Volume 2 (2018): Issue s1 (September 2018)

Cardiovascular disorders include various conditions characterized by morphological and functional defects of the heart and vascular system. Molecular biology techniques (in particular DNA sequencing) have recently offered new insights into the etiology of cardiovascular defects, revealing their association with germline as well as somatic mutations.

Genetic tests are evaluated on the basis of their analytical and clinical validity, clinical utility, and ethical, legal and social implications. Next generation sequencing is so far the best approach for molecular diagnosis of congenital heart defects and vascular anomalies, the genetic and phenotypic heterogeneity of which makes them difficult to diagnose. Understanding the molecular causes of congenital heart defects and vascular anomalies has permitted clinical trials of drugs targeting affected genes and pathways.

The articles in this Special Issue aim to provide guidance for those concerned with diagnosis and research in the field of cardiovascular defects. The approach to genetic testing is discussed.

Lymphatic malformations (LMs) show phenotypic variability, as well as clinical and genetic heterogeneity. Inheritance is autosomal dominant, recessive or X-linked and major genes involved in predisposition for LMs are continuously being discovered. The literature also indicates that somatic mutations play an important role in the development of LMs. In fact, activating somatic mutations in PIK3CA have been reported in lymphatic endothelial cells obtained from patients with different kinds of LM. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Variants affecting the function of genes in the RAS–mitogen-activated protein kinase (MAPK) signal transduction pathway have been identified as responsible for a group of developmental syndromes known as RASopathies. Noonan (NS) and cardiofaciocutaneous syndromes (CFC) represent the most frequent and best characterized RASopathies. Many cases of RASopathies are associated with lymphatic malformations that finally may result in lymphedema. We developed the test protocol “Lymphedema in RASopathies” on the basis of the latest research findings and diagnostic protocols on lymphatic malformation in RASopathies. The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

We studied the scientific literature and disease guidelines to summarize the clinical utility of genetic testing for lymphedema distichiasis (LD) syndrome. LD is inherited in an autosomal dominant manner, and has unknown prevalence. It is caused by variations in the FOXC2 gene. Clinical diagnosis involves clinical examination, targeted at identifying primary lymphedema (chronic swelling of the extremities) and distichiasis (double row of eyelashes). The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Hennekam Syndrome (HS) is a combination of congenital lymphatic malformation, lymphangiectasia and other disorders. It is a very rare disorder with autosomal recessive inheritance. We developed the test protocol “Hennekam Syndrome” on the basis of the latest research findings and diagnostic protocols on lymphatic malformation in HS. The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Emberger Syndrome (ES) is a very rare genetic disorder associated with primary lymphedema, myelodysplasia and immunodeficiency. The syndrome has autosomal dominant inheritance with incomplete penetrance. Sporadic cases caused by de novo germinal mutations in the GATA2 gene have also been described. We developed the test protocol on the basis of the latest research findings and diagnostic protocols on lymphatic malformation in ES. The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Cystic hygroma (CH) is characterized by abnormal accumulation of fluid in the region of the fetal neck and is a major anomaly associated with aneuploidy. Morphologically characterized by failure of the lymphatic system to communicate with the venous system in the neck, the clinical manifestations of CH depend on its size and location. Incidence is estimated at one case per 6000-16,000 live births. CH has autosomal dominant or autosomal recessive inheritance. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Vascular anomalies (VAs) have phenotypic variability within the same entity, overlapping clinical features between different conditions, allelic and locus heterogeneity and the same disorder can be inherited in different ways. Most VAs are sporadic (paradominant inheritance or de novo somatic or germline mutations), but hereditary forms (autosomal dominant or recessive) have been described. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by telangiectases and arteriovenous malformations. These lesions cause bleeding, particularly in the nose, gastrointestinal tract and brain. HHT has incomplete penetrance, variable expressivity and genetic heterogeneity. De novo mutations associated with the onset of sporadic HHT have been reported. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Marfan syndrome (MFS) is an inherited connective tissue disorder caused by heterozygous mutations in the FBN 1 gene. Clinical manifestations of MFS include aortic dilatation and dissection, as well as cardiac valvular, ocular, skeletal and neurological manifestations. Prevalence varies from 6 to 20 per 100,000 individuals. Revised Ghent Nosology (2010) is used to establish a clinically based suspected diagnosis to be confirmed by molecular testing. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. Molecular testing is useful for diagnosis confirmation, as well as differential diagnosis, appropriate genetic counselling and access to clinical trials.

Marfan-like disorders are inherited conditions with features resembling Marfan syndrome but without a pathogenic variant in FBN1, and/or without a clinical diagnosis of Marfan syndrome according to the Revised Ghent criteria, and/or with a pathogenic variant in a different disease gene. Marfan-like disorders are clinically and genetically heterogeneous and have variable prognosis. They may have autosomal dominant or autosomal recessive patterns of inheritance. The prevalence of most Mar-fan-like disorders is unknown. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. Molecular testing is useful for diagnosis confirmation, as well as differential diagnosis, appropriate genetic counselling and access to clinical trials.

Ehlers-Danlos syndrome (EDS) is an umbrella term for various inherited connective tissue disorders associated with mutations in genes involved in extracellular matrix formation. “The 2017 International Classification of Ehlers-Danlos Syndromes and related disorders” identifies 13 clinical types with mutations in 19 distinct genes. The present module focuses on forms with major vascular involvement: vascular EDS (vEDS) caused by heterozygous mutations in COL3A1, “vascular-like” EDS (vlEDS) caused by recurrent mutations in COL1A1, classical EDS with vascular fragility associated with heterozygous mutations in COL5A1, and kyphoscoliotic EDS associated with recessive variations in PLOD1 and FKBP14. The overall prevalence of EDS is estimated between 1/10,000 and 1/25,000 and vEDS accounts for about 5 to 10% of all EDS cases. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. Molecular testing is useful for diagnosis confirmation, as well as differential diagnosis, appropriate genetic counselling and access to clinical trials.

Atrial septal defect (ASD) is a congenital heart defect characterized by an opening in the atrial septum. About 1/3 of patients with Noonan syndrome caused by mutation in the PTPN11 gene have ASD. The prevalence of ASD is estimated at 100 per 100,000 live births. ASD may have autosomal dominant or recessive inheritance. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Atrioventricular septal defect (AVSD) is a congenital heart defect characterized by a shared atrioventricular junction coexisting with deficient atrioventricular septation. The main morphological characteristic of AVSD is a common atrioventricular canal. The prevalence of AVSD is estimated at 0.31/1000 live births and is higher among subjects with PTPN11 mutations. ASD may have autosomal dominant or autosomal recessive inheritance. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Ventricular septal defects (VSDs) are the commonest heart malformations and may affect the membranous or the muscular septum. Clinical presentation depends on the amount of interventricular flow, which is determined by the size of the defect and the relative resistances of the pulmonary and systemic vascular beds. The prevalence of VSD is estimated at about 5% among infants. Many small malformations present at birth may later undergo spontaneous closure. VSD may have autosomal dominant or autosomal recessive inheritance and may exist as isolated forms or as part of a syndrome. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Ebstein anomaly (EA) is a rare congenital tricuspid valve malformation, characterized by downward displacement of the septal leaflet and an atrialized right ventricle. About 80% of cases of EA are non-syndromic; in the other 20%, the anomaly is associated with a chromosomal or Mendelian syndrome. The prevalence of EA is estimated at about 1 per 20,000 live births, and accounts for less than 1% of all congenital heart defects. EA has autosomal dominant inheritance. Likely causative genes are: NKX2-5, MYH7 and TPM1. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, potential risk assessment and access to clinical trials.

Pulmonary stenosis (PS) is a congenital pulmonary valve malformation. It can be classified as valvular, subvalvular or supravalvular. Isolated forms of PS are rare. PS is associated with the development of massive pulmonary arterial dilatation. Patients with PS have a high consanguinity rate and the disorder is highly familial, which is why knowing the genetic aetiology of this defect is important. Prevalence is estimated at about 4/10,000 live births, and incidence at about 10% of all children with congenital heart defects. PS has prevalently autosomal dominant and rarely autosomal recessive inheritance. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Aortic valve stenosis (AVS) is a congenital aortic defect in which the aortic lumen narrows due to thickening or calcification of the aortic valve without obstructing left ventricular outflow. Depending on the site of obstruction, AVS is classified as valvular, sub-valvular or supra-valvular. The prevalence of AVS is about 3% and increases with age. One in eight persons over the age of 75 years has moderate or severe AVS. AVS has autosomal dominant inheritance. It can be associated with mutations in the following genes: NOTCH1, SMAD6, SMAD4, and ELN. This Utility Gene Test was developed on the basis of the analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials, when available.

Coarctation of the aorta (CoA) is an inherited narrowing of the proximal descending thoracic aorta. Histological features include localized medial thickening and infolding with superimposed neointimal tissue. CoA is diagnosed by detection of a murmur or hypertension during routine examination. Typical clinical features are delayed or absent femoral pulses and difference in blood pressure between the arm and legs. These symptoms may appear in the first weeks of life or after the neonatal period. CoA accounts for 4-6% of all congenital heart defects and has a reported prevalence of about 4 per 10,000 live births. It is more common in males than females (59% vs 41%). This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Bicuspid aortic valve (BAV) is a congenital defect in which the aortic valve has two rather than three leaflets. In many patients valve function may be normal but valve decompensation may occur due to other associated congenital abnormalities and secondary valve and aortic complications. Decompensation manifests as stenosis or regurgitation and thoracic aortic aneurysm and dissection. Cystic medial necrosis plays an important role in the pathogenesis of BAV. Prevalence of BAV is estimated at 0.5-2.0%. In children, 70-85% of stenotic aortic valves are bicuspid, compared to at least 50% in adults. BAV has autosomal dominant inheritance. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Tetralogy of Fallot (ToF) combines congenital cardiac defects including ventricular septal defect, pulmonary stenosis, an overriding aorta and right ventricular hypertrophy. Clinical manifestation of this defect depends on the direction and volume of shunting of blood through the ventricular septal defect and the associated right ventricular and pulmonary artery pressures. ToF accounts for 3-5% of congenital heart defects or 0.28 cases every 1000 live births. ToF has autosomal dominant inheritance. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Large-caliber vessels are those with a diameter of 10 mm or more. Most aneurysms remain asymptomatic until they expand or rupture. Aortic aneurysms are of special interest for physicians and scientists because of their prevalence. Aortic aneurysms and dissections account for 1-2% of all deaths in western countries. Expansion and rupture of vascular aneurysms show a strong correlation with hyperlipidemia, hypertension, smoking, sex and age. Heritability estimates have been as high as 70%. This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Stroke is defined as a focal or at times global neurological impairment of sudden onset and presumed vascular origin. 85% of strokes are due to cerebral ischemia and the other 15% to primary intracerebral hemorrhage.

Ischemic stroke (IS) is characterized by complete or partial obstruction of a vessel in the brain, resulting in lack of blood supply and death of brain tissue. The most common causes of IS are atherosclerosis, cardioembolism and small-vessel disease (lacunar stroke). Genetic factors play important role. Incidence rates for IS in the 15- to 45-year age range are ≈10 per 100,000 person years.

Hemorrhagic stroke (HS) is the least treatable and the most fatal form of cerebrovascular disease. Genetic mechanisms play a role in its development. Occurrence depends on many risk factors, including hypertension, heavy alcohol intake and anticoagulant treatment. According to the World Health Organization, 15 million people suffer stroke worldwide each year. The overall incidence of spontaneous HS worldwide is 24.6 per 100,000 person years. Strokes are the third most common cause of death and the most common cause of disability in developed countries.

This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Cavernous cerebral malformations (CCM) are vascular malformations of the brain and spinal cord. CCM affect up to 0.5% of the general population, predisposing to headaches, seizures, cerebral hemorrhage and focal neurological deficit. CCM may be familial or sporadic. Familial forms have autosomal dominant inheritance. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.