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A Laboratory Assessment: Diagnostic Yield of Next Generation Sequencing and Prenatal Clinical Indications

Prenatal Genetics
  • Primary Categories:
    • Prenatal Genetics
  • Secondary Categories:
    • Prenatal Genetics
Introduction:
As new gene-disease discoveries have been made, genetic testing has become more common in prenatal care and offered as a follow-up due to abnormal ultrasound findings, prenatal cell-free DNA screening, maternal serum screening, or based on family history. Understanding the most common clinical indications for which prenatal testing is ordered and the expected diagnostic yields are important for clinicians to know so they can offer appropriate testing for their patients. Studies have shown that genetic testing of prenatal cases, in which at least one structural anomaly is detected, can have a diagnostic rate between 12-45%, where one study has reported prenatal cases with multiple anomalies with a 23.6% diagnostic rate from exome sequencing. To aid clinicians in ordering prenatal testing and proper consenting, it is useful to identify diagnostic rates amongst genetic tests performed on fetal specimens for a large range of indications, including specific physical abnormalities detected by ultrasound or autopsy, abnormal serum screening, noted family history, genetic variants detected via microarray, and multiple combinations of these clinical indications.

Methods:
A review of prenatal genetic test orders completed at a commercial laboratory from January 2018 to December 2023 was conducted. Information regarding clinical indication for each order was required and reviewed by a certified genetic counselor prior to test initiation. For each prenatal single gene, panel, and exome test order, the clinical indications were evaluated and organized into categories based on family history of genetic conditions or parents who are heterozygous for a pathogenic variant in a gene associated with autosomal or X-linked recessive conditions, microarray findings for the pregnancy, abnormal serum screening of the pregnancy, and physical abnormalities noted on ultrasound or autopsy. Physical abnormalities were further divided into groups according to the affected organ or body system: brain, heart, skeletal, neuromuscular, echogenic bowel/gastrointestinal, eye, cystic hygroma and increased nuchal translucency and fold, genital anomalies, situs inversus, and the urinary system and abnormal levels of amniotic fluid. Additionally, if two or more clinical indications were listed on the same test requisition form, the case was included in a separate category. Results were considered diagnostic when variants met the American College of Medical Genetics and Genomics (ACMG) variant interpretation standards and internal laboratory variant classification guidelines for pathogenic (P) or likely pathogenic (LP) classification. Heterozygous P/LP variants in genes associated with autosomal and X-linked dominant conditions and P/LP variants identified in the homozygous or compound heterozygous state in genes associated with autosomal and X-linked recessive conditions were diagnostic.

Results:
A total of 1,033 cases were reviewed and diagnostic rate was determined for clinical indications divided into categories. The clinical indications with the highest diagnostic rate were physical anomalies that affect the eye (2/2 cases), the skeletal system (79/164 cases), and the neuromuscular system (5/12 cases). Diagnostic variants were not identified among 4 out of 4 cases with situs inversus. Other categories with the lowest diagnostic rate observed were microarray findings (2/71 cases), echogenic bowel/gastrointestinal anomalies (2/48 cases), abnormal maternal serum screening (1/18 cases), and genital anomalies (1/16 cases). Among cases with more than one indication, 7 of 58 cases were found to have a diagnostic result. An overall 24% of cases (145/603 cases) with physical anomalies were observed to have a diagnostic genetic finding.

Conclusion:
Documenting the diagnostic rate for different clinical indications may influence healthcare professionals to consider genetic testing due to family history and abnormal findings in the prenatal context. This information is vital for appropriate clinician test ordering, accurate pretest counseling, and assisting with decision-making for family planning. This can lead to the expansion of prenatal testing options and understanding for all providers.

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