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.

National clinical Genetic Networks - GENets - Establishment of expert collaborations in Denmark.

Genetic conditions are often familial, but not all relatives receive counseling from the same institution. It is therefore necessary to ensure consistency in variant interpretation, counseling practices, and clinical follow up across health care providers. Furthermore, as new possibilities for gene-specific treatments emerge and whole genome sequencing becomes more widely available, efficient data handling and knowledge sharing between clinical laboratory geneticists and medical specialists in clinical genetics are increasingly important.

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.

Early diagnosis enabling precision medicine treatment in a young boy with PIK3R1-related overgrowth.

Mosaic PIK3R1 variants have recently been demonstrated in patients with complex vascular malformations and overgrowth in a syndrome resembling PIK3CA-related overgrowth syndrome (PROS). The PIK3CA-inhibitor, alpelisib, seems to be a promising treatment option for PROS patients. We describe a young boy with overgrowth and a pathogenic mosaic variant in PIK3R1; c.

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.

First reported adult patient with TARP syndrome: A case report.

TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistence of the left superior vena cava) is a rare X-linked syndrome often resulting in pre- or post-natal lethality in affected males. In 2010, RBM10 was identified as the disease-causing gene, and we describe the first adult patient with TARP syndrome at age 28 years, hereby expanding the phenotypic spectrum. Our patient had Robin sequence, atrial septal defect, intellectual disability, scoliosis, and other findings previously associated with TARP syndrome.

Putative new childhood leukemia cancer predisposition syndrome caused by germline bi-allelic missense mutations in DDX41.

DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD-box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five.

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling.

A complex phenotype in a family with a pathogenic SOX3 missense variant.

Duplications and deletions of Xq26-27 including SOX3 (Xq27.1) have been associated with X-linked mental retardation and isolated growth hormone deficiency (OMIM 300123) or X-linked panhypopituitarism (OMIM 312000). Yet, pathogenic point mutations seem to be extremely rare.

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.