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Reanalysis of clinical exome identifies the second variant in two individuals with recessive disorders

European Journal of Human Genetics volume 31, pages 712–715 (2023)Cite this article

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Abstract

Clinical exome/genome sequencing is increasingly being utilized by clinicians to diagnose various likely genetic conditions, but many cases remain undiagnosed. In a subset of those undiagnosed cases, a single heterozygous variant in an autosomal recessive (AR) condition with consistent phenotype may be identified, raising the question if a second variant is missing. Here, we report two cases of recessive conditions in which only one heterozygous variant was initially reported by clinical exome sequencing, and on research reanalysis a second heterozygous variant in trans was identified. We performed a review of the existing exome reanalysis literature and found that this aspect is often not emphasized. These findings highlight the importance of data reanalysis in undiagnosed cases where only a single disease-associated variant is identified in an AR condition with a strong link to presenting phenotype.

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Data availability

The genetic tests analyzed in this paper were ordered as clinical tests and thus the data are not able to be made available for privacy reasons, but these confirmed variants were submitted to ClinVar (#SUB12473625).

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Acknowledgements

The authors would like to thank all the subjects’ physicians and caregivers, and especially the patients and families for their participation in this research.

Funding

The Manton Center Gene Discovery Core is supported by a generous gift from The Manton Foundation. This work was also supported by grants NICHD/NHGRI U19HD077671 and by the resources of the IDDRC Molecular Genetics Core funded by U54HD090255 from the NIH.

Author information

Author notes

  1. Qifei Li

    Present address: Department of Pediatrics, Harvard Medical School, Boston, MA, USA

  2. These authors contributed equally: Qifei Li, Rohan Agrawal.

Authors and Affiliations

  1. Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA

    Qifei Li, Rohan Agrawal, Klaus Schmitz-Abe, Jill A. Madden & Pankaj B. Agrawal

  2. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA

    Qifei Li, Rohan Agrawal, Klaus Schmitz-Abe, Casie A. Genetti, Melissa A. Fernandes, Noah L. Fryou, Jill A. Madden, Catherine A. Brownstein, Farrah Rajabi, Alan H. Beggs & Pankaj B. Agrawal

  3. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA

    Qifei Li, Rohan Agrawal, Klaus Schmitz-Abe, Casie A. Genetti, Melissa A. Fernandes, Noah L. Fryou, Jill A. Madden, Catherine A. Brownstein, Farrah Rajabi, Alan H. Beggs & Pankaj B. Agrawal

  4. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Klaus Schmitz-Abe, Catherine A. Brownstein, Farrah Rajabi, Alan H. Beggs & Pankaj B. Agrawal

  5. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Klaus Schmitz-Abe, Alan H. Beggs & Pankaj B. Agrawal

  6. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Edward C. Smith

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  1. Qifei Li
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Contributions

QL, RA, KS, CAG, JAM, and PBA drafted the paper. All authors edited the paper and approved the final version.

Corresponding author

Correspondence to Pankaj B. Agrawal.

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Competing interests

The authors declare no competing interests.

Ethics approval

The study was conducted in accordance with the ethical standards of the participating Institutional Review Board at Boston Children’s Hospital (IRB number 10-02-0053, approval date 20 May 2021).

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Li, Q., Agrawal, R., Schmitz-Abe, K. et al. Reanalysis of clinical exome identifies the second variant in two individuals with recessive disorders. Eur J Hum Genet 31, 712–715 (2023). https://doi.org/10.1038/s41431-023-01291-2

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  • DOI: https://doi.org/10.1038/s41431-023-01291-2

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