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. 2022 Jul;10(7):e1952.
doi: 10.1002/mgg3.1952. Epub 2022 Apr 16.

Noninvasive prenatal diagnosis based on cell-free DNA for tuberous sclerosis: A pilot study

Xiao-Yan Yang  1   2 , Yan Meng  2 , Yang-Yang Wang  2 , Yan-Ping Lu  3 , Qiu-Hong Wang  1   2 , Yan-Qin You  3 , Xiao-Xiao Xie  3 , Ling Bai  4 , Nan Fang  4 , Li-Ping Zou  1   2   5
Affiliations

Noninvasive prenatal diagnosis based on cell-free DNA for tuberous sclerosis: A pilot study

Xiao-Yan Yang et al. Mol Genet Genomic Med. 2022 Jul.

Abstract

Background: Noninvasive prenatal diagnosis (NIPD) based on cell-free DNA (cfDNA) has been introduced into the clinical application for some monogenic disorders but not for tuberous sclerosis (TSC) yet, which is an autosomal dominant disease caused by various variations in TSC1 or TSC2 gene. We aimed to explore the feasibility of NIPD on TSC.

Methods: We recruited singleton pregnancies at risk of TSC from 14 families with a proband child. Definitive NIPD for TSC was performed using targeted next-generation sequencing of cfDNA in parallel with maternal white blood cell DNA (wbcDNA). The NIPD results were validated by amniocentesis or postnatal gene testing and follow-up of the born children.

Results: Missense mutations, nonsense mutations, frameshift mutations, and splice-site variants which were obtained through de-novo, maternal, or paternal inheritance were included. The mean and minimum gestational weeks of NIPD were 17.18 ± 5.83 and 8 weeks, respectively. The NIPD results were 100% consistent with the amniocentesis or postnatal gene testing and follow-up of the born children.

Conclusion: This study demonstrates that NIPD based on cfDNA is feasible for TSC, but required to be confirmed with more samples. Studies on TSC can contribute to the application and promotion of NIPD for monogenic disorders.

Keywords: autosomal dominant disease; cell-free DNA; monogenic disorder; noninvasive prenatal diagnosis; tuberous sclerosis.

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Conflict of interest statement

The authors report no conflict of interest.

Figures

FIGURE 1
FIGURE 1
The workflow of this study. TSC, tuberous sclerosis; VTP, voluntary termination of pregnancy
FIGURE 2
FIGURE 2
Representative results of NIPD. Fetal genotypes were deduced based on the deviations from maternal genetic alleles and maternal background. When p > 70%, the results were reliable. The letters ‘A’ and ‘B’ referred to the maternal wild and mutant alleles, respectively, and letters ‘a’ and ‘b’ referred to the fetal wild and mutant alleles, respectively. (a) Family 1. The maternal‐fetal genotype was AAab, the mutation ratio was 0.080 and p = 100.0%. (b) Family 2. The maternal‐fetal genotype was ABaa, the mutation ratio was 0.438 and p = 97.8%. (c) the result of first NIPD of family 5. The maternal‐fetal genotype was AAaa, the mutation ratio of cfDNA was 0 and p = 100.0%. (d) Family 10. The maternal‐fetal genotype was ABab, the mutation ratio was 0.479 and p = 78.8%. TSC1 accession: NM_000368.5, TSC2 accession: NM_000548.5
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