| 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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| 11. |
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| 12. |
- Clewemar, Pantelis, et al.
(författare)
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Expanding the phenotypic spectrum of osteogenesis imperfecta type V including heterotopic ossification of muscle origins and attachments
- 2019
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Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOsteogenesis imperfecta (OI) is a clinical and genetic heterogeneous group of connective tissue disorders, characterized by bone fragility and a propensity to fracture.MethodsIn this report we describe the clinical phenotype of two patients, a 28‐year‐old woman and her mother (54 years old), both with a history of short stature and multiple fractures.ResultsExome sequencing revealed the recurring IFITM5:c.‐14 C>T variant causing OI type V. Both patients had several fractures during childhood. CT‐scan and scintigraphy showed ossification of the origin and attachment of muscles and hypertrophic callus formation.ConclusionOssification of the origin and attachment of muscles seems to be part of the phenotype in patients with OI type V.
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| 13. |
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| 14. |
- Diamant, Ulla-Britt, 1955-, et al.
(författare)
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Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene
- 2013
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 115:10, s. 1423-1432
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Tidskriftsartikel (refereegranskat)abstract
- Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.
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| 15. |
- Diamant, Ulla-Britt, et al.
(författare)
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Two automatic QT algorithms compared with manual measurement in identification of long QT syndrome
- 2010
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Ingår i: Journal of Electrocardiology. - : Elsevier BV. - 0022-0736 .- 1532-8430. ; 43:1, s. 25-30
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Long QT syndrome (LQTS) is an inherited disorder that increases the risk of syncope and malignant ventricular arrhythmias, which may result in sudden death.METHODS: We compared manual measurement by 4 observers (QT(manual)) and 3 computerized measurements for QT interval accuracy in the diagnosis of LQTS: 1. QT measured from the vector magnitude calculated from the 3 averaged orthogonal leads X, Y, and Z (QTVCG) and classified using the same predefined QTc cut-points for classification of QT prolongation as in manual measurements; 2. QT measured by a 12-lead electrocardiogram (ECG) program (QTECG) and subsequently classified using the same cut-points as in (1) above; 3. The same QT value as in (2) above, automatically classified by a 12-lead ECG program with thresholds for QT prolongation adjusted for age and sex (QTinterpret). The population consisted of 94 genetically confirmed carriers of KCNQ1 (LQT1) and KCNH2 (LQT2) mutations and a combined control group of 28 genetically confirmed noncarriers and 66 unrelated healthy volunteers.RESULTS: QT(VCG) provided the best combination of sensitivity (89%) and specificity (90%) in diagnosing LQTS, with 0.948 as the area under the receiver operating characteristic curve. The evaluation of QT measurement by the 4 observers revealed a high interreader variability, and only 1 of 4 observers showed acceptable level of agreement in LQTS mutation carrier identification (kappa coefficient >0.75).CONCLUSION: Automatic QT measurement by the Mida1000/CoroNet system (Ortivus AB, Danderyd, Sweden) is an accurate, efficient, and easily applied method for initial screening for LQTS.
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| 16. |
- Diamant, Ulla-Britt, et al.
(författare)
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Vectorcardiographic recordings of the Q-T interval in a pediatric long Q-T syndrome population
- 2013
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Ingår i: Pediatric Cardiology. - : Springer Science and Business Media LLC. - 0172-0643 .- 1432-1971. ; 34:2, s. 245-249
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of the Q-T interval are less reliable in children than in adults. Identification of superior diagnostic tools is warranted. This study aimed to investigate whether a vectorcardiogram (VCG) recorded from three orthogonal leads (X, Y, Z) according to Frank is superior to a 12-lead electrocardiogram (ECG) in providing a correct long Q-T syndrome (LQTS) diagnosis in children. This LQTS group consisted of 35 genetically confirmed carriers of mutations in the KCNQ1 (n = 29) and KCNH2 (n = 6) genes. The control group consisted of 35 age- and gender-matched healthy children. The mean age was 7 years in the LQTS group and 6.7 years in the control group (range, 0.5-16 years). The corrected Q-T interval (QT(c)) was measured manually (QT(man)) by one author (A.W.). The 12-lead ECG automatic measurements (QT(ECG)) and interpretation (QT(Interpret)) of QT(c) were performed with the Mac5000 (GE Medical System), and the VCG automatic measurements (QT(VCG)) were performed with the Mida1000, CoroNet (Ortivus AB, Sweden). By either method, a QT(c) longer than 440 ms was considered prolonged and indicative of LQTS. Of the 35 children with genetically confirmed LQTS, 30 (86 %) received a correct diagnosis using QT(VCG), 29 (82 %) using QT(man), 24 (69 %) using QT(ECG), and 17 (49 %) using QT(Interpret). Specificity was 0.80 for QT(VCG), 0.83 for QT(man), 0.77 for QT(ECG), and 0.83 for QT(Interpret). The VCG automatic measurement of QT(c) seems to be a better predictor of LQTS than automatic measurement and interpretation of 12-lead ECG.
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| 17. |
- Eisfeldt, Jesper, et al.
(författare)
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Multi-Omic Investigations of a 17-19 Translocation Links MINK1 Disruption to Autism, Epilepsy and Osteoporosis
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:16
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Tidskriftsartikel (refereegranskat)abstract
- Balanced structural variants, such as reciprocal translocations, are sometimes hard to detect with sequencing, especially when the breakpoints are located in repetitive or insufficiently mapped regions of the genome. In such cases, long-range information is required to resolve the rearrangement, identify disrupted genes and, in symptomatic carriers, pinpoint the disease-causing mechanisms. Here, we report an individual with autism, epilepsy and osteoporosis and a de novo balanced reciprocal translocation: t(17;19) (p13;p11). The genomic DNA was analyzed by short-, linked- and long-read genome sequencing, as well as optical mapping. Transcriptional consequences were assessed by transcriptome sequencing of patient-specific neuroepithelial stem cells derived from induced pluripotent stem cells (iPSC). The translocation breakpoints were only detected by long-read sequencing, the first on 17p13, located between exon 1 and exon 2 of MINK1 (Misshapen-like kinase 1), and the second in the chromosome 19 centromere. Functional validation in induced neural cells showed that MINK1 expression was reduced by >50% in the patient's cells compared to healthy control cells. Furthermore, pathway analysis revealed an enrichment of changed neural pathways in the patient's cells. Altogether, our multi-omics experiments highlight MINK1 as a candidate monogenic disease gene and show the advantages of long-read genome sequencing in capturing centromeric translocations.
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| 18. |
- Gkourogianni, Alexandra, et al.
(författare)
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Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant
- 2018
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Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 90:Suppl.1, s. 424-424
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: Heterozygous mutations in the aggrecan gene (ACAN) are associated with idiopathic short stature, with or without advanced bone age (BA), osteochondritis dissecans (OCD) and early onset of severe osteoarthritis (OA). Variable features also include midface hypoplasia, brachydactyly, short thumbs and intervertebral disc degenerative disease.Methods: We reviewed 173 radiographs in 22 individuals (8F:14M), (3shoulders, 10hands, 10wrists, 17spines, 10pelvis, 31hips, 79knees, 5 lower-legs, 4ankles, 4feet).Furthermore 2 computed tomography scans (1hip; 1knee), and 5 magnetic resonance scans (2hips; 3knees). All included individuals belong to a five generation Swedish family with short stature, OCD, and early onset OA (MIM#165800), caused by a pathogenic sequence variant, p.V2303M, in the C-type lectin domain of ACAN.Results: In the group of children (n=6; age ≤15yo; 3F:3M), six had moderately advanced BA (range:6-17.5months). There was no clear sign of a metaphyseal or epiphyseal dysplasia, but subtle defects of the distal radial growth plate were present in four children. There were 3 males with OCD in the knees and one of them also present-ed OCD of the hip, scoliosis and schmorl’s nodes of intervertebral discs. Actually he went through a derotation osteotomy in both hips and later a proximal tibia osteotomy and distal fibula osteotomy.Among 16 adult patients (5F:11M), 16 had OCD (7elbows,4 hips,13 knees, 5 patellas), 13 developed early onset (>40y) OA, (1shoulder, 5elbows, 3 spines, 1 metatarsophalangeal joint, 6 hips, 12 knees, 1 patella). Radiological manifestations of the spine were detected in 4 patients and included 1 scoliosis, 1 spina bifida occulta, 1 platyspondyly, 1 schmorl’s nodes, and 3 with lowering of the intervertebral discs.Moreover 8 adult patients (3F:5M) have been operated, 4 pa-tients had hip replacement (1F:3M;3bilateral;1unilateral) and 5 knee arthroplasties (2F:3M; 3bilateral;2unilateral) in particular 5 patients had tibia osteotomy of which one had combined tibia and fibula osteotomy. We measured all phalanges of eight adult hand x-rays and found no brachydactyly.Conclusions: The pathogenic heterozygous p.V2303M variant in the ACAN gene causes mildly disproportionate short stature with early-onset OA and intervertebral disc degeneration often requiring multiple orthopedic interventions. Radiologic findings, included moderately advanced BA, OCD in knees, hips, and elbows as well as OA in 13 individuals. Further studies are needed to identify preventive measures that may slow the progression of OA and intervertebral disc disease and to determine the role of rhGH to improve final height
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| 19. |
- Hannuksela, Matias, et al.
(författare)
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A novel variant in MYLK causes thoracic aortic dissections : genotypic and phenotypic description
- 2016
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mutations in MYLK cause non- syndromic familial thoracic aortic aneurysms and dissections (FTAAD). Very little is known about the phenotype of affected families. We sought to characterize the aortic disease and the presence of other vascular abnormalities in FTAAD caused by a deletion in MYLK and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers.Methods: We studied FTAAD in a 5-generation family that included 19 living members. Exome sequencing was performed to identify the underlying gene defect. Aortic elastic properties measured by TTE, MRI and pulse wave velocity were then compared between mutation carriers and non-carriers.Results: Exome sequencing led to the identification of a 2-bp deletion in MYLK (c3272_ 3273del, p. Ser1091*) that led to a premature stop codon and nonsense-mediated decay. Eleven people were mutation carriers and eight people were non-carriers. Five aortic ruptures or dissections occurred in this family, with two survivors. There were no differences in aortic diameter or stiffness between carriers and non-carriers of the mutation.Conclusions: Individuals carrying this deletion in MYLK have a high risk of presenting with an acute aortic dissection or rupture. Aortic events occur over a wide range of ages and are not always preceded by obvious aortic dilatation. Aortic elastic properties do not differ between carriers and non-carriers of this mutation, rendering it uncertain whether and when carriers should undergo elective prophylactic surgery.
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| 20. |
- Hannuksela, Matias, 1969-
(författare)
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Familial thoracic aortic aneurysms and dissections : studies on genotype and phenotype
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Thoracic aortic aneurysms and dissections (TAAD) have a genetic component with an estimated 20-25% of the patients having a positive family history. An aneurysm often precedes a dissection. Acute aortic dissections are associated with high mortality and morbidity, even when operated on. Complications due to prophylactic surgery are considerably fewer. Therefore, patients at risk for dissection should be identified, followed-up and evaluated for prophylactic intervention.Aims: 1. To establish reference values for ascending (AoA) and descending aortic (AoD) diameters measured by computed tomography. 2. To study the effectiveness of phenotypic cascade screening in families with an inherited form of thoracic aortic aneurysms and dissections (FTAAD) and to address questions that arise when screening for a genetic disorder is applied. 3. To study the agreement of aortic diameters obtained by TTE and MRI and to study aortic stiffness in individuals from families with FTAAD. 4. To perform exome sequencing in order to identify pathogenic sequence variants causing FTAAD, to characterize the phenotype, and to compare thoracic aortic diameter and stiffness in mutation carriers and non-carriers.Results: Paper I: The diameter of the thoracic aorta increased by 0.17 mm (0.12 – 0.20 mm) per year. The mean sex-related difference in diameter was 1.99 mm (1.28 – 2.60 mm) with men having larger aortas than women. The mean difference in aortic diameter per unit BMI was 0.27 mm (0.14 – 0.44 mm). Upper normal limits for the AoA can be calculated by the formula D (mm)=31+0.16*age and for the AoD by D (mm)=21+0.16*age.Paper II: Of 106 individuals from families with FTAAD but without known thoracic aortic disease, 19 individuals (18%) were identified to have a dilated AoA. The expected number of individuals in this group with an autosomal dominant disease would have been 40 (p<0.0001). In first-degree relatives younger than 40, we found only one individual with a dilated aorta although the expected number of individuals with disease causing mutation would have been 10.Paper III: Of 116 individuals investigated, 21 were identified with thoracic aortic dilatation and 95 individuals with normal thoracic aortic diameter. Aortic stiffness increased with age and diameter. The individuals with aortic dilatation were older than those without (49 vs. 37 years, p=0.001) and showed lower aortic elastic properties. The diameters measured by TTE and MRI correlated strongly (r2=0.93). The mean difference in diameters between the two methods was 0.72 mm (95% CI 0.41-1.02) with TTE giving larger diameters than MRI.Paper IV: From exome sequencing and segregation analysis, a 2-bp deletion in the MYLK gene (c.3272_3273del) was identified to cause FTAAD. The age and the aortic diameter at dissection or rupture varied in the family members. We did not find any differences in aortic diameter, aortic stiffness, or pulse wave velocity between carriers and non-carriers.Conclusions: Thoracic aortic diameter increases with age, and sex and body size are also associated with the diameter. In FTAAD, screening identifies family members with a previously unknown aortic dilatation. However, a normal aortic diameter does not exclude an individual from being a carrier of FTAAD. TTE can be used in follow-up for the ascending aorta. Individuals identified to have a dilated thoracic aorta have increased aortic stiffness compared to individuals with normal thoracic aortic diameter. The MYLK mutation (c.3272_3273del) causes thoracic aortic dissections with variable clinical expression. No differences in aortic stiffness were identified between MYLK mutation carriers and non-carriers.
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| 21. |
- Hannuksela, Matias, et al.
(författare)
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Familära torakala aortaaneurysm och dissektioner : flera former finns
- 2014
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Ingår i: Läkartidningen. - Stockholm : Sveriges läkarförbund. - 0023-7205 .- 1652-7518. ; 111:9-10, s. 399-403
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Tidskriftsartikel (refereegranskat)abstract
- Thoracic aortic aneurysms and dissections (TAAD) can be divided into three different main categories. 1. Inherited syndromes predisposing to TAAD such as Marfan syndrome, Ehlers-Danlos syndrome type IV and Loeys-Dietz syndrome (less than 5% of all TAAD). 2. Familial TAAD (FTAAD) with more than one affected family member (20 % of all TAAD). Inheritance shows an autosomal dominant pattern and there are no features of known syndromes. 3. Sporadic forms of TAAD with no family history or features of syndromic forms. FTAAD present earlier in life and dissections occur in smaller diameter than in sporadic cases. The underlying genetic cause can be found in about 20 % of the inherited cases. The pathogenesis seems to be an involvement of the transforming growth factor β (TGFβ) signaling pathway or a dysfunction of the smooth muscle cell contraction. The role of β-blockers for aneurysm prevention is uncertain and there are on-going studies comparing angiotensin receptor blockers and β-blockers.
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| 22. |
- Hannuksela, Matias, et al.
(författare)
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Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential aarriers of the disease
- 2015
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Ingår i: Aorta. - : Georg Thieme Verlag KG. - 2325-4637. ; 3:1, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Background: About 20% of patients with thoracic aortic aneurysm or dissection (TAAD) have a first-degree relative with a similar disease. The familial form (FTAAD) of the disease is inherited in an autosomal-dominant pattern. Current guidelines for thoracic aortic disease recommend screening of first-degree relatives of TAAD patients. In known familial disease, screening of both first- and second-degree relatives is recommended. However, the outcomes of such a screening program are unknown.Methods: We screened all first- and second-degree relatives in seven families with known FTAAD with echo- cardiography. No underlying gene defect had been detected in these families.Results: Of 119 persons investigated, 13 had known thoracic aortic disease. In the remaining 106 cases, we diagnosed 19 additional individuals with a dilated ascending thoracic aorta; for an autosomal-dominant disease, the expected number of individuals in this group would have been 40 (p<0.0001). Further, only one of the 20 first-degree relatives younger than 40 years had a dilated aorta, although the expected number of individuals with a disease-causing mutation would have been 10.Conclusions: In most families with TAAD, a diagnosis still relies on measuring the diameter of the thoracic aorta. We show that a substantial number of previously unknown cases of aortic dilatation can be identified by screening family members. It is, however, not possible to consider anyone free of the condition, even if the aortic diameter is normal, especially at a younger age.
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| 23. |
- Hilton, Emma N, et al.
(författare)
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Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination.
- 2007
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 16:14, s. 1773-1782
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Tidskriftsartikel (refereegranskat)abstract
- Oculofaciocardiodental (OFCD) syndrome is an X-linked male lethal condition encompassing cardiac septal defects, as well as ocular and dental anomalies. The gene mutated in OFCD syndrome, the BCL-6 corepressor (BCOR), is part of a transcriptional repression complex whose transcriptional targets remain largely unknown. We reviewed cases of OFCD syndrome and identified patients exhibiting defective lateralization including dextrocardia, asplenia and intestinal malrotation, suggesting that BCOR is required in normal laterality determination. To study the function of BCOR, we used morpholino oligonucleotides (MOs) to knockdown expression of xtBcor in Xenopus tropicalis, thus creating an animal model for OFCD syndrome. The resulting tadpoles had cardiac and ocular features characteristic of OFCD syndrome. Reversed cardiac orientation and disorganized gut patterning were seen when MOs were injected into the left side of embryos, demonstrating a left-sided requirement for xtBcor in lateral determination in Xenopus. Ocular defects displayed no left-right bias and included anterior and posterior segment disorders such as microphthalmia and coloboma. Expression of xtPitx2c was shown to be downregulated when xtBcor was depleted. This identifies a pathway in which xtBcor is required for lateral specification, a process intrinsically linked to correct cardiac septal development.
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| 24. |
- Hooper, Sean D., et al.
(författare)
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Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder
- 2012
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 13, s. 123-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor and verbal tics. Although several genes have been suggested in the etiology of TS, the genetic mechanisms remain poorly understood. Methods: Using cytogenetics and FISH analysis, we identified an apparently balanced t(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). In order to map the breakpoints and to identify additional submicroscopic rearrangements, we performed whole genome mate-pair sequencing and CGH-array analysis on DNA from the proband. Results: Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of the chromosome 6q breakpoint, which has not been reported in controls. The deletion affects three genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deleted in a girl with autistic features and speech delay. The proband's mother, also a carrier of the translocation, was diagnosed with OCD and shares the deletion. We also describe a further potentially related rearrangement which, while unmapped in Homo sapiens, was consistent with the chimpanzee genome. Conclusions: We conclude that genome-wide sequencing at relatively low resolution can be used for the identification of submicroscopic rearrangements. We also show that large rearrangements may escape detection using standard analysis of whole genome sequencing data. Our findings further provide a candidate region for TS and OCD on chromosome 6q16.
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| 25. |
- Hopfgarten, Johan, et al.
(författare)
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Spontaneous Coronary Artery Dissection and Papillary Muscle Rupture in Patient With Undiagnosed Vascular Ehler-Danlos Syndrome.
- 2022
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Ingår i: JACC. - : Elsevier. - 2666-0849. ; 4:14, s. 902-905
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Tidskriftsartikel (refereegranskat)abstract
- We present the case of a woman with acute coronary syndrome on the basis of spontaneous coronary artery dissection causing a papillary muscle rupture with severe mitral regurgitation and acute heart failure. The patient subsequently underwent successful emergent surgery of both the mitral and tricuspid valves. Postoperatively, the patient was diagnosed with vascular Ehlers-Danlos syndrome. (Level of Difficulty: Advanced.).
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