Even with the increased sensitivity of genetic evaluation techniques, an underlying genetic cause of ASD is still only identified in a minority (< 25%) of ASD cases³.  One of the major challenges in the clinical interpretation of genetic screening lies in differentiating between pathogenic and benign genetic variants identified in ASD patients.  The pathogenic relevance of the vast majority of ASD-linked genetic variants remains unknown; such variants are frequently classified as variants of unknown significance, or VOUS.  While the identification of a genetic lesion in an existing ASD susceptibility gene or CNV locus is suggestive of a possible genetic cause of disease, variants in these genes and CNV loci have also been observed in seemingly unaffected individuals.  In many cases, a detailed family history and genetic evaluation of additional family members (parents, siblings, etc.) is essential in determining the signficance of genetic variants identified in ASD cases.

A number of guidelines have already been proposed to aid clinicians and clinical geneticists in the interpretation and reporting of copy number variants (CNVs)⁴.  With the increasing use of high resolution NGS technologies, similar guidelines will likely be proposed for the interpretation and reporting of single nucleotide variants (SNVs).

Informed consent, and the extent to which participants have been sufficiently informed as to the purpose of a research or clinical study, has long been an issue in the field of genetic evaluation.  For example, the extent to which research findings should be released and made available is one that participants in genetic evaluation studies should be informed of beforehand.  In some cases, the participants themselves may not be able to gain access to the findings of genetic evaluation.  This is an issue that has only been compounded with the rise of next generation sequencing and chromosomal microarray and the subsequent explosion in the amount of genetic data generated by these techniques.

The sheer volume of genetic information generated by current evaluation techniques not only leads to the identification of potential genetic causes of a disease of interest, but also frequently leads to the detection of other variants that are not directly related to the disease under investigation but are related to other inherited human diseases.  The extent to which these incidental findings should be reported is a subject of some controversy, particularly in those situations in which genetic predisposition to an adult-onset disease is discovered in a child being evaluated for genetic causes of childhood developmental disorders.  One such situation was described in a recent news feature in Nature in which the family of a child who had undergone genetic testing for developmental disability had to be informed that the child carried a genetic predisposition to colon cancer after extensive debate between clinical geneticists and ethics reviewers as to the extent to which such genetic information should be reported.  The degree to which clinical geneticists should report incidental findings in research participants has been considered by numerous authors, but as of yet there is not consensus.  Many of these same ethical concerns must be considered in the reporting of genetic evaluation results in individuals with ASD.

Another consideration lies in the use of genetic evaluation to determine the recurrence risk in the siblings of children with ASD and in family planning.  Given a recent estimate that the recurrence rate of ASD in siblings may be as high as ~20%, the identification of inherited variants that potentially impart susceptibility to ASD is of critical importance both in identifying at-risk siblings that have not yet began to manifest symptoms of ASD and in making informed decisions with regards to family planning.