebral palsy (CP). We postulated, therefore, that variations in the COL4A1 gene might play an important role in the etiology of CP. In this study, six single nucleotide polymorphisms (SNPs) in the COL4A1 gene were genotyped among 351 CP patients and 220 healthy controls from the Chinese Han population. Significant association was found for an association between CP and rs1961495 (allele: p = 0.008, odds ratio (OR) = 1.387, 95% confidence interval (CI) = 1.088–1.767) and rs1411040 (allele: p = 0.009, OR = 1.746, 95% CI = 1.148–2.656) SNPs of the COL4A1 gene. Multifactor dimensionality reduction analysis suggested that these SNPs had interactive effects on the risk of CP. This study is the first attempt to investigate the contribution of polymorphisms in the COL4A1 gene to the susceptibility of CP in a Chinese Han population. This study shows an association of the COL4A1 gene with CP and suggests a potential role of COL4A1 in the pathogenesis of CP. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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| 15. |
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| 17. |
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| 18. |
- Blomquist, H K, et al.
(författare)
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Glycerol kinase deficiency in two brothers with and without clinical manifestations.
- 1996
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Ingår i: Clinical genetics. - 0009-9163 .- 1399-0004. ; 50:5, s. 375-9
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Tidskriftsartikel (refereegranskat)abstract
- We report two brothers with glycerol kinase deficiency (GKD). The older brother had serious clinical symptoms, mental and growth retardation, abnormal skeleton, spontaneous fractures and premature loss of abnormal teeth. He and his mother had low serum phosphate levels. He had elevated serum and urine glycerol levels and GKD was found in cultured fibroblasts. Prenatal diagnosis was performed in the second pregnancy. Glycerol kinase activity was considered normal in a chorionic villus sample of the foetus. After birth, it was found that the boy had elevated serum and urine glycerol levels. Enzymatic analysis in cultured fibroblasts revealed that this boy also had GKD, in spite of having no expression of the disease. Chromosomal analyses in the parents and both boys were normal. Major rearrangements or deletions were not detected in molecular studies of DNA from the two brothers. The hybridisation pattern was normal and no allelic loss was observed.
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| 19. |
- Bondeson, Marie-Louise, 1960-, et al.
(författare)
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A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.
- 2017
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 92:5, s. 510-516
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.
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| 20. |
- Borgwardt, L., et al.
(författare)
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Alpha-mannosidosis: characterization of CNS pathology and correlation between CNS pathology and cognitive function
- 2016
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 89:4, s. 489-494
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty-four patients, aged 6-35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF-oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age-inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.
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| 21. |
- Broman, Marcus, et al.
(författare)
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Next generation DNA sequencing of a Swedish Malignant Hyperthermia cohort.
- 2015
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 88:4, s. 381-385
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Tidskriftsartikel (refereegranskat)abstract
- Malignant Hyperthermia (MH) related mutations have been identified in the ryanodine receptor type 1 gene (RYR1) and in the dihydropyridine gene (CACNA1S), but about half of the patients do not have causative mutations in these genes. We wanted to study the contribution of other muscle genes to the RYR1 phenotypes.
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| 22. |
- Bruland, O, et al.
(författare)
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Accurate determination of the number of CAG repeats in the Huntington disease gene using a sequence-specific internal DNA standard.
- 1999
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 55:3, s. 198-202
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Tidskriftsartikel (refereegranskat)abstract
- We have developed a sequence-specific internal DNA size standard for the accurate determination of the number of CAG repeats in the Huntington disease (HD) gene by cloning key fragments (between 15 and 64 CAG repeats) of the HD gene. These fragments, pooled to produce a sequence-specific DNA ladder, enabled us to observe the true number of CAG repeats directly, with no need for calculations. Comparison of the calculated numbers of CAG repeats in the HD gene using this sequence-specific DNA standard with a commercially available standard (GENESCAN-500 TAMRA) showed that the latter underestimated the number of CAG repeats by three when analyzed by capillary electrophoresis on the ABI 310 Genetic Analyzer (POP4 polymer). In contrast, the use of the same standard overestimated the number of CAG repeats by one when the samples were analyzed by denaturing polyacrylamide electrophoresis on ABI 377 DNA Sequencer (6% denaturing polyacrylamide gel). This suggests that our sequence-specific standard provides greater accuracy for the determination of the true number of CAG repeats in the HD gene than commercially available standards. The sequence-specific standard can be radioactively labeled and successfully replace conventional DNA size standards when analyzing polymerase chain reaction (PCR)-amplified HD alleles by denaturing polyacrylamide electrophoresis.
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| 23. |
- Børresen, A L, et al.
(författare)
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Prenatal diagnosis of glycerol-kinase deficiency associated with a DNA deletion on the short arm of the X-chromosome.
- 1987
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Ingår i: Clinical genetics. - 0009-9163. ; 32:4, s. 254-9
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Tidskriftsartikel (refereegranskat)abstract
- Amniocentesis was performed in a woman who previously had given birth to a boy who died at 12 months of age with a diagnosis of glyceroluria and adrenal insufficiency. A high amount of glycerol (9.0 standard deviations above mean for controls) was found in the amniotic fluid. Enzyme activity of glycerol-kinase (ATP:glycerol-3-phosphotransferase, EC 2.7.1.30) in the cultured amniotic fluid cells was very low. The pregnancy was terminated and a male fetus was aborted. Examinations of DNA isolated from the fetus did demonstrate deletions of two out of 16 DNA probes mapping to the short arm of the X-chromosome. The probes failing to hybridize to DNA from the fetus were C7 (DXS28) and L1.4 (DXS68), both mapping to Xp21.3 and located terminal to the Duchenne locus.
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| 24. |
- 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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| 25. |
- 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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| 26. |
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| 27. |
- Christaller, Wilhelm A A, et al.
(författare)
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L1 syndrome diagnosis complemented with functional analysis of L1CAM variants located to the two N-terminal Ig-like domains.
- 2016
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163.
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Tidskriftsartikel (refereegranskat)abstract
- L1CAM gene mutations cause neurodevelopmental disorders collectively termed L1 syndrome. Insufficient information about L1CAM variants complicates clinical prognosis, genetic diagnosis and genetic counseling. We combined clinical data, in silico effect predictions and functional analysis of four L1CAM variants, p.I37N, p.D202Y, p.M172I and p.T38M, located to the two N-terminal Ig-like domains present in five families with symptoms of L1 syndrome. Software tools predicted destabilizing effects of p.I37N and p.D202Y but results for p.T38M and p.M172I were inconsistent. Cell surface expression of mutant proteins L1-T38M, L1-M172I and L1-D202Y was normal. Conversely, L1-I37N accumulated in the endoplasmic reticulum and showed temperature-sensitive protein maturation suggesting that p.I37N induces protein misfolding. L1CAM-mediated cell-cell aggregation was severely impaired by L1CAM variants p.I37N, p.M172I and p.D202Y but was preserved by the variant p.T38M. Our experimental data indicate that protein misfolding and accumulation in the endoplasmic reticulum affect function of the L1CAM variant p.I37N whereas the variants p.M172I and p.D202Y impair homophilic interaction at the cell surface.
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| 28. |
- Ciuculete, Diana-Maria, et al.
(författare)
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A genetic risk score is significantly associated with statin therapy response in the elderly population
- 2017
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 91:3, s. 379-385
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Tidskriftsartikel (refereegranskat)abstract
- The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.
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| 29. |
- Ciuculete, Diana-Maria, et al.
(författare)
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Response to Leusink et al.
- 2017
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 92:5, s. 566-566
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 30. |
- Creighton, S, et al.
(författare)
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Predictive, pre-natal and diagnostic genetic testing for Huntington's disease : the experience in Canada from 1987 to 2000.
- 2003
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 63:6, s. 462-75
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Tidskriftsartikel (refereegranskat)abstract
- Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.
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| 31. |
- Davidsson, Josef, et al.
(författare)
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Array-based genotype-phenotype correlation in a case of supernumerary ring chromosome 12
- 2008
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 73:1, s. 44-49
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Tidskriftsartikel (refereegranskat)abstract
- Supernumerary ring chromosomes (SRC) account for approximately 10% of prenatal marker chromosomes and 60% of these SRCs are associated with an abnormal phenotype of the patient carrying them. SRCs have, with few exceptions, not been characterized at the molecular genetic level. Here, we present the first case of a SRC 12 thoroughly investigated with tiling resolution array-based comparative genomic hybridization (array CGH); multicolor, centromere, subtelomeric and whole chromosome painting fluorescence in situ hybridization. In addition, to be able to correlate phenotypic manifestations with a possible pathogenetic outcome of the SRC 12, we retrospectively compared and reviewed all 14 cases of SRC 12 reported, including our present case. Our analyses revealed that the SRC comprised 25.53-46.40 Mb of chromosome 12, a region known to harbor 47 annotated genes of which nine were of putative pathogenetic relevance. Reviewing the previously described cases of SRC 12, we could not establish any specific recurrent features associated with this type of SRC. This most probably reflects heterogeneity in break-point distribution among the reported cases, resulting in differently sized ring chromosomes and hence varying phenotypic traits of the patients. Detailed genomic evaluation, by array CGH or similar techniques may thus be of importance to predict the clinical course in individual cases.
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| 32. |
- Delvallée, Clarisse, et al.
(författare)
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A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome
- 2021
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Ingår i: Clinical Genetics. - : John Wiley & Sons. - 0009-9163 .- 1399-0004. ; 99:2, s. 318-324
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Tidskriftsartikel (refereegranskat)abstract
- Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
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| 33. |
- Ekström, Ulf, et al.
(författare)
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An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)
- 1999
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 55:5, s. 332-339
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Tidskriftsartikel (refereegranskat)abstract
- Familial hypercholesterolemia (FH) is caused by a defect in the function of the low density lipoprotein (LDL) receptor and inherited in an autosomal, codominant way. In this study we present a 13-year-old girl, compound heterozygote for the LDL receptor mutations C240F and Y167X. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation compared to normal fibroblasts (< 2%, 8%, and < 2%, respectively). The C240F mutant was expressed in LDL receptor deficient CHOMldlA7 cells. Analysis of cell extracts by immunoblotting demonstrated delayed processing of the mutated LDL receptor, which was accumulated as a precursor protein of normal size. A high molecular weight form of the receptor was also detectable in these cells, which probably reflects cross-linking through the unpaired cysteine residue in the binding domain. Cells expressing the C240F mutant protein were unable to mediate uptake and degradation of LDL. The two siblings of the index case also carried the C240F mutation, but surprisingly one of them (a 17-year-old brother) showed no signs of hypercholesterolemia. This observation is consistent with the view that there may be cholesterol lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes.
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| 34. |
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| 35. |
- Frisk, Sofia, et al.
(författare)
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Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth
- 2019
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Ingår i: Clinical Genetics. - : WILEY. - 0009-9163 .- 1399-0004. ; 96:2, s. 118-125
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Tidskriftsartikel (refereegranskat)abstract
- PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.
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| 36. |
- Gillberg, Christopher, 1950, et al.
(författare)
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Long-term follow-up of children born after amniocentesis.
- 1982
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Ingår i: Clinical Genetics. - 0009-9163. ; 21:1, s. 69-73
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Tidskriftsartikel (refereegranskat)abstract
- Paediatric and neurodevelopmental examinations were made of 122 children between the ages of 5 and 7 years. The mothers of 62 of these children had undergone amniocentesis for prenatal chromosome determination. The other 60 children were controls, matched for time of birth and maternal age. The fact that no difference between the groups was revealed in respect of paediatric and neurodevelopmental disorders, orthopaedic abnormalities, or respiratory problems during the neonatal period indicates that the risk for developmental complications is not increased in children born after amniocentesis in the second trimester.
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| 37. |
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| 38. |
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| 39. |
- Goonewardena, P, et al.
(författare)
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Analysis of fragile X-mental retardation families using flanking polymorphic DNA probes.
- 1986
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 30:4, s. 249-54
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Tidskriftsartikel (refereegranskat)abstract
- Fragile-X mental retardation (FRAX-MR) is one of the more common X-linked disorders affecting 1 in 1,500 newborn males. This disease is characterized by the expression of fragile site in the region q27.3 of the X-chromosome of affected boys when their lymphocytes are cultured in folate deficient medium. In most patients there is macroorchidism postpubertally. The clinical diagnosis of carrier females based on the expression of fragile site in Xq27.3 is usually difficult and sometimes impossible. About half of the carrier females escape diagnosis by this method. Furthermore, prenatal diagnosis is not always feasible. Using Restriction Fragment Length Polymorphism (RFLP) and cloned DNA segments from the region Xq27-Xqter as probes, we have investigated Swedish families with FRAX-MR in three generations. Interesting observations, previously unreported to our knowledge, have been made in some patients and carrier mothers, using one of the probes which is localized to the distal end of Xq. The significance of these findings and the linkage of the disease locus to the different probes used in this study is presented.
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| 40. |
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| 41. |
- 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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| 42. |
- Holmgren, G, et al.
(författare)
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Linkage of G8 (D4S10) in two Swedish families with Huntington's disease.
- 1987
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Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 32:5, s. 289-94
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Tidskriftsartikel (refereegranskat)abstract
- Two Swedish families with Huntington's disease (HD) have been investigated for linkage with G8 (D4S10). In one family from northern Sweden (Family 1) 48 family members were examined, and in another family from the southwestern part of Sweden (Family 2) 14 family members were examined. The lod scores were 1.531 for Family 1 and 2.057 for Family 2, and the combined lod score was 3.59. The HD gene was segregating with the haplotype C in Family 1 and with haplotype A in Family 2. The predictive value of the test was obvious. Before the testing with the G8 probe, 84.2% of the family members in Family 1 had a theoretical risk of 25% or 50% of having the HD gene. After the testing with the G8 probe, only 23.7% of the family members remained at the same risk, and it could also be certified that 63.2% had no or little risk of having the HD gene. Only one asymptomatic person was predicted to have HD.
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| 43. |
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| 44. |
- 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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| 45. |
- Johansson, Edvard, et al.
(författare)
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A rare disease and education: Neurofibromatosis type 1 decreases educational attainment.
- 2021
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Ingår i: Clinical genetics. - : Wiley. - 1399-0004 .- 0009-9163. ; 99:4, s. 529-539
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Tidskriftsartikel (refereegranskat)abstract
- Rare heritable syndromes may affect educational attainment. Here, we study education in neurofibromatosis 1 (NF1) that is associated with multifaceted medical, social and cognitive consequences. Educational attainment in the Finnish population-based cohort of 1408 individuals with verified NF1 was compared with matched controls using Cox proportional hazards model with delayed entry and competing risk for death. Moreover, models accounting for the effects of cancer at age 15-30years, parental NF1 and developmental disorders were constructed. Overall, the attainment of secondary education was reduced in individuals with NF1 compared to controls (hazard ratio 0.83, 95%CI 0.74-0.92). History of cancer and developmental disorders were major predictors of lack of secondary education. Individuals with NF1 obtained vocational secondary education more often than general upper secondary education. Consequently, NF1 decreased the attainment of Bachelor's and Master's degrees by 46-49% and 64-74%, respectively. Surprisingly, the non-NF1 siblings of individuals with NF1 also had lower educational attainment than controls, irrespective of parental NF1. In conclusion, NF1 is associated with reduced educational attainment and tendency for affected individuals to obtain vocational instead of academic education. Individuals living with NF1, especially those with cancer, developmental disorders or familial NF1, need effective student counselling and learning assistance. This article is protected by copyright. All rights reserved.
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| 46. |
- Kalnak, N., et al.
(författare)
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Enrichment of rare copy number variation in children with developmental language disorder
- 2018
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 94:3-4, s. 313-320
-
Tidskriftsartikel (refereegranskat)abstract
- Developmental language disorder (DLD) is a common neurodevelopmental disorder with largely unknown etiology. Rare copy number variants (CNVs) have been implicated in the genetic architecture of other neurodevelopmental disorders (NDDs), which have led to clinical genetic testing recommendations for these disorders; however, the evidence is still lacking for DLD. We analyzed rare and de novo CNVs in 58 probands with severe DLD, their 159 family members and 76 Swedish typically developing children using high-resolution microarray. DLD probands had larger rare CNVs as measured by total length (P =.05), and average length (P =.04). In addition, the rate of rare CNVs overlapping coding genes was increased (P =.03 and P =.01) and in average more genes were affected (P =.006 and P =.03) in the probands and their siblings, respectively. De novo CNVs were found in 4.8% DLD probands (2/42) and 2.4% (1/42) siblings. Clinically significant CNVs or chromosomal anomalies were found in 6.9% (4/58) of the probands of which 2 carried 16p11.2 deletions. We provide further evidence that rare CNVs contribute to the etiology of DLD in loci that overlap with other NDDs. Based on our results and earlier literature, families with DLD should be offered molecular genetic testing as a routine in their clinical follow-up.
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| 47. |
- Kharaziha, Pedram, et al.
(författare)
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Functional characterization of novel germline TP53 variants in Swedish families
- 2019
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 96:3, s. 216-225
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Tidskriftsartikel (refereegranskat)abstract
- Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.
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| 48. |
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| 49. |
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| 50. |
- Kvarnung, Malin, et al.
(författare)
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Genomic screening in rare disorders : new mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability
- 2018
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Ingår i: Clinical Genetics. - : John Wiley & Sons. - 0009-9163 .- 1399-0004. ; 94:6, s. 528-537
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14.
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