Congenital aortic stenosis due to unicuspid unicommissural aortic valve: a case report

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesBACKGROUND: Unicuspid unicommissural aortic valve is an extremely rare congenital anomaly that usually presents in adulthood but can rarely present in infancy. We report a 17-year-old patient with congenital aortic stenosis secondary to unicuspid unicommissural aortic valve that was successfully treated with aortic valve replacement. CASE PRESENTATION: The patient was diagnosed with aortic stenosis after a murmur was heard in the newborn nursery and subsequently underwent aortic balloon valvuloplasty 6 weeks after birth. He had been regularly followed up since and underwent numerous cardiac catheterizations, including another aortic balloon valvuloplasty at age 13. During follow-up at age 17, the patient presented with symptomatic severe aortic stenosis and mild left ventricular hypertrophy. Aortic valve replacement was planned since the patient was nearly adult-sized and to reduce the risk of cardiac decompensation. During the operation an unicuspid unicommissural aortic valve was revealed. The patient recovered well post-operatively. He was discharged 5 days after the surgery in good condition and was completely symptom-free at follow-up 6 weeks later. CONCLUSIONS: Unicuspid aortic valve is a rare congenital anomaly that can cause congenital aortic stenosis. It is seldom diagnosed pre-operatively but should be suspected in infants presenting with aortic stenosis

Congenital cardiac malformations in Iceland from 1990 through 1999

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldINTRODUCTION AND BACKGROUND: About 1% of live-born children have congenital malformations of the heart. The aim of our study was to investigate the incidence of such defects in children born in Iceland during a period of 10 years, extending from 1990 through 1999. MATERIALS AND METHODS: Information about the patients was obtained from medical records from two hospitals that cover the whole country, a private clinic of pediatric cardiologists, an echocardiography database, autopsy reports, and death certificates. We investigated the distribution of specific malformations, the age at diagnosis, the symptoms leading to the diagnosis, the source of referral, and treatment and quality of life. RESULTS: Between 1990 and 1999, there were 44,013 live births in Iceland, of which 740 patients were diagnosed with congenital cardiac malformations, accounting for 1.7% of the live-born children. The distribution was made up of 338 patients with ventricular septal defect (45.7%), 90 with atrial septal defect (12.2%), 85 with patency of the arterial duct (11.5%), 48 with pulmonary valvar stenosis (6.5%), 38 with a bicuspid aortic valve (5.1%), 28 with aortic coarctation (3.8%), 22 with tetralogy of Fallot (3.0%), 14 with transposed great arteries (1.9%), 11 with aortic stenosis (1.5%), 10 with atrioventricular septal defect and common atrioventricular orifice (1.4%), 9 with mitral valvar regurgitation (1.2%), 7 with sub-aortic stenosis (0.9%), and 5 with hypoplasia of the left heart (0.7%). Extracardiac anomalies were seen in 89 patients (12.0%). Chromosomal defects were seen in 36 patients, of whom 28 had Down's syndrome. DISCUSSION: The annual incidence of diagnosis of patients with congenital cardiac malformations increased during the period of study. This was noted for minor defects, but the incidence of the major anomalies did not alter. Our observed yearly incidence, at 1.7%, was higher than noted in a previous study covering the years 1985 through 1989, and is also higher than in other population-based studies. The most likely explanation is the fact that access to pediatric cardiologists in Iceland is very good. Diagnosis, registration, and follow-up are conducted by only a few cardiologists, and take place at a single center for pediatric cardiology

Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland

Background Long‐QT syndrome (LQTS) is a cardiac repolarization abnormality that can lead to sudden cardiac death. The most common causes are rare coding variants in the genes KCNQ1, KCNH2, and SCN5A. The data on LQTS epidemiology are limited, and information on expressivity and penetrance of pathogenic variants is sparse. Methods and Results We screened for rare coding variants associated with the corrected QT (QTc) interval in Iceland. We explored the frequency of the identified variants, their penetrance, and their association with severe events. Twelve variants were associated with the QTc interval. Five in KCNQ1, 3 in KCNH2, 2 in cardiomyopathy genes MYBPC3 and PKP2, and 2 in genes where coding variants have not been associated with the QTc interval, ISOC1 and MYOM2. The combined carrier frequency of the 8 variants in the previously known LQTS genes was 530 per 100 000 individuals (1:190). p.Tyr315Cys and p.Leu273Phe in KCNQ1 were associated with having a mean QTc interval longer than 500 ms (P=4.2×10−7; odds ratio [OR], 38.6; P=8.4×10−10, OR, 26.5; respectively), and p.Leu273Phe was associated with sudden cardiac death (P=0.0034; OR, 2.99). p.Val215Met in KCNQ1 was carried by 1 in 280 Icelanders, had a smaller effect on the QTc interval (P=1.8×10−44; effect, 22.8 ms), and did not associate with severe clinical events. Conclusions The carrier frequency of associating variants in LQTS genes was higher than previous estimates of the prevalence of LQTS. The variants have variable effects on the QTc interval, and carriers of p.Tyr315Cys and p.Leu273Phe have a more severe disease than carriers of p.Val215Met. These data could lead to improved identification, risk stratification, and a more precise clinical approach to those with QTc prolongation

A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation

Aims Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in man, causing substantial morbidity and mortality with a major worldwide public health impact. It is increasingly recognized as a highly heritable condition. This study aimed to determine genetic risk factors for early-onset AF. Methods and results We sequenced the whole genomes of 8453 Icelanders and imputed genotypes of the 25.5 million sequence variants we discovered into 1799 Icelanders with early-onset AF (diagnosed before 60 years of age) and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. We discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset AF under a recessive mode of inheritance (allelic frequency = 0.58%). We found eight homozygous carriers of the mutation, all of whom had early-onset AF. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischemic stroke, and one suffered sudden cardiac death. Conclusions Through a population approach we found a loss of function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset AF. The finding may provide novel mechanistic insight into the pathophysiology of this complex arrhythmia

Large-scale whole-genome sequencing of the Icelandic population.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageHere we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity