Article Category: Technical Report
Online veröffentlicht: 19. Sept. 2018
Seitenbereich: 45 - 47
DOI: https://doi.org/10.2478/ebtj-2018-0035
Schlüsselwörter
© 2018 Yeltay Rakhmanov, Paolo Enrico Maltese, Alessandra Zulian, Tommaso Beccari, Munis Dundar, Matteo Bertelli, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.
(Other synonyms: Atrial septal defect, primum type, atrial septal defect, secundum type)
Atrial septal defect (ASD) is the most common congenital heart defect and is characterized by an aperture in the atrial septum. It is estimated to be a major cause of prenatal birth losses. ASD has different morphological types determined by the location of the defect. The defect usually borders the oval fossa and its antero-inferior rim. Communication between the two atria, such as superior or inferior sinus venosus defects, coronary sinus defect and
Patients with ASD remain asymptomatic throughout most of their childhood. Most patients consult their physician for a heart murmur. Infants with ASD may have tachypnoea, slow weight gain and recurrent respiratory infections (3, 4). Large size ASD might manifest with different clinical symptoms such as didyspnea, fatigue, exercise intolerance, or palpitations (5). Right-sided heart failure may be accompanied by cyanosis, syncope and peripheral edema (6).
The prevalence of ASD is estimated at 100 per 100,000 live births (7). About 65–70% of patients with a secundum defect, roughly 50% of those with a primum atrial septal defect, and 40–50% of those with a sinus venosus defect are females (5).
To visualize ASD and characterize its size, determine the direction of flow, evaluate associated abnormalities, examine the right heart and estimate pulmonary/systemic flow ratio (6), the methods used include echocardiogram, electrocardiogram, chest radiogram, spinecho MR imaging, CT and diagnostic catheterisation. To diagnose inheritance pattern, genetic testing is used. Differential diagnosis should consider ASD caused by Down syndrome and other chromosomal disorders.
ASD1 (OMIM disease 108800) caused by variations in a locus mapping to chromosome 5p;
ASD2 (OMIM disease 607941) -
ASD3 (OMIM disease 614089) -
ASD4 (OMIM disease 611363) -
ASD5 (OMIM disease 612794) -
ASD6 (OMIM disease 613087) -
ASD7, with or without AV conduction defects (OMIM disease 108900) -
ASD8 (OMIM disease 614433) -
ASD9 (OMIM disease 614475) -
Noonan Syndrome 1 (NS1, OMIM disease 163950) -
Holt-Oram syndrome (HOS, OMIM disease 142900) -
Cardiofaciocutaneous syndrome 1 (CFC1, OMIM disease 115150) -
Mowat-Wilson syndrome (MOWS, OMIM disease 235730) -
Floating-Harbor syndrome (FLHS, OMIM disease 136140) –
Ellis-van Creveld syndrome (EVC, OMIM disease 225500) -
Pathogenic variants may include missense, nonsense, splicing, small insertions, small deletions and small indels.
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.
The test is listed in the Orphanet database and is offered by 16 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 10 accredited medical genetic laboratories in the US.
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 region 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 above genes confirms the clinical diagnosis and is an indication for family studies.
A pathogenic variant is known to be causative for a given genetic disorder based on previous reports, or predicted to be causative based on loss of protein function or expected significant damage to proteins 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 emerge from the test, for example information regarding consanguinity, absence of family correlation or other 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%.
Clinical sensitivity: the variations in the aforementioned genes are linked to ASD, but may be individual variations (identified in one or 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% (8).
The genetic test is appropriate when:
the patient meets the diagnostic criteria for ASD;
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 | |