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Review Open Access

Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review)

  • Authors:
    • Ruihao Xu
    • Haoming Ren
    • Zhengwei Yuan
    • Wanqi Huang
    • Hui Gu
  • View Affiliations / Copyright

    Affiliations: Second Clinical College, Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China, Clinical College, Alberta Institute, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China, NHC Key Laboratory of Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China
    Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 27
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    Published online on: November 20, 2025
       https://doi.org/10.3892/ijmm.2025.5698
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Abstract

Structural birth defects (SBDs) represent a major subset of congenital malformations arising from abnormalities during organogenesis and subsequent tissue morphogenesis. The triad of congenital heart defects (CHDs), orofacial clefts (OFCs) and neural tube defects (NTDs) dominates the global epidemiology of SBDs, collectively contributing to considerable neonatal mortality while imposing profound clinical and socioeconomic burdens. Conventional genetic screening approaches, such as karyotype and non‑invasive prenatal testing, remain limited in their capacity to decipher the complex genomic factors underlying these SBDs. The advent of advanced genomic technologies (including chromosomal microarray analysis and next‑generation sequencing) and integrated genomic analysis methods [such as copy number variation analysis, single nucleotide variation/insertion and deletion analysis and genome‑wide association studies (GWAS)] has enhanced the capacity to identify pathogenic genetic factors, thereby transforming the mode of prenatal diagnosis and genetic counseling. The application of these technologies, by virtue of more accurate diagnosis and finer disease classification, not only provides a more comprehensive basis for assessing disease severity and prognosis in clinical decision‑making but also offers support for implementing targeted intervention and treatment. The present review systematically evaluates state‑of‑the‑art genomic methodologies and computational approaches for detecting genomic aberrations in CHDs, OFCs and NTDs, and integrates insights from GWAS to elucidate the underlying genetic architecture, contributing to achieving precise predictive modeling and targeted therapeutic innovation for SBDs.
View Figures

Figure 1

Advanced genomic technologies propel
the diagnosis of SBDs. Research and diagnosis of SBDs have
gradually shifted from traditional diagnostic technologies (such as
ultrasound, karyotyping and NIPT) to advanced genomic technologies
(such as CMA, CNV-seq, targeted-sequencing, WES and WGS). These
advanced genomic technologies, with their distinct application
scopes and clear clinical recommendations in clinical practice, not
only deeply unravel the genomic landscape of structural birth
defects but also provide critical support for genetic counseling
and targeted therapy. SBDs, structural birth defects; NIPT,
non-invasive prenatal testing; CMA, chromosomal microarray
analysis; CNV-seq, copy number variation sequencing; WES, whole
exome sequencing; WGS, whole genome sequencing; CHDs, congenital
heart defects; ASD, atrial septal defect; VSD, ventricular septal
defect; PDA, patent ductus arteriosus; PS, pulmonary stenosis;
OFCs, orofacial clefts; CLO, cleft lip only; CPO, cleft palate
only; CLP, cleft lip and palate; NTDs, neural tube defects.

Figure 2

Overview of using genomics to screen
the candidate genes of SBDs. The analysis of differential variation
of various candidate genes in pregnant women, fetuses or patients
with SBDs based on genomics of saliva, peripheral blood, amniotic
fluid and fetal tissue samples provides crucial information for
comprehending the genetics factors underlying SBDs. SBDs,
structural birth defects; CMA, chromosomal microarray analysis;
WES, whole exome sequencing; WGS, whole genome sequencing; CNV,
copy number variation; SNV, single nucleotide variant; Indel,
insertions-deletions; GWAS, genome-wide association study.

Figure 3

Future approaches for investigating
the genetics factor in SBDs. The interdisciplinary effort of
probing into the genetic factors of SBDs will require the
combination of several disciplines, including advanced genomics
technologies, valuable multi-center and large-population biobanks,
precise bioinformatics analysis and the integration of multi-omics
data. The fusion of these fields will contribute to improving the
detection ability of pathogenic variations and optimizing the
screening strategy of candidate genes in SBDs. SBDs, structural
birth defects.
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Spandidos Publications style
Xu R, Ren H, Yuan Z, Huang W and Gu H: Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review). Int J Mol Med 57: 27, 2026.
APA
Xu, R., Ren, H., Yuan, Z., Huang, W., & Gu, H. (2026). Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review). International Journal of Molecular Medicine, 57, 27. https://doi.org/10.3892/ijmm.2025.5698
MLA
Xu, R., Ren, H., Yuan, Z., Huang, W., Gu, H."Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review)". International Journal of Molecular Medicine 57.1 (2026): 27.
Chicago
Xu, R., Ren, H., Yuan, Z., Huang, W., Gu, H."Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 27. https://doi.org/10.3892/ijmm.2025.5698
Copy and paste a formatted citation
x
Spandidos Publications style
Xu R, Ren H, Yuan Z, Huang W and Gu H: Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review). Int J Mol Med 57: 27, 2026.
APA
Xu, R., Ren, H., Yuan, Z., Huang, W., & Gu, H. (2026). Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review). International Journal of Molecular Medicine, 57, 27. https://doi.org/10.3892/ijmm.2025.5698
MLA
Xu, R., Ren, H., Yuan, Z., Huang, W., Gu, H."Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review)". International Journal of Molecular Medicine 57.1 (2026): 27.
Chicago
Xu, R., Ren, H., Yuan, Z., Huang, W., Gu, H."Decoding structural birth defects through genomic landscapes: Innovative frameworks for diagnosis (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 27. https://doi.org/10.3892/ijmm.2025.5698
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