Background Dilated and non-dilated left ventricular cardiomyopathy (DCM/NDLVC) are commonly caused by pathogenic genetic variants. Heart failure (HF) treatment recommendations for genotype-positive patients with early disease are lacking. Objectives We aimed to assess HF outcome in HF treated and not treated DCM/NDLVC genotype-positive patients in early disease stages. Methods Genotype-positive DCM/NDLVC patients were enrolled in an observational study. We recorded the use of HF medication and analyzed echocardiographic examinations at baseline and last follow-up. Patients were stratified according to left ventricular ejection fraction (LVEF) as preserved (≥50%), mildly reduced (40-49%), and reduced (<40%). HF outcome was defined as decline of LVEF <40% in patients with preserved/mildly reduced LVEF at baseline. In patients with mildly reduced LVEF, all echocardiographic examinations were analyzed by mixed model regression analyses stratified by HF treated and untreated. Genotype-specific analyses were performed for high-risk and low-risk genotypes. Results 712 patients were followed for 3.1 years (mean age 40 years, 52% females, 20% probands). In 407 patients with preserved/mildly reduced LVEF, 24 (6%) patients declined to LVEF <40%. In 130 patients with mildly reduced LVEF, HF treatment was associated with a 1.8 percentage points (95% CI, 0.7 to 2.9; P=0.01) higher LVEF, and 2.4 percentage points (95% CI, 0.3 to 4.4; P=0.02) higher LVEF in high-risk genotypes. Conclusions In genotype-positive DCM/NDLVC patients with mildly reduced LVEF, we found a 1.8 percentage points higher LVEF in those receiving HF treatment. This should be considered when planning larger trials for guideline-directed HF treatment.

BACKGROUND:Peripartum cardiomyopathy (PPCM) occurs in 0.02% to 0.1% of live births in European countries. Truncating variants in the Titin gene (TTNtv) are the most common genetic findings in women with PPCM. However, data on pregnancy-associated cardiomyopathy (PAC) and pregnancy tolerance among TTNtv-positive women are limited. OBJECTIVES:The objectives of the study were to report maternal cardiac outcomes during pregnancy and postpartum and fetal outcomes in women with TTNtv and to explore the effect of parity on long-term cardiac phenotype. METHODS:We conducted an ambispective cohort study including consecutive TTNtv genotype-positive women, regardless of phenotype, with ≥1 cardiological evaluation. Data on pregnancies and maternal and fetal outcomes were collected from questionnaires and medical records. Arrhythmic burden and device implantation were recorded. Left ventricular dimensions and function were assessed by echocardiography. RESULTS:A total of 107 TTNtv-positive women were included (age 43 [IQR: 32-55] years, 17% probands). Among 78 women with prior pregnancies, 206 pregnancies resulted in 167 (81%) live births. PAC occurred in 3 of 167 live births and in 3 of 76 women, corresponding to a cumulative incidence of 1.8% and 3.9%. All affected women recovered completely with medical therapy. Remaining pregnancies were largely uncomplicated, without increased maternal or fetal adverse events. At median of 18 years (IQR: 9-31) after pregnancy, no differences were observed between parous and nulliparous women in arrhythmic burden, cardiac function, or ventricular dimensions. CONCLUSIONS:In this TTNtv-positive cohort, PAC incidence appeared higher than reported PPCM rates in the general European population. However, pregnancy was well tolerated and was not associated with adverse long-term cardiac remodeling.

BACKGROUND AND AIMS:Cholesterol screening in children, with subsequent genetic testing of top percentile, has been suggested as an efficient universal screening approach in familial hypercholesterolaemia (FH). The potential cholesterol-based screening efficacy was investigated in a national genetically based screening programme. METHODS:Data were from the Norwegian national family cascade screening programme in FH children from 1998 to 2023. Cholesterol levels [umbilical cord in newborns (n = 113) and venous blood in children 1-12 years old (n = 1346)] in variant positive and variant negative children were compared. RESULTS:LDL cholesterol (LDL-C) was higher in FH newborns vs non-FH newborns [1.22 (.48) vs .68 (.32) mmol/L, P < .001], but overlapped widely. Cut-off levels corresponding to the 95th and 85th percentile would only identify 55.7% and 75.4% of newborns with FH, respectively. Screening efficacy in newborns did not differ in subgroups: boys and girls, null and non-null variants, variant gene, and neither for total cholesterol nor for non-HDL cholesterol. In all other age groups (from 1 to 12 years), LDL-C discriminated highly between mutation FH and non-FH children. Cut-off levels corresponding to 95th and 85th percentile of LDL-C would identify 88.4% and 94.1% of 1-12-year-old children with FH, respectively. CONCLUSIONS:Previous studies investigating lipid or genetic screening approaches for FH have limitations of only performing genetic testing in children with high LDL-C levels. The present study is the first to show the true LDL-C overlap in children with FH vs non-FH by utilizing unique data from a national family cascade screening programme. Cholesterol-based screening approaches for FH only seem feasible from 1 year of age onward.

The aim of this study was to explore the prevalence of likely pathogenic or pathogenic variants and assess the diagnostic yield from genetic testing for cardiac arrhythmias in Norway since 2003. Data from 1991 probands and 2782 relatives were retrospectively collected from the laboratory information management system at Unit for Cardiac and Cardiovascular Genetics, Oslo University hospital. Of 1991 probands, 57.4% were females, age at genetic testing was 33.1 (±22.7) years, and 32.5% were under the age of 18. A likely pathogenic or pathogenic variant (including 14 novel) was detected in 15.4% in total. Of the 2782 relatives, 53.7% were females, age at genetic testing was 35.6 (±22.5) years, 27.3% were under the age of 18, and 45.3% carried the family variant. Probands and relatives combined, 1/3356 persons in the Norwegian population were heterozygous for an arrhythmia-causing variant. The founder variant p.Q530X (NM_000218.2: c.1588C>T) in KCNQ1 accounted for 34% of all variants in Norway. In conclusion, genetic testing provided a genetic basis of the arrhythmia in 15.4% of the probands. Familial cascade screening identified four times as many variant-positive relatives, allowing early detection and prompt stratification of arrhythmic risk of those variant carriers.

PURPOSE:Congenital aniridia is a serious eye disease characterized by absence of iris to various degrees. The aims of this study were to investigate health-related quality of life (HRQoL) in adults with aniridia and assess the relationships between HRQoL, psychological status, ocular health and obesity. METHODS:Twenty-nine adults with congenital aniridia (48% male, aged 18-79 years) participated. HRQoL was measured with SF-36 and the EQ visual analogue scale (VAS). The physical (PCS) and mental (MCS) component summaries of the SF-36 were calculated with higher scores indicating better HRQoL. Symptoms of anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS). Obesity was assessed with the Patient-Reported Outcomes in Obesity (PROS). Sociodemographic characteristics, genetic variants and ocular and medical health variables were also analysed. RESULTS:The participants scored significantly lower in the general health domain of the SF-36 than the general population (65.2 vs. 75.3, p = 0.017). The EQ VAS score was also lower in the aniridia group (64.9 vs. 77.9, p = 0.021). Low PCS score was correlated with presence of ocular pain (p = 0.019), high HADS score (p = 0.017) and high PROS score (p = 0.009). Low MCS score was related to higher educational level (p = 0.038) and high HADS score (p < 0.001). High HADS and PROS scores were both related to low EQ VAS scores. CONCLUSION:Adults with congenital aniridia scored worse on certain measures of HRQoL than the general population. Poorer HRQoL was associated with increased symptoms of anxiety, depression and obesity and with presence of ocular pain.

Background Hypokalaemic paralysis is a rare group of disorders with concomitant muscle weakness and hypokalaemia. Thyrotoxicosis is a recognized and a common cause for hypokalaemic paralysis among Asians, in which intracellular shift of potassium is enhanced. Gitelman syndrome, an autosomal recessive renal salt loosing condition is characterized by hypokalaemia, hypocalciuria and hypomagnesaemia. Concurrence of these two conditions is very rarely reported.Case Presentation We report two genetically unrelated Sri Lankan patients who presented with concurrent thyrotoxicosis and Gitelman syndrome. Both of them presented with symptomatic hypokalaemia and detected to have thyrotoxicosis. One had Grave’s disease, while the other patient had toxic multinodular goiter. They were initially managed symptomatically for thyrotoxic hypokalaemic paralysis. Despite rendering euthyroidism with medical management, they persisted to have symtomatic hypokalaemia. On evaluation for a second pathology, we detected them to have Gitelman syndrome, which is a rare concurrence.Conclusion Elevated thyroid hormone levels can precipitate a paralytic episode in a patient with subclinical chronic hypokalaemia due to an additional underlying disease. Gitelman syndrome is such a disease which should be considered and actively looked for in a patient with persistent hypokalaemia following rendering euthyroidism.

En rekke genetiske skjelettmuskeldystrofier er assosiert med kardiomyopati med hjertesviktutvikling og risiko for plutselig død. Grad av kardial affeksjon er ikke nødvendigvis relatert til grad av skjelettmuskelaffeksjon, og plutselig hjertedød kan være første tegn på kardiomyopati. For å iverksette behandling og forebyggende tiltak mot livstruende kardiale hendelser er det nødvendig med økt oppmerksomhet blant allmennleger og spesialister.

Background: We aimed to investigate if history of vigorous exercise was associated with changes in left ventricular morphology, left ventricular function and ventricular arrhythmias (VAs) in hypertrophic cardiomyopathy genotype positive, phenotype negative (Genotype+LVH-) and in phenotype positive (HCM LVH+). Methods: In this cross sectional study we included 187 subjects (age 49 +/- 16 years, 89(48%) female, 121(65%) HCMLVH+ and 66 (35%) Genotype+LVH-) who answered a questionnaire on physical activity history. Exercise >= 6 metabolic equivalents was defined as vigorous. Subjects with a history of vigorous exercise = >= 4 h/week during >= 6 years were defined as athletes. All underwent echocardiography and Holter monitoring. VAs were defined as aborted cardiac arrest, sustained or non-sustained ventricular tachycardia. Results: In both Genotype+LVH- and HCM LVH+, lifetime vigorous exercise correlated with larger left ventricular end-diastolic volume (rho 0.44 and 0.38 respectively, both p < 0.001). Lifetime vigorous exercise correlated with increased left ventricular mass in Genotype+LVH-(rho 0.28, p = 0.03), but not in HCM LVH+ (p=0.53). Left ventricular systolic function was similar between athletes and non-athletes in Genotype+LVH- and HCM LVH+. HCMLVH+ athletes had lower E/e' (p=0.03) and higher e' (p=0.02) compared to non-athletes, while this difference was not observed in Genotype+LVH-. Lifetime vigorous exercise was similar among HCM LVH+ with and without VAs (p=0.89). Conclusions: Increased lifetime vigorous exercise was associated with larger left ventricular volumes in hypertrophic cardiomyopathy, but correlated to left ventricular mass only in Genotype+LVH-. Vigorous exercise was associated with favorable diastolic function in HCM LVH+, and was not associated with VAs. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.

Aims Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy (DCM) with frequent conduction blocks and arrhythmias. We explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among familial DCM in Norway. Furthermore, we explored the risk factors and the outcomes in LMNA patients. Methods and results During 2003-15, genetic testing was performed in patients referred for familial DCM. LMNA genotype-positive subjects were examined by electrocardiography, Holter monitoring, cardiac magnetic resonance imaging, and echocardiography. A positive cardiac phenotype was defined as the presence of atrioventricular (AV) block, atrial fibrillation/flutter (AF), ventricular tachycardia (VT), and/or echocardiographic DCM. Heart transplantation was recorded and compared with non-ischaemic DCM of other origin. Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation. Family screening diagnosed an additional 93 LMNA genotype-positive family members. We clinically followed up 79 LMNA genotype-positive [age 42 +/- 16 years, ejection fraction (EF) 45 +/- 13%], including 44 (56%) with VT. Asymptomatic LMNA genotype-positive family members (age 31 +/- 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 +/- 2.9 years of follow-up. Ten (32%) had AV block, 7 (23%) AF, and 12 (39%) non-sustained VT. Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 +/- 6.3 years of follow-up. Conclusion LMNA mutation prevalence was 6.2% of familial DCM in Norway. Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up. Nearly 20% of the LMNA patients required heart transplantation.

ObjectiveWe explored cardiac volumes and the effects on systolic function in hypertrophic cardiomyopathy (HCM) patients with left ventricular hypertrophy (HCM LVH+) and genotype-positive patients without left ventricular hypertrophy (HCM LVH−).MethodsWe included 180 HCM LVH+, 100 HCM LVH− patients and 80 healthy individuals. End-Diastolic Volume Index (EDVI), End-Systolic Volume Index (ESVI) and ejection fraction (EF) were assessed by echocardiography. Left ventricular (LV) global longitudinal strain (GLS) was measured by speckle tracking echocardiography.ResultsEDVI and ESVI were significantly smaller in HCM LVH+ compared with HCM LVH− patients (41±14 mL/m2vs 49±13 mL/m2and 16±7 mL/m2vs 19±6 mL/m2, respectively, both p<0.001) and in healthy individuals (41±14 mL/m2vs 57±14 mL/m2and 16±7 mL/m2vs 23±9 mL/m2, respectively, both p<0.001). HCM LVH− patients had significantly lower EDVI and ESVI compared with healthy individuals (49±13 mL/m2vs 57±14 mL/m2and 19±6 mL/m2vs 23±9 mL/m2, both p<0.001). EF was similar (61%±7% vs 60%±8% vs 61%±6%, p=0.43) in the HCM LVH+, HCM LVH– and healthy individuals, despite significantly worse GLS in the HCM LVH+ (−16.4%±3.7% vs −21.3%±2.4% vs −22.3%±3.7%, p<0.001). GLS was worse in the HCM LVH− compared with healthy individuals in pairwise comparison (p=0.001). Decrease in ESVI was closely related to EF in HCM LVH+ and HCM LVH− (R=0.45, p<0.001 and R=0.43, p<0.001) as expected, but there was no relationship with GLS (R=0.02, p=0.77 and R=0.11, p=0.31). Increased maximal wall thickness (MWT) correlated significantly with worse GLS (R=0.58, p<0.001), but not with EF (R=0.018, p=0.30) in the HCM LVH+ patients.ConclusionHCM LVH+ had smaller cardiac volumes that could explain the preserved EF, despite worse GLS that was closely related to MWT. HCM LVH− had reduced cardiac volumes and subtle changes in GLS compared with healthy individuals, indicating a continuum of both volumetric and systolic changes present before increased MWT.

Data presented in this paper are supplementary material to our study "Vigorous exercise in patients with hypertrophic cardiomyopathy" [1]. The current article presents supplementary data on collection and analyses of exercise parameters and genetic data in the original research article.

There is a lack of comprehensive patient-datasets regarding prevalence of severe hypertriglyceridemia (sHTG; triglycerides ≥10 mmol/L), frequency of co-morbidities, gene mutations, and gene characterization in sHTG. Using large surveys combined with detailed analysis of sub-cohorts of sHTG patients, we here sought to address these issues.

Background: Gitelman syndrome (GS) is a rare autosomal recessively inherited salt-wasting tubulopathy associated with mutations in the SLC12A3 gene, which encodes for NaCl cotransporter (NCC) in the kidney.Case presentation: In this report, we describe two siblings from a Sri Lankan non-consanguineous family presenting with hypokalaemia associated with renal potassium wasting, hypomagnesemia, hypocalciuria and hypereninemic hyperaldosteronism with normal blood pressure. Genetic testing showed that both were homozygotes for a novel missense mutation in exon 10 of the SLC12A3 gene [NM_000339.2, c.1276A > T; p.N426Y], which has not previously been reported in the literature in association with GS. Their mother was a heterozygous carrier for the same mutation. The father was not alive at the time of testing. This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS. Interestingly both siblings had young onset Diabetes with strong family history.Conclusion: These findings have implications in providing appropriate genetic counseling to the family with regard to the risk associated with inbreeding, the detection of carrier/presymptomatic relatives. It further expands the known spectrum of genotypic and phenotypic characteristics of Gitelman syndrome.

Subjects with hypercholesterolemia who do not carry a mutation in the low density lipoprotein receptor gene, in the apolipoprotein B gene or in the proprotein convertase subtilisin/kexin type 9 gene, could possible carry a mutation in the apolipoprotein E (APOE) gene. DNA from 844 unrelated hypercholesterolemic subjects who did not carry a mutation in any of the three above mentioned genes, was subjected to DNA sequencing of the APOE gene. Two subjects were found to be heterozygous for mutation p.Thr5*. This mutation which generates a stop codon in the signal peptide, is assumed to prevent the synthesis of APOE. Family studies revealed that the mutation was carried on an APOE4 allele in both families. In one of the families only those who had an APOE2 allele as the second allele, had hypercholesterolemia. These were functionally hemizygous for APOE2 and presented with a Type III hyperlipoproteinemia phenotype. However, in the second family, hypercholesterolemia was observed in the index patient who had APOE3 as the second allele, but not in four heterozygous family members who also had APOE3 as the second allele. These findings underscore that the phenotypic expression of mutations in the APOE gene is variable and that the trait exhibits reduced penetrance.

Background: Primary immunodeficiency diseases (PIDDs) are inherited disorders of the immune system. The most severe form, severe combined immunodeficiency (SCID), presents with profound deficiencies of T cells, B cells, or both at birth. If not treated promptly, affected patients usually do not live beyond infancy because of infections. Genetic heterogeneity of SCID frequently delays the diagnosis; a specific diagnosis is crucial for life-saving treatment and optimal management.Objective: We developed a next-generation sequencing (NGS)-based multigene-targeted panel for SCID and other severe PIDDs requiring rapid therapeutic actions in a clinical laboratory setting.Methods: The target gene capture/NGS assay provides an average read depth of approximately 10003. The deep coverage facilitates simultaneous detection of single nucleotide variants and exonic copy number variants in one comprehensive assessment. Exons with insufficient coverage (<20 x read depth) or high sequence homology (pseudogenes) are complemented by amplicon-based sequencing with specific primers to ensure 100% coverage of all targeted regions.Results: Analysis of 20 patient samples with low T-cell receptor excision circle numbers on newborn screening or a positive family history or clinical suspicion of SCID or other severe PIDD identified deleterious mutations in 14 of them. Identified pathogenic variants included both single nucleotide variants and exonic copy number variants, such as hemizygous nonsense, frameshift, and missense changes in IL2RG; compound heterozygous changes in ATM, RAG1, and CIITA; homozygous changes in DCLRE1C and IL7R; and a heterozygous nonsense mutation in CHD7.Conclusion: High-throughput deep sequencing analysis with complete clinical validation greatly increases the diagnostic yield of severe primary immunodeficiency. Establishing a molecular diagnosis enables early immune reconstitution through prompt therapeutic intervention and guides management for improved long-term quality of life.