Actionability and familial uptake following opportunistic genomic screening in a pediatric cancer cohort.

The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified.

Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

Background: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in or . Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum.

Aortic dissection in a young male with persistent ductus arteriosus and a novel variant in MYLK.

Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection.

Carriers of COL3A1 pathogenic variants in Denmark: Interfamilial variability in severity and outcome of elective surgical procedures.

The study describes all patients in Denmark with vascular Ehlers-Danlos syndrome (vEDS). Carriers of pathogenic or likely pathogenic COL3A1 variants were retrospectively identified through registries and specialized clinics. Medical records were reviewed for vascular- or organ ruptures and invasive procedures performed.

Novel Variants in Five Families with Aortic/Arterial Aneurysm and Dissection with Variable Connective Tissue Findings.

Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in , encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying variants, including two missense variants affecting highly conserved amino acids in the catalytic domain and three truncating variants.

Severe congenital cutis laxa: Identification of novel homozygous LOX gene variants in two families.

We report three babies from two families with a severe lethal form of congenital cutis laxa. All three had redundant and doughy-textured skin and two siblings from one family had facial dysmorphism. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity.

[Genetic screening of prospective parents].

Risk of genetic diseases with autosomal recessive or X-linked inheritance can be unknown to prospective parents until an affected child is born. New technology has enabled carrier screening for hundreds of genetic diseases (expanded carrier screening, ECS). I Denmark, each year estimated 100-180 children are born affected with a serious condition which could have been detected with ECS of the parents.

Direct to consumer genetic testing in Denmark-public knowledge, use, and attitudes.

Direct to consumer genetic testing (DTC-GT) is offered by commercial companies, but the use in the general population has only been sparsely investigated. A questionnaire was sent to 2013 representative Danish citizens asking about their awareness and use of DTC-GT. Individuals who had undergone a genetic test were interviewed to determine if the results had been understood correctly.

[The Danish screening programme for haemoglobinopathies].

The prevalence of people in Denmark descending from areas with a high prevalence of haemoglobinopathies is approximately one tenth and increasing. Since 1995, the Danish Health Authority has recommended haemoglobinopathy screening of pregnant women with ethnic roots outside Northern Europe. Partners of pregnant haemoglobinopathy carriers are also tested.

Expanding the cerebrovascular phenotype of the p.R258H variant in ACTA2 related hereditary thoracic aortic disease (HTAD).

Heterozygous variants in smooth muscle alpha-actin gene (ACTA2) are the most frequent cause of autosomal dominant hereditary thoracic aortic disease (HTAD). Several genotype-phenotype associations have been described, including a severe multisystemic smooth muscle disorder associated with de novo ACTA2 p.R179 variants, characterized by highly penetrant and early onset vascular disease, involvement of smooth muscle cell (SMC)-dependent organs and a distinct cerebrovascular phenotype.

Phenotypic presentations of Hajdu-Cheney syndrome according to age - 5 distinct clinical presentations.

We present five Danish individuals with Hajdu-Cheney syndrome (HJCYS) (OMIM #102500), a rare multisystem skeletal disorder with distinctive facies, generalised osteoporosis and progressive focal bone destruction. In four cases positive genetic screening of exon 34 of NOTCH2 supported the clinical diagnosis; in one of these cases, mosaicism was demonstrated, which, to our knowledge, has not previously been reported. In one case no genetic testing was performed since the phenotype was definite, and the diagnosis in the mother was genetically confirmed.

Translation and Adaptation of the Genetic Counselling Outcome Scale (GCOS-24) for Use in Denmark.

Outcome measurement in clinical genetics is challenging. Robust outcome measures are needed to provide evidence to support service development within genetic counseling. The Genetic Counselling Outcome Scale (GCOS-24), a Patient Reported Outcome Measure (PROM), was developed in English and validated with clinical genetics patients in the British NHS.

[Presymptomatic genetic testing in minors should only be performed when intervention is possible].

Presymptomatic genetic testing in minors is subject to debate. We reviewed guidelines on the subject from four large medical genetics societies. A general consensus exists regarding presymptomatic testing with the main justification for such testing being the direct benefit to the child through medical intervention or preventive measures.

[The genome and cardiology].

Several cardiac diseases are autosomal dominantly inherited. This includes cardiomyopathies, primary arrhythmias (channelopathies), dyslipidaemias, premature ischaemic heart diseases and diseases of the thoracic aorta. Sudden cardiac death in the young is also often due to one of the inherited cardiac diseases.

[Potential problems in obtaining insurance concern patients referred for genetic counseling].

In Denmark insurance companies may request information regarding current and past disease of the applicants and their family when insurance is requested but they are prohibited from requesting information regarding the applicants' genetically determined risk of future disease. We report a web-based survey in which 46 health-care providers reported how often they met concerns regarding insurance. Concerns were expressed in 1:17 contacts and led to discontinuation of the work-up in 1:200.

[Thorough family history and a multidisciplinary approach are important in sudden cardiac deaths].

Sudden cardiac death (SCD) is rare, yet well-known in children and adolescents. We present two cases of aborted SCD which reminds us of the importance of comprehensive family history as it proved difficult to ask the right questions revealing the number of family members with cardiac symptoms. Earlier recognition of sudden deaths in the family might have led to more extensive multidisciplinary examinations, and earlier diagnosis.

Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial.

Background: Studies from low-income countries have suggested that diphtheria-tetanus-pertussis (DTP) vaccine provided after Bacille Calmette-Guerin (BCG) vaccination may have a negative effect on female survival. The authors examined the effect of DTP in a cohort of low birthweight (LBW) infants.

Methods: 2320 LBW newborns were visited at 2, 6 and 12 months of age to assess nutritional and vaccination status.

Attitudes towards abortion among trainees in obstetrics/gynecology and clinical genetics.

This study aimed to provide knowledge about attitudes towards abortion among Danish physicians in training in the specialties of obstetrics/gynecology and clinical genetics. The study was a questionnaire survey among trainees in these specialties. Ninety-six responded.

The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life.

Vitamin A supplements may interact with diphtheria-tetanus-pertussis (DTP) vaccine causing increased female mortality. In a randomised trial of neonatal vitamin A supplementation (VAS), we examined growth during the first year of life in 808 children, pursuing the hypothesis that a negative interaction between VAS and DTP in girls would be reflected in growth. Length and weight were measured at 6 weekly visits and WHO-growth-reference z-scores derived.

Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?

Background: Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG.

Methods: In the period 2004-2008 we recruited 2320 LBW children in Bissau.

The effect of high-dose vitamin A supplementation given with bacille Calmette-Guérin vaccine at birth on infant rotavirus infection and diarrhea: a randomized prospective study from Guinea-Bissau.

Background: Prophylactic vitamin A supplementation (VAS) reduces mortality and may reduce morbidity associated with diarrhea in children >6 months of age. Rotavirus is the most common cause of acute dehydrating diarrhea among children worldwide.

Methods: In a randomized placebo-controlled study of 50,000 IU of vitamin A versus placebo given with bacille Calmette-Guérin vaccine at birth, 287 infants were followed up with weekly interviews and stool sample obtainment to test the hypothesis that VAS reduced the risk of rotavirus infection.