The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

Abstract

This points to consider document is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this points to consider document is completely voluntary and does not necessarily assure a successful medical outcome. This points to consider document should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this points to consider document. Clinicians also are advised to take notice of the date this points to consider document was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.

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].…”

Systematic evaluation of genome sequencing for the assessment of fetal structural anomalies

“…1 This is particularly true for neonatal and pediatric diagnostics, where individuals with multiple congenital anomalies (MCA) and developmental disorders (DDs) of unknown etiology routinely undergo chromosomal microarray analysis (CMA) as a first-tier diagnostic test, 2 and are often followed-up with targeted gene panels and/or whole exome sequencing (WES) when CMA is negative. [3][4][5] The combination of CMA and WES can provide a molecular diagnosis in 25-45% of such clinically referred cases. 2,6,7 However, CMA and WES are unable to detect certain classes of pathogenic variation, including balanced structural variants (SVs) that are accessible to routine karyotyping, small copy number variants (CNVs), and non-coding single nucleotide variants (SNVs) and small insertions/deletions (indels).…”

“…15,16 There have been no comparable analyses of the utility of WGS using consecutive referrals in the prenatal setting, and guidelines for the assessment of FSAs advocate for sequential testing of targeted genes when a specific genetic etiology is suspected. 3 However, the challenges of prenatal phenotyping, including the difficulty in recognizing the fetal presentation of syndromes that are well-characterized postnatally, can lead to missed molecular diagnoses due to a failure to investigate clinically relevant genes through panel testing. 17 By contrast, WGS can survey almost all genes and classes of variation in a single test, 8,9 though it increases the complexity of interpretation and requires efficient computational strategies to identify diagnostic variants.…”

Comprehensive genome sequencing analysis as a promising option in the prenatal diagnosis of fetal structural anomalies: a prospective study

“…The result that was unanimously agreed upon to explain the fetal phenotype included P/LP variants consistent with the inheritance pattern and phenotype of related disorders, as well as variants of unknown significance (VUS) among Online Mendelian Inheritance in Man (OMIM) disease-causing genes that matched the fetal phenotype and was found in trans with a P/LP variant in an autosomal recessive condition, was designated positive or diagnostic; otherwise, was designated negative or undiagnostic. The pregnant women and their partners were informed of the ACMG secondary findings [27], and fetal and parental incidental findings were reported only when consented in the pretest informed consent process according to the ACMG document [28].…”