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Towards solving the genetic diagnosis odyssey in Iranian patients with congenital anomalies

European Journal of Human Genetics (2024)Cite this article

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Abstract

Understanding the underlying causes of congenital anomalies (CAs) can be a complex diagnostic journey. We aimed to assess the efficiency of exome sequencing (ES) and chromosomal microarray analysis (CMA) in patients with CAs among a population with a high fraction of consanguineous marriage. Depending on the patient’s symptoms and family history, karyotype/Quantitative Fluorescence- Polymerase Chain Reaction (QF-PCR) (n = 84), CMA (n = 81), ES (n = 79) or combined CMA and ES (n = 24) were performed on 168 probands (66 prenatal and 102 postnatal) with CAs. Twelve (14.28%) probands were diagnosed by karyotype/QF-PCR and seven (8.64%) others were diagnosed by CMA. ES findings were conclusive in 39 (49.36%) families, and 61.90% of them were novel variants. Also, 64.28% of these variants were identified in genes that follow recessive inheritance in CAs. The diagnostic rate (DR) of ES was significantly higher than that of CMA in children from consanguineous families (P = 0·0001). The highest DR by CMA was obtained in the non-consanguineous postnatal subgroup and by ES in the consanguineous prenatal subgroup. In a population that is highly consanguineous, our results suggest that ES may have a higher diagnostic yield than CMA and should be considered as the first-tier test in the evaluation of patients with congenital anomalies.

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Fig. 1: Study flowchart.
Fig. 2: Comparison of detection rate of ES and CMA in CA patients.
Fig. 3: Consanguinity and detection rate.
Fig. 4: Suggested genetic diagnostic algorithm for patients with CA.

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Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are thankful to the all participants and their parents who have shown enthusiasm towards this project. We are grateful to the all nurses and other medical staffs who helped us in this project.

Funding

This study was supported by Tehran University of Medical Sciences through two grants to A.R.N. (grant no. 52367) and S.M.A. (grant no. 52355).

Author information

Author notes

  1. These authors contributed equally: Laleh Habibi, Julie A. Neidich, Yang Cao.

Authors and Affiliations

  1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Parisa Vaseghi & Seyed Mohammad Akrami

  2. Department of Photo Healing and Regeneration, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran

    Parisa Vaseghi

  3. Ronash Medical Genetics Laboratory, Tehran, Iran

    Laleh Habibi, Neda Fattahi, Ramin Rashidi-Nezhad, Tayebeh Salehnezhad, Mahtash Malekian, Mahdieh Mokhberdezfuli & Amirhosein Mehrtash

  4. Department of Pathology & Immunology, Division of Laboratory & Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Julie A. Neidich, Yang Cao & Reza Ghasemi

  5. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

    Julie A. Neidich

  6. Breastfeeding Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran

    Hossein Dalili

  7. Department of Pediatrics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Hossein Dalili, Vafa Ghorbansabagh, Parvane Sadeghimoghadam, Amir Naddaf, Tahereh Esmaeilnia Shirvany & Ziba Mosayebi

  8. Department of Obstetrics and Gynecology, School of Medicine, Yas Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Fatemeh Rahimi Sharbaf, Behrokh Sahebdel, Fatemeh Golshahi & Mahboobeh Shirazi

  9. Department of Neonatology, Yas Hospital Complex, Tehran university of medical sciences, Tehran, Iran

    Mohammad Reza Zarkesh, Shirin Shamel & Roksana Moeini

  10. Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

    Mahdieh Mokhberdezfuli

  11. Cimorgh Medical IT Solutions, Tehran, Iran

    Amin Ardeshirdavani

  12. Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran

    Roxana Kariminejad

  13. Maternal, Fetal and Neonatal Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran

    Vafa Ghorbansabagh, Parvane Sadeghimoghadam, Amir Naddaf, Tahereh Esmaeilnia Shirvany, Ziba Mosayebi & Ali Rashidi-Nezhad

  14. Sana Medical Genetics Laboratory, Ghazvin, Iran

    Abolfazl Heidari

  15. Former teacher of Pathology, Arak Medical University, Arak, Iran

    Mohammad Ali Daneshmand

  16. Genetics Ward, Yas Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Ali Rashidi-Nezhad

Authors
  1. Parisa Vaseghi
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  2. Laleh Habibi
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Contributions

Conceptualization: H.V., J.A.N., Y.C., S.M.A.; Supervision: S.M.A., A.R.N; Writing-original draft: H.V., S.M.A., A.R.N.; Data curation: H.V., L.H., Y.C., A.M., R.G., A.R.N.; Validation: H.V., N.F., R.R.N., T.S., M.M., M.M.D., R.K., A.R.N.; Software: A.A.; Resources: H.D., F.R.S., M.R.Z., V.G., P.S., A.N., T.E.S., Z.M., B.S., F.G., M.S., S.S., R.M., A.H., M.A.D.; Writing-review & editing: J.A.N., Y.C., R.G., A.H., S.M.A., A.R.N. All the authors approved the final draft.

Corresponding authors

Correspondence to Seyed Mohammad Akrami or Ali Rashidi-Nezhad.

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Competing interests

The authors declare no competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. In particular, this research was conducted with the voluntary, informed consent of any research participants, free of coercion or coercive circumstances, and approval was granted by the research ethics committee of Tehran University of Medical Sciences (No. IR.TUMS.MEDICINE.REC.1399.1278).

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Vaseghi, P., Habibi, L., Neidich, J.A. et al. Towards solving the genetic diagnosis odyssey in Iranian patients with congenital anomalies. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01533-x

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