A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant condition characterized by aortic aneurysm, skeletal abnormalities, and lens dislocation, and is caused by variants in the FBN1 gene. To explore causes of MFS and the prevalence of the disease in Iceland we collected information from all living individuals with a clinical diagnosis of MFS in Iceland (n = 32) and performed whole-genome sequencing of those who did not have a confirmed genetic diagnosis (27/32). Moreover, to assess a potential underdiagnosis of MFS in Iceland we attempted a genotype-based approach to identify individuals with MFS. We interrogated deCODE genetics' database of 35,712 whole-genome sequenced individuals to search for rare sequence variants in FBN1. Overall, we identified 15 pathogenic or likely pathogenic variants in FBN1 in 44 individuals, only 22 of whom were previously diagnosed with MFS. The most common of these variants, NM_000138.4:c.8038 C > T p.(Arg2680Cys), is present in a multi-generational pedigree, and was found to stem from a single forefather born around 1840. The p.(Arg2680Cys) variant associates with a form of MFS that seems to have an enrichment of abdominal aortic aneurysm, suggesting that this may be a particularly common feature of p.(Arg2680Cys)-associated MFS. Based on these combined genetic and clinical data, we show that MFS prevalence in Iceland could be as high as 1/6,600 in Iceland, compared to 1/10,000 based on clinical diagnosis alone, which indicates underdiagnosis of this actionable genetic disorder.

[Resistant hypertension - pheochromocytoma].

We report a case of a man with a 30-year history of treatment-resistant hypertension, hydropoiesis, tachycardic spells and dysgeusia. Despite repeated visits to the emergency department and work-up in an out-patient clinic, the diagnosis was unknown. Three years prior to remittance to an endocrinologist, the hypertension worsened, and he developed diabetes type-II. Further work-up revealed a 3 cm extra-adrenal pheochromocytoma, a paraganglioma. After surgical removal of the tumor, he is without medication and symptom free. Pheochromocytoma and paraganglioma are rare causes of hypertension, estimated to explain 0.1-0.6% of all cases, but nonetheless an important diagnosis to make, due to serious side effects.

[Increased use of genetic health care in Iceland 2012-2017].

INTRODUCTION: A genetic counselling unit at Landspitali hospital (LSH) was established in 2006. Meanwhile, genetic testing has become an integral part of general health care. In this article we detail the outcome of genetic testing at the Department of Genetic and Molecular Medicine (DGM) at Landspitali over a five year period (2012-2017). Factors that were analyzed for the time period were: Number of patients, reason for referral, reason for genetic testing without genetic counselling and yield (proportion of positive tests) of genetic testing. METHODS: Data was analysed from two medical record databases, Shire and Saga, used by the DGM in the time period. RESULTS: The number of individuals coming for genetic counselling increased every year over the time period. Reasons for referral were cancer-related in two-thirds of cases. Other reasons for referral included various other familial disorders. Most common were autosomal dominant disorders like myotonic dystrophy, hypertrophic cardiomyopathy and autosomal recessive disorders like spinal muscular atrophy (SMA) and GM1-gangliosidosis. Most common reasons for genetic testing outside of the LSH GC unit was because of managable diseases like hemochromatosis and F5/Prothrombin-related thrombophilia. Yield of genetic testing was assessed for a) known mutation testing / carrier testing, b) single gene testing, c) gene panel testing and d) whole genome and whole exome sequencing. Known mutation testing was positive in 33% of cases and single gene testing in 46% of cases. The yield of gene panel testing for cancer was found to be lower (20%) than gene panel testing for other disorders (40%). The yield of whole exome and whole genome sequencing was 46%.

Impact of different ChIP-Seq protocols on DNA integrity and quality of bioinformatics analysis results.

Different ChIP-Seq protocols may have a significant impact on the final outcome in terms of quality, number and distribution of called peaks. Sample DNA undergoes a long procedure before the final sequencing step, and damaged DNA can result in excessive mismatches in the alignment with reference genome. In this letter, we present the effect of well-defined modifications (timing of formaldehyde crosslink reversal, brand of the sonicator) of standard ChIP-Seq protocol on parallel samples derived from the same cell line correlating the initial DNA quality control metrics to the final bioinformatics analysis results.

A de novo 1.13 Mb microdeletion in 12q13.13 associated with congenital distal arthrogryposis, intellectual disability and mild dysmorphism.

A girl presented with congenital arthrogryposis, intellectual disability and mild bone-related dysmorphism. Molecular workup including the NimbleGen Human CGH 2.1M platform revealed a 1.13 Mb de novo microdeletion on chromosome 12q13.13 of paternal origin. The deletion contains 33 genes, including AAAS, AMRH2, and RARG genes as well as the HOXC gene cluster. At least one gene, CSAD, is expressed in fetal brain. The deletion partially overlaps number of reported benign CNVs and pathogenic duplications. This case appears to represent a previously unknown microdeletion syndrome and possibly the first description in humans of a disease phenotype associated with copy loss of HOXC genes.

Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It is characterized by activating mutations in the tyrosine kinase genes c-kit or PDGFRA. This study examined the mutation rate and type in a population-based material. All gastrointestinal mesenchymal tumors over the years 1990-2004 were evaluated and GIST tumors identified using immunohistochemistry (c-kit) and conventional pathologic parameters. Paraffin sections from all tumors were subjected to mutation analysis on exons 9, 11, 13 and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene. To screen for mutations, we used a highly sensitive conformation-sensitive gel electrophoresis (CSGE) and to define the mutated alleles, we employed direct automated DNA sequencing. All c-kit-positive gastrointestinal mesenchymal tumors were entered into the study. Fifty-six tumors from 55 patients were analyzed. Mutations were found in 52 tumors representing a 92.9% mutational rate. Most of the mutations were found in c-kit exon 11 (76.8%), followed by c-kit exon 9 (10.7%). PDGFRA mutations were only found in three tumors. No correlation of mutation type with biologic behavior was found. This population-based study, using a sensitive CSGE method, identifies mutations in the great majority of patients with GIST.

[Acute abdominal pain caused by acute intermittent porphyria - case report and review of the literature]. / Bráoir kvioverkir af völdum slitróttrar bráoaporfýríu- sjúkratilfelli og yfirlit.

We describe a case of acute intermittent porphyria in a woman who presented repeatedly with abdominal pain. Porphyrias are caused by decreased enzyme activity in the heme biosynthetic pathway leading to overproduction of heme precursors if demand increases. This can cause symptoms such as abdominal pain, nausea and vomiting, constipation, tachycardia and hypertension. Treatment includes removal of causative factors, administration of carbohydrates or hemin to reduce the production of heme precursors as well as symptomatic treatment.

[A case report - Severe electrolyte disturbances in an eight week old boy]. / Sjúkratilfelli - lífshaettulegar truflanir á blódsöltum hjá átta vikna dreng.

Hyponatremia is the most common electrolyte abnormality in children and underlying causes are many. It is most often caused by excessive salt loss from the gut but is also associated with severe systemic disorders in which there is actual or apparent aldosterone deficiency, such as congenital adrenal hyperplasia (CAH), which is the most common inherited disorder of aldosterone synthesis, and pseudohypoaldosteronism (PHA). Abscent aldosterone activity also leads to hyperkalemia which is characteristic for PHA and can result in life threatening arrythmias. This is a case report about a boy presenting with life threatening electrolyte disturbances in conjunction with PHA resulting from pyelonephritis and vesicoureteral reflux.

Effects of knowledge, education, and experience on acceptance of first trimester screening for chromosomal anomalies.

OBJECTIVES: To assess pregnant women's knowledge and understanding of first trimester prenatal screening (nuchal translucency, maternal serum free beta-human chorionic gonadotrophin and pregnancy-associated plasma-protein-A), to evaluate the impact of a new information booklet and investigate the effects of education and experiential knowledge of congenital disabilities on the perceived likelihood of accepting prenatal screening. DESIGN: A quasi-experimental quantitative study with a self-completion questionnaire. SETTING: Five different maternity care clinics in Iceland. POPULATION: Expectant mothers in first trimester of pregnancy (n = 379). MATERIAL AND METHODS: Expectant mothers were divided into two groups, an intervention and a control group, both receiving traditional care and information. The intervention group additionally received an information booklet about prenatal screening and diagnosis. MAIN OUTCOME MEASURES: Women's knowledge score of prenatal screening. The correlation between education, knowledge score, experiential knowledge of congenital disabilities, and the likelihood of accepting prenatal screening. RESULTS: More than half of the women (57%) believed they received sufficient information to make an informed decision about screening. Knowledge scores were significantly higher for the intervention group (with mean 4.8 compared with 3.7 on a 0-8 scale, p < 0.0001). Those with higher scores were more likely to accept screening (p < 0.0001). Women with experiential knowledge of congenital anomalies in their own families were more likely to accept prenatal screening (p = 0.017). CONCLUSIONS: Various factors, e.g. experiential knowledge, education and information about prenatal screening affect the likelihood of participation in prenatal screening programs. More information results in better knowledge and higher uptake rate.

IFCC position paper: report of the IFCC taskforce on ethics: introduction and framework.

Laboratory Medicine organizations and their professional members have a goal and responsibility to benefit the health and wellbeing of the patients and communities they serve. Newer genetics and biochemical techniques raise significant issues of community concern, impacting on privacy, informed consent, access to and retention of samples and information. Balance may be required to ensure protection of individual rights against potential benefits to the broader community. While many national organizations may already have appropriate policies addressing various ethics issues, there is a need for an international framework to assist those nations that have not yet developed such policies, as well as to enable alignment of existing national policies. We have proposed a generic ethics framework, incorporating a hierarchy of four fundamental guiding principles: autonomy, justice, non-maleficence and beneficence. Proposals or issues requiring policy development can be considered and tested against this hierarchy, resulting in the development of policy and positions consistent with the above framework, acceptable to all participating stakeholders.

[Prevalence of myotonic dystrophy in Iceland]. / Spennuvisnun (Dystrophia Myotonica): almennt yfirlit og algengi á Islandi.

OBJECTIVE: Epidemiologic studies of Myotonic Dystrophy (Dystrophic Myotony, DM) have shown variable regional prevalence from 0,46 to 189/105. We carried out a total population survey of DM in Iceland in 2004 having Oct. 31 as the day of prevalence. MATERIAL AND METHODS: Patients were collected from multiple sources, including Landspitali University Hospital registry and through contact with neurologists, neuropaediatricians, paediatricians and rehabilitation specialists. All EMGs of DM patients were reviewed. Information was gathered about age, age of onset, family history of DM and clinical symptoms. RESULTS: Eighty-two patients were ascertained giving a crude prevalence of 28.2/105. The prevalence of the congenital form of DM was 7.9/105 (23 patients, 26%). Affected females outnumbered males with a gender ratio of 1.2:1 (NS). Mean age of onset of symptoms for those, who didn't have the congenital form was 27.5 years (range 5-70 years). Ten families with DM were identified and all prevalent patients belonged to those families. CONCLUSION: The prevalence of DM is high in Iceland and higher than generally reported. This study showed a three times higher total prevalence and a seven times higher prevalence of congenital DM than found in a previous study in Iceland. We believe that this increase in prevalence probably reflects increased awareness of inherited diseases in neonates and better detection of patients who have mild symptoms.