Article Category: Technical Report
Publicado en línea: 19 sept 2018
Páginas: 51 - 54
DOI: https://doi.org/10.2478/ebtj-2018-0037
Palabras clave
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Francesca Fanelli, Tommaso Beccari, Munis Dundar, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
Ventricular septal defects (VSDs) are the commonest congenital cardiac malformations. They may exist in isolated form or in combination with other anomalies, such as part of tetralogy of Fallot, or with double outlet right ventricle or common arterial trunk (1).
According to Soto et al. these malformations can be divided into membranous and muscular septal defects. The membranous septum is smaller than the muscular septum and is located at the base of the heart, below the right and noncoronary cusps of the aortic valve, between the inlet and outlet components of the muscular septum. The muscular septum is a nonplanar structure consisting of inlet, trabecular and infundibular components (2, 3).
The pathogenesis of VSD primarily depends on the amount and direction of interventricular shunting and volume loading of the heart chambers. Prolapse of the aortic valve and obstruction of the pulmonary or systemic outflow tract are considered to be secondary effects (4).
The manifestation of clinical symptoms is directly linked to the entity of interventricular flow, which is determined by the size of the defect and the relative resistances of the pulmonary and systemic vascular beds (4).
The prevalence of VSD is estimated at about 5% among infants. Many small malformations present at birth may later undergo spontaneous closure. Patients with medium and larger VSDs can undergo to severe complications such as arrhythmias, pulmonary arterial hypertension, ventricular dysfunction, congestive heart failure or develop Eisenmenger syndrome (3, 5).
Du et al. reported a high prevalence of VSD (56.6/1000 live births) among preterm neonates (6). This defect is the commonest congenital malformation of the heart at one week of age and in the first three decades of life: 32.1% of all patients with congenital heart disease have ventricular septal defects (7).
Diagnosis is based on clinical assessment to identify symptoms, echocardiogram, electrocardiogram, chest radiogram, integration of septal, colour Doppler and two-dimensional echocardiography, spin-echo MR imaging, CT, diagnostic catheterization and genetic testing (3).
Differential diagnosis should consider VSD caused by Down syndrome and other chromosomal disorders (8, 9).
Apert and Crouzon syndromes (OMIM diseases 101200 and 123500, respectively) -
Atrioventricular septal defect, partial, with heterotaxy syndrome (AVSD2, OMIM disease 606217) -
Cardiofaciocutaneous syndrome 1 (CFC1, OMIM disease 115150) -
Cornelia de Lange syndrome 3 (CDLS3, OMIM disease 610759) -
Holt-Oram syndrome (HOS, OMIM disease 142900) -
Kabuki syndrome 1 (KABUK1, OMIM disease 147920) -
Mowat-Wilson syndrome (MOWS, OMIM disease 235730) -
Myhre syndrome (MYHRS, OMIM disease 139210) -
Noonan Syndrome 1 (NS1, OMIM disease 163950) -
Dilated cardiomyopathy-1S and (CMD1S, OMIM disease 613426) and Ebstein anomaly (OMIM disease 224700) -
Aortic valve disease 1 (AVD1, OMIM disease 109730) -
Visceral heterotaxy 5 (HTX5, OMIM disease 270100) -
Ellis-van Creveld syndrome (EVC, OMIM disease 225500) -
Right atrial isomerism (RAI, OMIM disease 208530) -
Ventricular septal defect 1 (VSD1, OMIM disease 614429) -
Ventricular septal defect 2 (VSD2, OMIM disease 614431) -
Ventricular septal defect 3 (VSD3, OMIM disease 614432) -
The vast majority of these genes are key components of the Nodal signaling pathway that is important for specification and patterning of vertebrate embryos (30) and in mammalian cardiac development (31).
Pathogenic variants may include missense, nonsense, splicing, small insertions/deletions, small indels, gross deletions/insertions and regulatory substitutions.
To determine the gene defect responsible for the disease;
To confirm clinical diagnosis;
To assess the recurrence risk and perform genetic counselling for at-risk/affected individuals.
Guidelines for clinical use of the test are described in Genetics Home Reference (
Clinically distinguishable syndromes can be analyzed by sequencing only those genes known to be associated with that specific disease using Sanger or Next Generation Sequencing (NGS); if the results are negative, or more generally if clinical signs are ambiguous for diagnosis, a multi-gene NGS panel is used to detect nucleotide variations in coding exons and flanking introns of the above genes.
Potentially causative variants and regions with low coverage are Sanger-sequenced. Sanger sequencing is also used for family segregation studies.
Multiplex Ligation Probe Amplification (MLPA) is used to detect duplications and deletions in
To perform molecular diagnosis, a single sample of biological material is normally sufficient. This may be 1 ml peripheral blood in a sterile tube with 0.5 ml K3EDTA or 1 ml saliva in a sterile tube with 0.5 ml ethanol 95%. Sampling rarely has to be repeated.
Gene-disease associations and the interpretation of genetic variants are rapidly developing fields. It is therefore possible that the genes mentioned in this note may change as new scientific data is acquired. It is also possible that genetic variants today defined as of “unknown or uncertain significance” may acquire clinical importance.
Identification of pathogenic variants in the
A pathogenic variant is known to be causative for a given genetic disorder based on previous reports or predicted to be causative based on the loss of protein function or expected significant damage to protein or protein/protein interactions. In this way it is possible to obtain a molecular diagnosis in new/other subjects, establish the risk of recurrence in family members and plan preventive and/or therapeutic measures.
Detection of a variant of unknown or uncertain significance (
The absence of variations in the genomic regions investigated does not exclude a clinical diagnosis but suggests the possibility of:
alterations that cannot be identified by sequencing, such as large rearrangements that cause loss (deletion) or gain (duplication) of extended gene fragments;
sequence variations in gene regions not investigated by this test, such as regulatory regions (5’ and 3’ UTR) and deep intronic regions;
variations in other genes not investigated by the present test.
Unexpected results may come out from the test, for example information regarding consanguinity; absence of family correlation or the possibility of developing genetically based diseases.
If the identified pathogenic variant has autosomal dominant transmission, the probability that an affected carrier transmit the disease variant to his/her children is 50% in any pregnancy, irrespective of the sex of the child conceived.
In autosomal recessive mutations, both parents are usually healthy carriers. In this case, the probability of transmitting the disorder to the offspring is 25% in any pregnancy of the couple, irrespective of the sex of the child. An affected individual generates healthy carrier sons and daughters in all cases, except in pregnancies with a healthy carrier partner. In these cases, the risk of an affected son or daughter is 50%.
The test is limited by current scientific knowledge regarding the gene and disease.
NGS Analytical sensitivity >99.99%, with a minimum coverage of 10X; Analytical specificity 99.99%.
SANGER Analytical sensitivity >99.99%; Analytical specificity 99.99%.
MLPA Analytical sensitivity >99.99%; Analytical specificity 99.99%.
Clinical sensitivity: variations in the aforementioned genes are linked to VSD, but may be individual variations (identified in one or a few families) and total epidemiological data is therefore not available. Clinical sensitivity will be estimated based on internal cases.
Clinical specificity: is estimated at approximately 99% (33).
The genetic test is appropriate when:
the patient meets the diagnostic criteria for VSD;
the sensitivity of the test is greater than or equal to that of tests described in the literature.
| Clinical management | Utility |
|---|---|
| Confirmation of clinical diagnosis | Yes |
| Differential diagnosis | Yes |
| Couple risk assessment | Yes |
| Availability of clinical trials can be checked on-line at | |