A pilot study of the performance of NeoEXOME for NBS in China
To evaluate the performance of NeoEXOME in clinical practice. A pilot,
multi-center clinical trial was conducted. From Oct 2019 to Sep 2021,
3423 neonates were enrolled from 5
institutions (Fig 2). Of all these subjects, DBS was collected within 3
days of birth and next-generation sequencing was performed based on our
NeoEXOME panel.
Among the 3249 neonates eligible for the analysis, 934 infants were NGS
negative, and 389 infants were NGS positive (244 High risk, 4 Moderate
risk, 141 Low risk), and 1926 were carriers. NGS positive rate was
12.0%. 343 infants showed one genetic mutation, who were genetically
susceptible to mono gene-related diseases; 46 infants had more than one
gene mutations, who were genetically susceptible to multi-diseases.
Infants that were NGS reported as high-risk account for the highest
proportion (Fig 3A-B). While autosomal recessive inheritance was the
most common inheritance pattern (Fig 3A-B). Endocrine and metabolism
system disorders accounted for the highest proportion in healthy
neonates (Fig 3C). Most of the diseases detected were predicted to
develop within the first year of life (Fig 3D). Variants of DUOX2account for the most frequent mutant genes (18.3%, 131/716), followed
by UGT1A1 , PAH , GJB2 , FLG (Fig 3E). The top
five related disorders were thyroid dyshormonogenesis,
hyperbilirubinemia, phenylketonurics, deafness, hyperbilirubinemia, and
ichthyosis vulgaris, with the frequency of variant 5.7%, 5.4%, 5.0 %,
4.1%, respectively. 1926 infants were tested as carrier of the diseases
in our panel. There were 3462 variants, including 1224 pathogenic
variants and 2238 likely pathogenic variants (Fig 4A). Variants ofGJB2 account for the most frequent mutant genes of all the
centers, followed by UGT1A1 , DUOX2, FLG, andSLC25A13 (Fig 4B).
To further validate the use of NGS in NBS,
conventional NBS results were
collected to compare the consistency of both approaches. 200 out of 3249
neonates were conventionally NBS positive
(+). In the NBS (+) subgroup, 118
were NGS positive (64 High risk, 2 Moderate risk, 52 Low risk), 14 were
NGS negative, and 68 were NGS carrier (Table 2). Of the 118 NBS (+)/NGS
(+) cases, 90 (76.3%) had consistent results with conventional NBS and
NGS (Supplementary Table 3). In the 3049 NBS (-) subgroup, 271 (8.9%)
were NGS positive (180 High risk, 2 Moderate risk, 89 Low risk), 920
were NGS negative, and 1858 were NGS carrier (Table 2). 168 of the 271
NGS (+) /NBS (-) neonates were followed up till Dec 2021, and 9 of them
(including genes of DUXO2 , PAH , MUT , WAS ,
and SLC22A5 ) were clinically diagnosed.