Current controversies in prenatal diagnosis 2: The 59 genes ACMG recommends reporting as secondary findings when sequencing postnatally should be reported when detected on fetal (and parental) sequencing

Abstract

Genome sequencing is increasingly being used to aid genetic diagnosis in fetuses with structural abnormalities detected on ultrasound examination. However, with clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing, but of potential medical value for patient care. In the postnatal setting, the American College of Medical Genetics and Genomics (ACMG) has clear guidelines that state that when offering sequencing, secondary findings should be reported in 59 genes for which ACMG consider there is a clinical evidence that pathogenic variants may result in disease that might be prevented or treated, with the option to opt out of receiving this information. However, these guidelines specifically exclude prenatal sequencing. Here, we report the debate on whether or not pathogenic findings in these 59 genes should or should not be reported in the prenatal setting. Although more were in favour of reporting before the debate, there was no significant consensus from the audience. After the debate there was a swing toward not reporting, but a slim majority (55%) remained in favour, indicating that this is an area requiring further research and the development of evidence-based guidelines applicable to prenatal proband and trio sequencing.

A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review

“…Considerations for implementation of prenatal diagnostic exome and genome wide sequencing, are summarised in joint position statements [10,11]. Debate is ongoing whether secondary findings in the parental genome of the ACMG 59 genes (for which clinical evidence that pathogenic variants may result in disease that might be prevented or treated) should be returned [12].…”

“…10,11 Debate is ongoing whether secondary findings in the parental genome of the ACMG 59 genes (for which clinical evidence that pathogenic variants may result in disease that might be prevented or treated) should be reported. 12 Molecular diagnosis in cases of structural malformation allows for greater diagnostic accuracy and can have implications for management of pregnancy; although studies are limited in this area, decision making has reportedly been impacted in up to 70%. [13][14][15][16] Since 2018 we have undertaken exome sequencing in 110 cases of fetal anomaly.…”

The role of next‐generation sequencing in the investigation of ultrasound‐identified fetal structural anomalies

“…However, with this guidance, there is an exclusion of prenatal ES. The extension of this process to prenatal diagnosis (and the parental samples of trios) has been debated and is controversial 48 . An example of this would be the potential ES testing of a fetus with a phenotype suggestive of Fanconi anaemia 49 .…”

“…The extension of this process to prenatal diagnosis (and the parental samples of trios) has been debated and is controversial. 48 An example of this would be the potential ES testing of a fetus with a phenotype suggestive of Fanconi anaemia. 49 Somatic inactivation of the Fanconi anaemia/breast cancer gene (BRCA) pathway accounts for the chromosomal instability of the predisposition of some cancers (breast, bowel and ovary) in the general population.…”

The role of genomics in investigating ultrasound identified fetal structural anomalies

“…If fed back to patients they may cause significant anxiety and make patient decision making more complex (especially in the context of a fetal structural abnormality identified in a pregnancy were termination of pregnancy is an option). Parents report that such information is 'toxic' and emotional effects may last for a considerable period 41,42,43 .Therefore, as prenatal ES is used to evaluate congenital malformations in clinical practice there is a need to register VUS and the fetal phenotype in an international registry with comprehensive clinical access.…”