Clinical application of long-read sequencing in newborn genetic screening for congenital adrenal hyperplasia.

Biallelic pathogenic CYP21A2 variants, genotyped by long-read sequencing in neonates.

Newborn screening for congenital adrenal hyperplasia based on 17α-hydroxyprogesterone (17α-OHP) alone has limited diagnostic performance. The authors assessed long-read sequencing in primary and secondary newborn screening, in a retrospective cohort of 100,145 neonates (Fujian screening centre, 2019) and a prospective cohort of 2,100 newborns (May 2023) tested simultaneously by 17α-OHP and genetic analysis. In the retrospective cohort the 17α-OHP positive rate was 0.19% (190/100,145; 95% CI 0.17%-0.21%) and five infants received a confirmed diagnosis, a prevalence of 1:20,029; long-read genotyping identified the pathogenic CYP21A2 variants in all five. In the prospective cohort, two newborns (1/1050) with normal 17α-OHP carried biallelic pathogenic CYP21A2 variants, and 88 (4.2%) with normal 17α-OHP carried a heterozygous disease-related variant, 85 of them in CYP21A2 across 32 distinct genotypes. Calculated carrier frequencies were 1 in 78 for classic and 1 in 40 for non-classic disease.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The operative point is not the yield of the biochemical assay but the two biallelic newborns with normal 17α-OHP out of 2,100: the abstract states neither whether they were symptomatic nor how they were followed, which leaves open what is actually being detected. The study is single-centre, and the reported carrier frequencies derive from only 2,100 prospectively screened newborns, so the confidence intervals are wide. Positive predictive value and clinical outcome data from several centres would be required before genomic first-line newborn screening could be considered.

Analysis by Dr Thibaut Benquey