Genetic testing for atrioventricular septal defect

Pathogenic variants may include missense, nonsense, splicing, small insertions, small deletions, gross deletions, gross insertions, small indels and regulatory substitutions.

The test is listed in the Orphanet database and is offered by 10 accredited medical genetic laboratories in the EU, and in the GTR database, offered by 9 accredited medical genetic laboratories in the US.

Guidelines for clinical use of the test are described in Genetics Home Reference (ghr.nlm.nih.gov)

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 CRELD1 and GATA4 genes.

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 (VUS): a new variation without any evident pathogenic significance or a known variation with insufficient evidence (or with conflicting evidence) to indicate it is likely benign or likely pathogenic for a given genetic disorder. In these cases, it is advisable to extend testing to the patient’s relatives to assess variant segregation and clarify its contribution. In some cases, it could be necessary to perform further examinations/tests or to do a clinical reassessment of pathological signs.

The absence of variations in the genomic regions investigated does not exclude a clinical diagnosis but suggests the possibility of:

Unexpected results may emerge from the test, for example information regarding consanguinity, absence of family correlation or other genetically-based diseases.