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| 2. |
- Bryant, Patrick, et al.
(författare)
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Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer : investigating the presence of genetic risk modifiers in colorectal cancer risk
- 2023
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Ingår i: European Journal of Cancer Prevention. - 0959-8278 .- 1473-5709. ; 32:2, s. 113-118
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Tidskriftsartikel (refereegranskat)abstract
- Objective Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes, such as the PMS2 gene, and is characterised by a familial accumulation of colorectal cancer. The penetrance of cancer in PMS2 carriers is still not fully elucidated as a colorectal cancer risk has been shown to vary between PMS2 carriers, suggesting the presence of risk modifiers.Methods Whole exome sequencing was performed in a Swedish family carrying a PMS2 missense mutation [c.2113G>A, p.(Glu705Lys)]. Thirteen genetic sequence variants were further selected and analysed in a case-control study (724 cases and 711 controls).Results The most interesting variant was an 18 bp deletion in gene BAG1. BAG1 has been linked to colorectal tumour progression with poor prognosis and is thought to promote colorectal tumour cell survival through increased NF-κB activity.Conclusions We conclude the genetic architecture behind the incomplete penetrance of PMS2 is complicated and must be assessed in a genome wide manner using large families and multifactorial analysis.
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| 3. |
- Carlsson, Göran, 1951, et al.
(författare)
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Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia.
- 2012
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Ingår i: British journal of haematology. - : Wiley. - 1365-2141 .- 0007-1048. ; 158:3, s. 363-369
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Tidskriftsartikel (refereegranskat)abstract
- Severe congenital neutropenia (SCN) is characterized by low blood neutrophil counts, early bacterial infections, and risk of leukaemia development. As yet, no population-based incidence estimates of SCN have been reported. Children less than 16years of age with SCN were sought in Sweden during the 20-year period 1987-2006 by a questionnaire to all Swedish Departments of Paediatrics and by reviewing the Swedish Health and Welfare Statistical Databases. Thirty-two patients were diagnosed with congenital neutropenia during this period. All received treatment with recombinant granulocyte-colony stimulating factor (G-CSF). Twenty-one patients were diagnosed as SCN or probable SCN, corresponding to 1·0 per 100000 live births. Nine (43%) had ELANE mutations, four (19%) HAX1 mutations and eight (38%) were children with disease of unknown genetic aetiology. Four out of 21 patients (19%) developed myelodysplastic syndrome/leukaemia and three (14%) died, all with leukaemia. The cumulative incidence of myelodysplastic syndrome/leukaemia was 31%. The observed incidence of SCN in this population-based study was higher than previously estimated, possibly because genetic testing now can identify SCN cases previously thought to be idiopathic or benign neutropenia. The risk of developing myelodysplastic syndrome/leukaemia is considerable. ELANE mutations are the most commonly identified genetic defects.
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| 4. |
- Karimi, Masoud, et al.
(författare)
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A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families
- 2018
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Ingår i: Hereditary Cancer in Clinical Practice. - : BMC. - 1731-2302 .- 1897-4287. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundLynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families.MethodsData were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population.ResultsA total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations.ConclusionLynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.
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| 5. |
- Karimi, Masoud, et al.
(författare)
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A retrospective study of extracolonic, non-endometrial cancer in Swedish Lynch syndrome families 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 11 Medical and Health Sciences 1117 Public Health and Health Services
- 2018
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Ingår i: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1731-2302 .- 1897-4287. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2. Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families. Methods: Data were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population. Results: A total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations. Conclusion: Lynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2-carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types.
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| 6. |
- 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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| 7. |
- Lagerstedt-Robinson, Kristina, et al.
(författare)
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A retrospective two centre study of Birt-Hogg-Dube syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:2
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Tidskriftsartikel (refereegranskat)abstract
- Birt-Hogg-Dube syndrome (BHDS) (MIM: 135150) is a rare autosomal dominant disorder with variable penetrance, caused by pathogenic variants in the FLCN gene. Only a few hundreds of families have so far been described in the literature. Patients with BHDS present with three distinct symptoms: fibrofolliculomas, pneumothorax due to lung cyst formation, and increased lifetime risk of kidney tumours. The aim of the current study was to estimate the incidence of BHDS in the Swedish population and further describe the clinical manifestations and their frequency. Splice variant c.779+1G>T was the most common pathogenic variant, found in 57% of the families, suggesting this may be a founder mutation in the Swedish population. This was further investigated using haplotype analysis in 50 families that shared a common haplotype. Moreover, according to gnomAD the carrier frequency of the c.779+1G>T variant has been estimated to be 1/3265 in the Swedish population, however our data suggest that the carrier frequency in the Swedish population may be significantly higher. These findings should raise awareness among physicians of different specialties to patients presenting with fibrofolliculomas, pneumothorax and/or kidney tumours. We also stress the importance of consensus recommendations regarding diagnosis and clinical management of this, not that uncommon, syndrome.
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| 8. |
- Lindstrand, Anna, et al.
(författare)
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From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability
- 2019
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Ingår i: Genome Medicine. - : BMC. - 1756-994X .- 1756-994X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
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| 9. |
- Lindstrand, Anna, et al.
(författare)
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Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability
- 2022
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Ingår i: Genetics in Medicine. - : ELSEVIER SCIENCE INC. - 1098-3600 .- 1530-0366. ; 24:11, s. 2296-2307
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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| 10. |
- Paucar, Martin, et al.
(författare)
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Genetic screening for Huntington disease phenocopies in Sweden : A tertiary center case series focused on short tandem repeat (STR) disorders
- 2023
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Ingår i: Journal of the Neurological Sciences. - : Elsevier. - 0022-510X .- 1878-5883. ; 451
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo perform a screening for Huntington disease (HD) phenocopies in a Swedish cohort.MethodsSeventy-three DNA samples negative for HD were assessed at a tertiary center in Stockholm. The screening included analyses for C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis (C9orf72-FTD/ALS), octapeptide repeat insertions (OPRIs) in PRNP associated with inherited prion diseases (IPD), Huntington's disease-like 2 (HDL2), spinocerebellar ataxia-2 (SCA2), spinocerebellar ataxia 3 (SCA3) and spinocerebellar ataxia-17 (SCA17). Targeted genetic analysis was carried out in two cases based on the salient phenotypic features.ResultsThe screening identified two patients with SCA17, one patient with IPD associated with 5-OPRI but none with nucleotide expansions in C9orf72 or for HDL2, SCA2 or SCA3. Furthermore, SGCE-myoclonic-dystonia 11 (SGCE-M-D) and benign hereditary chorea (BHC) was diagnosed in two sporadic cases. WES identified VUS in STUB1 in two patients with predominant cerebellar ataxia.ConclusionsOur results are in keeping with previous screenings and suggest that other genes yet to be discovered are involved in the etiology of HD phenocopies.
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