Biochemical Testing Promotes Interpretation of Variants of Uncertain Significance in Prenatal Genetic Disease Testing in Four Organic Acidurias.

Abstract

Advances in next-generation sequencing (NGS) have revolutionized clinical and translational medicine. NGS is increasingly used in the diagnosis of genetic diseases, including newborn screening, prenatal screening and diagnosis, and preimplantation screening. While advancements in sequencing and bioinformatics have facilitated the discovery of novel genes and diseases, the identification of variants continues to outpace our ability to classify them accurately. Variants of uncertain significance (VUS), defined as genetic alterations with insufficient evidence for clinical interpretation, present significant diagnostic challenges. Clinically available functional studies, such as biochemical testing, offer valuable insights for interpreting VUS. This review synthesizes recent literature on amniotic fluid metabolite analysis for prenatal diagnosis and VUS interpretation in four organic acidurias. It aims to guide the application of biochemical testing for inherited metabolic disorders and enhance clinical decision-making regarding VUS classification.