Newborn Genetic Screening Revealed Increased Levels of Biochemical Indicators in Carriers of Heterozygous Variants

Abstract

Background: Conventional newborn screening (NBS) is usually based on biochemical methods to predict the risk of inborn errors of metabolism. Recent studies have applied next-generation sequencing in NBS and revealed much more information, including carrier status. Whether these carriers of variants differ from other individuals was not fully determined. Objective: This research investigated the effect of heterozygous carrier status of pathogenic variants on biochemical indicators during NBS. Methods: We enrolled newborns participating in both conventional NBS and our previous Newborn Screening with Targeted Sequencing (NESTS) program from January 2021 to December 2021 in the Shunyi Maternal and Children's Hospital of Beijing Children's Hospital. Newborn levels of phenylalanine (Phe), thyroid stimulating hormone (TSH), and 17-hydroxyprogesterone (17-OHP) were measured to be analyzed together with associated sequencing results. Results: A total of 2351 newborns in the NESTS program was examined in the study. None had biallelic variants in genes related to congenital hypothyroidism (CH), hyperphenylalaninemia (HPA) or congenital adrenal hyperplasia. Forty-nine heterozygous carriers with phenylalanine hydroxylase (PAH) variants had significantly higher levels of Phe (p < 0.0001), and 11 heterozygous carriers of thyroid-stimulating hormone receptor (TSHR) variants had significantly higher levels of TSH (p < 0.05). Although heterozygous carriers had higher biochemical levels, they were below the diagnostic threshold of HPA and CH. Conclusions: Carriers of heterozygous variants in PAH or TSHR had significantly increased biochemical levels of associated factors in NBS. For individuals with higher Phe or TSH levels within the normal reference intervals, attention should be paid to the possibility of heterozygous carrier status.