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Vertical inheritance and unique differential phenotypes of reciprocal recombinant chromosome 18 within a multi-generation family

European Journal of Human Genetics volume 34, pages 128–133 (2026)Cite this article

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Abstract

Carriers of balanced pericentric inversions are at risk for producing unbalanced gametes because of meiotic recombination resulting in de novo deletion and duplication of distal chromosome ends. Recombinant chromosomes generally lead to significant imbalances resulting in anomalous clinical phenotypes in offspring, hence they are typically not inherited. Therefore, the vertical transmission of recombinant chromosomes is a clinically rare event. Using genomic microarray and karyotyping, we describe inheritance of recombinant chromosomes in a three-generation family with the grandmother carrying a mosaic pericentric inversion of chromosome 18. Three children inherited the balanced inversion and one child with a mild phenotype inherited a de novo recombinant chromosome 18. In the third generation, a newborn with a variant of holoprosencephaly inherited an unmodified recombinant chromosome from her mother. Despite having the same karyotype predicting loss of the TGIF1 gene from the 18p terminus, the mother exhibits a relatively unaffected phenotype. The cousin of the child with holoprosencephaly carries the reciprocal recombinant chromosome 18 with a much milder phenotype. We verified the cytogenetic mechanism and corresponding clinical phenotypes in affected individuals and illustrated possible recombinant chromosome consequences of the inversion of chromosome 18 in this three-generation family.

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Fig. 1: Pedigree and karyotype/microarray results.
Fig. 2: Microarray depiction of the pair of reciprocal recombinant chromosome 18 in the family and TGIF1 deletion topology.
Fig. 3: Vertical inheritance of the recombinant chromosome 18 and relevant genetic mechanisms.

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The study presented here does not involve sharable genomic data contents or public resources.

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Acknowledgements

We would like to thank our patients’ family for their willingness to share their stories, in hopes of helping families with rare cytogenetic disorders and their providers.

Funding

This study was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UM1TR004409. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Author notes

  1. These authors contributed equally: Ting Wen, Gulsen Akay.

Authors and Affiliations

  1. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Ting Wen, Erica F. Andersen & Bo Hong

  2. ARUP Laboratories, Salt Lake City, UT, USA

    Ting Wen, Denise I. Quigley, Allen N. Lamb, Erica F. Andersen & Bo Hong

  3. Pathology and Laboratory Medicine, Henry Ford Hospital, Detroit, MI, USA

    Ting Wen

  4. Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

    Gulsen Akay, Janice Palumbos & David Viskochil

  5. Children’s Hospital of Richmond, Virginia Commonwealth University, Richmond, VA, USA

    Gulsen Akay

  6. Division of Pediatric Neurology, Department of Pediatrics University of Utah School of Medicine, Salt Lake City, UT, USA

    Betsy Ostrander

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  1. Ting Wen
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  2. Gulsen Akay
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  7. Erica F. Andersen
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  8. Bo Hong
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  9. David Viskochil
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Contributions

TW drafted the manuscript. TW, GA and DV conceptualized and designed the study. TW, BO, DIQ, ANL, EFA and BH analyzed and interpreted the data. GA, TW, DV, and JP collected samples and provided genetic counseling. GA, BO, and DV recruited patients and provided clinical care. DV obtained funding for the studies and oversaw the clinical work. All authors reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding authors

Correspondence to Ting Wen or David Viskochil.

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Competing interests

The authors declare no competing interests.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and approved by Ethics Committee of Intermountain Healthcare for studies involving humans. Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/ relative of the patient. A copy of the consent form is available for review by the Editor of this journal.

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Wen, T., Akay, G., Palumbos, J. et al. Vertical inheritance and unique differential phenotypes of reciprocal recombinant chromosome 18 within a multi-generation family. Eur J Hum Genet 34, 128–133 (2026). https://doi.org/10.1038/s41431-025-01878-x

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