| 1. |
- Börjesson, Erik, et al.
(författare)
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Symptoms and ECG changes precede sudden cardiac death in hypertrophic cardiomyopathy-A nationwide study among the young in Sweden.
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:9
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Tidskriftsartikel (refereegranskat)abstract
- Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death (SCD) in the young. We aimed to characterize detailed family history, symptoms, hospital utilization and ECG changes before SCD.We extracted all cases suffering SCD with HCM from the SUDDY cohort, which includes all cases of SCD between 2000-2010 in Sweden among individuals aged 0-35 years along with their controls. We gathered data from mandatory national registries, autopsy reports, medical records, ECGs (including military conscripts), and detailed family history from an interview-based questionnaire (with relatives, post-mortem).Thirty-eight cases (7 female), mean age 22 years, with HCM were identified. Among these, 71% presented with possible cardiac symptoms (chest pain [26%], syncope [22%], palpitations [37%]), before death; 69% received medical care (vs 21% in controls) within 180 days before death. The majority (68%) died during recreational activity (n = 14) or exercise/competitive sports (n = 12). Fifteen (39%) had a known cardiac disorder prior to death, with HCM being diagnosed pre-mortem in nine cases. 58% presented with abnormal ECG recordings pre-mortem, and 50% had a positive family history (1st-3rd generation) for heart disease.In this comprehensive, nationwide study of SCD due to HCM, 87% (33/38) of cases had one or more abnormality prior to death, including cardiac symptoms, a positive family history, known cardiac disease or ECG abnormalities. They sought medical care prior death, to a larger extent than controls. These findings suggest that cardiac screening should be expanded beyond competitive athletes to aid SCD prevention in the young population with HCM.
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| 2. |
- Delgado-Vega, Angelica Maria, et al.
(författare)
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Family History and Warning Symptoms Precede Sudden Cardiac Death in Arrhythmogenic Right Ventricular Cardiomyopathy (From A Nationwide Study in Sweden)
- 2022
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Ingår i: American Journal of Cardiology. - : Elsevier. - 0002-9149 .- 1879-1913. ; 178, s. 124-130
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Tidskriftsartikel (refereegranskat)abstract
- Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiacdisease explaining about 4% of sudden cardiac death (SCD) cases among the youngin Sweden. The aim of this study was to describe the circumstances preceding SCDdue to ARVC in all victims <35 years of age who received an autopsy-confirmeddiagnosis of ARVC from January 1st, 2000 to December 31st, 2010 in Sweden (n=22).Data on demographics, medical and family history, circumstances of death, andanatomopathological findings were collected from several compulsory national healthregistries, clinical records, family interviews, and autopsy reports. Registry-based datawas compared with age-, sex- and geographically-matched population controls. Duringthe 6 months preceding SCD, 15 cases (68%) had experienced symptoms of cardiacorigin, mainly syncope or presyncope (54%), and chest discomfort (27%). Eight cases(36%) had sought medical care due to cardiac symptoms. The occurrence of hospitalvisits was significantly increased in cases compared with controls (OR 4.62 [1.35-15.8]). Ten cases (45%) had a family history of SCD. The most common activity at thetime of death was exercise (41%). Complete cardiac investigation was seldomperformed, only one case was diagnosed with ARVC before death. In conclusion, inthis nationwide study we observed a high prevalence of symptoms of cardiac origin,health-care utilization, and family history of SCD preceding SCD due to ARVC amongthe young. Increased awareness of these warning signals in the young is critical toimprove risk stratification and early disease detection.
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| 3. |
- Entesarian, Miriam, et al.
(författare)
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A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent in the Swedish population
- 2009
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Ingår i: American Journal of Medical Genetics. - : Wiley Interscience. - 0148-7299 .- 1096-8628 .- 1552-4825 .- 1552-4833. ; 149A:3, s. 380-386
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Tidskriftsartikel (refereegranskat)abstract
- We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four non-related Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden.
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| 4. |
- Gkourogianni, Alexandra, et al.
(författare)
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Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - Cary, USA : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 460-469
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Tidskriftsartikel (refereegranskat)abstract
- Context: Heterozygous mutations in the Aggrecan gene (ACAN) cause autosomal dominant short stature with bone age (BA) acceleration, premature growth cessation and minor skeletal abnormalities.Objective: Characterize the phenotypic spectrum, associated conditions and response to growth-promoting therapies.Design: Retrospective international cohort study.Patients: Information from 103 individuals (57 female, 46 male) from 20 families with confirmed heterozygous ACAN mutations were included.Methods: Families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next generation sequencing, and/or Sanger sequencing. Clinical information was collected from medical records.Results: Identified ACAN variants showed perfect co-segregation with phenotype. Adult individuals had mildly disproportionate short stature (median height: -2.8 SDS, range: -5.9 to -0.9) and histories of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). There was no apparent genotype-phenotype correlation between type of ACAN mutation and presence of joint complaints. During childhood, height was less affected (median height: -2.0 SDS, range: -4.2 to -0.6). In contrast to most children with short stature, the majority of children had advanced BA (BA - CA, median: +1.3y; range +0.0 to +3.7y) reflecting a reduction in remaining growth potential. Nineteen individuals had received GH with some evidence of increased growth velocity.Conclusions Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. In several of the families, affected individuals developed early-onset osteoarthritis and degenerative disc disease requiring intervention, suggesting dysfunction of articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
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| 5. |
- Lennartsson, Otto, et al.
(författare)
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Case Report : Bilateral Epiphysiodesis Due to Extreme Tall Stature in a Girl With a De Novo DNMT3A Variant Associated With Tatton-Brown-Rahman Syndrome
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To present a rare clinical case of a patient with Tatton-Brown-Rahman syndrome and the outcome of tall stature management with bilateral epiphysiodesis surgery at the distal femur and proximal ends of tibia and fibula.Study Design: Clinical case report.Results: This is a 20-year-old female with a history of proportional tall stature, developmental psychomotor and language delay with autism spectrum behavior and distinctive facial features. At 12 years and 2 months of age she was in early puberty and 172.5 cm tall (+ 2.8 SDS) and growing approximately 2 SDS above midparental target height of 173 cm (+ 0.9 SDS). A bone age assessment predicted an adult height of 187.1 cm (+3.4 SDS). To prevent extreme tall stature, bilateral epiphysiodesis surgery was performed at the distal femur and proximal ends of tibia and fibula at the age of 12 years and 9 months. After the surgery her height increased by 12.6 cm to 187.4 cm of which approximately 10.9 cm occurred in the spine whereas leg length increased by only 1.7 cm resulting in a modest increase of sitting height index from 50% (-1 SDS) to 53% (+ 0.5 SDS). Genetic evaluation for tall stature and intellectual disability identified a de novo nonsense variant in the DNMT3A gene previously associated with Tatton-Brown-Rahman syndrome.Conclusion: Tatton-Brown-Rahman syndrome should be considered in children with extreme tall stature and intellectual disability. Percutaneous epiphysiodesis surgery to mitigate extreme tall stature may be considered.
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| 6. |
- Stattin, Eva-Lena, et al.
(författare)
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Novel missense ACAN gene variants linked to familial osteochondritis dissecans cluster in the C-terminal globular domain of aggrecan
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- The cartilage aggrecan proteoglycan is crucial for both skeletal growth and articular cartilage function. A number of aggrecan (ACAN) gene variants have been linked to skeletal disorders, ranging from short stature to severe chondrodyplasias. Osteochondritis dissecans is a disorder where articular cartilage and subchondral bone fragments come loose from the articular surface. We previously reported a missense ACAN variant linked to familial osteochondritis dissecans, with short stature and early onset osteoarthritis, and now describe three novel ACAN gene variants from additional families with this disorder. Like the previously described variant, these are autosomal dominant missense variants, resulting in single amino acid residue substitutions in the C-type lectin repeat of the aggrecan G3 domain. Functional studies showed that neither recombinant variant proteins, nor full-length variant aggrecan proteoglycan from heterozygous patient cartilage, were secreted to the same level as wild-type aggrecan. The variant proteins also showed decreased binding to known cartilage extracellular matrix ligands. Mapping these and other ACAN variants linked to hereditary skeletal disorders showed a clustering of osteochondritis dissecans-linked variants to the G3 domain. Taken together, this supports a link between missense ACAN variants affecting the aggrecan G3 domain and hereditary osteochondritis dissecans.
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| 7. |
- Stattin, Eva-Lena, et al.
(författare)
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SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Vasterbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.
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| 8. |
- Winbo, Annika, et al.
(författare)
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Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations : a pedigree-based measured genotype association analysis
- 2017
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Ingår i: BMC Medical Genetics. - : BIOMED CENTRAL LTD. - 1471-2350. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1AP sequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations.Methods: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs.Results: A substantial variance in mean QTc was seen in genotype positives 476 +/- 36 ms (Y111C 483 +/- 34 ms; R518* 462 +/- 34 ms) and genotype negatives 433 +/- 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, + 18 ms (p = 0.0007) and + 17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0. 001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with QTc in females (both p = 0.16) while in males, a prolongation of + 19 ms and + 8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males.Conclusions: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS.
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| 9. |
- Wisten, Aase, et al.
(författare)
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Exercise related sudden cardiac death (SCD) in the young — Pre-mortal characterization of a Swedish nationwide cohort, showing a decline in SCD among athletes
- 2019
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Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 144, s. 99-105
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To study the frequency, etiology, and premortal abnormalities in exercise-related sudden cardiac death (SCD) in the young in Sweden. Methods: All subjects with SCD in 10–35-year olds in Sweden during 2000–10, were included (n = 514). Information about each case was retrieved from death certifications, autopsy- and medical records. The number of SCD in athletes was compared to national figures from 1992-99. Results: Exercise-related SCD occurred in 12% (62/514) of the SCD-population, a majority being men (56/62; 90%). Cardiopulmonary resuscitation (CPR) was started in 87% (54/62). In total, 48% (30/62), had a cardiac diagnosis, symptoms, family history and/or ECG-changes, before the fatal event. The most prevalent autopsy diagnosis was sudden arrhythmic death syndrome (15/62; 24%). The frequency of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) was significantly higher in exercise-related SCD compared to non-exertional SCD. Exercise-related SCD was more common in athletes (21/29) than in non-athletes (41/485) (P < 0.0001). The total number of SCDs/year in athletes 15–35 years old, are approximately halved in 2000-10 compared to the years 1992–99. Conclusion: The increased risk of exercise-related SCD in HCM and ARVC underlines the importance of early detection and eligibility recommendations. There is a major reduction in deaths among athletes in the 2000s, compared to the previous decade. These results may partly be explained by improved acute preparedness for sudden cardiac arrest (CPR, defibrillation), but as a substantial percentage have preceding risk factors, such as symptoms and ECG-abnormalities, increased cardiac screening and increased general awareness, may also play a role.
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| 10. |
- Wisten, Aase, et al.
(författare)
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Sudden cardiac death among the young in Sweden from 2000 to 2010 : an autopsy-based study
- 2017
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Ingår i: Europace. - : OXFORD UNIV PRESS. - 1099-5129 .- 1532-2092. ; 19:8, s. 1327-1334
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To study the incidence and aetiology of sudden cardiac death (SCD) in 1-to 35-year-olds in Sweden from 2000 to 2010.Methods and results: We used the database of the Swedish National Board of Forensic Medicine and the Swedish Cause of Death Registry and identified SCD cases by review of forensic files and death certificates. We identified 552 individuals with SCD in 1-to 35-year-olds; 156 (28%) were women. In 393 (71%), a forensic autopsy had been performed; in 131 (24%), a clinical autopsy had been performed; in 28 (5%) with no autopsy, a cardiac disease was diagnosed before death. The incidence of SCD per 100 000 person-years was 1.3 in 1- to 35-year-olds and 1.8 in 15- to 35-year-olds. In women, the incidence rates yearly decreased during the study period by 11% (95% confidence interval 6.6-14.2). The most common aetiology in 1- to 35-year-olds was sudden arrhythmic death syndrome (31%) and coronary artery disease (15%). In cases with forensic autopsy, death occurred during daily activity (48%), sleep (38%), and physical activity (14%); death was unwitnessed in 60%. Co-morbidity in 15- to 35-year-olds, e.g. psychiatric disorder, obesity, or diabetes, was present in 93/340 (27%) (73 men).Conclusion: The incidence of SCD among 1- to 35-year-olds in Sweden during 2000-10 was 1.3 per 100 000 person-years (28% women); incidence was decreasing in women. Sudden arrhythmic death syndrome was the most common diagnosis. Co-morbidity such as psychiatric disorders and obesity was common among men.
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