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Identification and characterization of the largest deletion in the PCCA gene causing severe acute early-onset form of propionic acidemia

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Abstract

Whole-exome sequencing (WES) is an excellent method for the diagnosis of diseases of uncertain or heterogeneous genetic origin. However, it has limitations for detecting structural variations such as InDels, which the bioinformatics analyzers must be aware of. This study aimed at using WES to evaluate the genetic cause of the metabolic crisis in a 3-day-old neonate admitted to the neonatal intensive care unit (NICU) and deceased after a few days. Tandem mass spectrometry (MS/MS) showed a significant increase in propionyl carnitine (C3), proposing methylmalonic acidemia (MMA) or propionic acidemia (PA). WES demonstrated a homozygous missense variant in exon 4 of the BTD gene (NM_000060.4(BTD):c.1330G > C), responsible for partial biotinidase deficiency. Segregation analysis of the BTD variant revealed the homozygous status of the asymptomatic mother. Furthermore, observation of the bam file, around genes responsible for PA or MMA, by Integrative Genomics Viewer (IGV) software displayed a homozygous large deletion in the PCCA gene. Comprehensive confirmatory studies identified and segregated a novel outframe deletion of 217,877 bp length, “NG_008768.1:g.185211_403087delinsTA”, extended from intron 11 to 21 of the PCCA, inducing a premature termination codon and activation of nonsense-mediated mRNA decay (NMD). Homology modeling of the mutant PCCA demonstrated eliminating the protein's active site and critical functional domains. Thereupon, this novel variant is suggested as the largest deletion in the PCCA gene, causing an acute early-onset PA. These results could expand the PCCA variants spectrum, and improve the existing knowledge on the molecular basis of PA, as well as provide new evidence of pathogenicity of the variant (NM_000060.4(BTD):c.1330G > C.

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Data availability

The datasets analyzed during the WES and Primer sets are not publicly available because the individual privacy could be compromised, but they are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank the patient's family for participation, the NICU section staff (academic members, fellowships, residents, and nurses) of Ali-Asghar Pediatrics hospital, Tehran, Iran, and Dr. Saman Nahid and the staff of Farzanegan metabolic laboratory, Shiraz, Iran, for their excellent collaboration.

Funding

This work was financially supported by “The Deputy of Research and Technology,” Pasteur Institute of Iran, Tehran, Iran, in partial fulfillment of the Ph.D. thesis of Mrs. Fereshteh Maryami under the supervision of Professor Sirous Zeinali.

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  1. Hamzeh Rahimi

    Present address: Texas Biomedical Research Center, San Antonio, USA

  2. Nasrin Khalesi and Sirous Zeinali contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Pasteur St., Tehran, Iran

    Fereshteh Maryami, Elham Davoudi-Dehaghani, Elham Rismani, Hamzeh Rahimi & Sirous Zeinali

  2. Department of Pediatrics and Neonatal Intensive Care Unit, Ali-Asghar Children’s Hospital, Iran University of Medical Sciences, Shahid Vahid Dastgerdi Street, Modarres Highway, Tehran, Iran

    Nasrin Khalesi

  3. Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran

    Saeed Talebi

  4. Department of Medical Genetics, Ali-Asghar Children’s Hospital, Iran University of Medical Sciences, Tehran, Iran

    Saeed Talebi

  5. Medical Genetics Lab, Kawsar Human Genetics Research Center, No. 41 Majlesi St., ValiAsr St., 1595645513, Tehran, Iran

    Sirous Zeinali

  6. Iranian Molecular Medicine Network, Pasteur Institute of Iran, Pasteur St, Tehran, Iran

    Sirous Zeinali

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Contributions

This is to certify that co-authors have had full access to the data in the present study and contributed to the decision to submit it for publication. Conceptualization: FM, ED-D, NK, ER, HR, ST, SZ. Methodology: FM, HR, ST, NK, SZ. Providing clinical data and clinical management: FM, NK, ST. Genetic counseling and sampling and consent: FM, ST, NK. WES and data analysis: FM, HR, ST, ED-D, ER, SZ. Homology modeling: FM, ER, HR. Variant’s interpretation of pathogenicity: FM, ST, ED-D, ER, HR, NK, SZ. Confirmatory tests interpretation and segregation analysis: FM, ED-D, ST, SZ. Writing—original draft preparation: FM, ER. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Editing: ED-D, ER, ST, HR, NK, SZ. Funding acquisition: SZ.

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Maryami, F., Davoudi-Dehaghani, E., Khalesi, N. et al. Identification and characterization of the largest deletion in the PCCA gene causing severe acute early-onset form of propionic acidemia. Mol Genet Genomics 298, 905–917 (2023). https://doi.org/10.1007/s00438-023-02023-3

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