Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach

Archana Rai¹, Jonathan Klonowski², Bo Yuan³, Karen J Coveler⁴, Zain Dardas⁴, Iman Egab¹, Jiaoyang Xu¹, Philip J Lupo⁵, A J Agopian¹, Dennis Kostka⁶, Cecilia W Lo², S Stephen Yi⁷, Bruce D Gelb⁸, Christine E Seidman⁹, Eric Boerwinkle¹⁰, Jennifer E Posey⁴, Richard A Gibbs³, James R Lupski¹¹, Shaine A Morris¹², Zeynep Coban-Akdemir¹³

Affiliations

¹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
² Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Computational & Systems Biology and Pittsburgh Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁷ Baylor Research Institute and School of Medicine, Baylor College of Medicine, Temple, TX 76508, USA.
⁸ Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Howard Hughes Medical Institute, Harvard University, Boston, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁰ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
¹² Division of Cardiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: shainem@bcm.edu.
¹³ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: zeynep.h.cobanakdemir@uth.tmc.edu.

PMID: 40543504
PMCID: PMC12256918 (available on 2026-01-03)
DOI: 10.1016/j.ajhg.2025.05.014

Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach

Archana Rai et al. Am J Hum Genet. 2025.

. 2025 Jul 3;112(7):1664-1680.

doi: 10.1016/j.ajhg.2025.05.014. Epub 2025 Jun 20.

Authors

Affiliations

¹ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
² Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Computational & Systems Biology and Pittsburgh Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
⁷ Baylor Research Institute and School of Medicine, Baylor College of Medicine, Temple, TX 76508, USA.
⁸ Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ Howard Hughes Medical Institute, Harvard University, Boston, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁰ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
¹² Division of Cardiology, Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: shainem@bcm.edu.
¹³ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: zeynep.h.cobanakdemir@uth.tmc.edu.

PMID: 40543504
PMCID: PMC12256918 (available on 2026-01-03)
DOI: 10.1016/j.ajhg.2025.05.014

Abstract

Laterality defects are defined by perturbations in the usual left-right asymmetry of organs. The genetic etiology that underlies congenital heart disease (CHD) is often unknown (less than 40%), so we used a digenic model approach for the identification of contributing variants in known laterality-defect-associated genes (n = 115) in the exome/genome sequencing (ES/GS) data from individuals with clinically diagnosed laterality defects. The unsolved ES/GS data were analyzed from three CHD cohorts: Baylor College of Medicine-Genomics Research to Elucidate the Genetics of Rare Diseases (BCM-GREGoR; n= 251 proband ES), Gabriella Miller Kids First Pediatric Research Program (Kids First; n = 158 trio GS), and Pediatric Cardiac Genomics Consortium (PCGC; n = 163 trio ES). trans-heterozygous digenic variants were identified in 2.8% (inherited digenic variants in 0.4%), 8.2%, and 13.5% of individuals, respectively; this was significantly higher than in 602 control trios provided by the 1000 Genomes Project (p = 0.001, 1.4e-07, and 8.9e-13, respectively). trans-heterozygous digenic variants were also identified in 0.4% and 1.4% of individuals with non-laterality CHD in Kids First and PCGC datasets, respectively, which was not statistically significant as compared to control trios (p = 1 and 0.059, respectively). Altogether, in laterality cohorts, 23% of digenic pairs were in the same structural complex of motile cilia. Out of 39 unique digenic pairs in laterality CHD, 29 are more likely to be potential digenic hits as predicted by the DiGePred tool. These findings provide further evidence that digenic epistatic interactions can contribute to the complex genetics of laterality defects.

Keywords: cilia; digenic; laterality defect; trans-heterozygous.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach.
Rai A, Klonowski J, Yuan B, Coveler KJ, Dardas Z, Egab I, Xu J, Lupo PJ, Agopian AJ, Kostka D, Lo CW, Yi SS, Gelb BD, Seidman CE, Boerwinkle E, Posey JE, Gibbs RA, Lupski JR, Morris SA, Coban-Akdemir Z. Rai A, et al. medRxiv [Preprint]. 2024 Nov 21:2024.11.19.24317385. doi: 10.1101/2024.11.19.24317385. medRxiv. 2024. Update in: Am J Hum Genet. 2025 Jul 3;112(7):1664-1680. doi: 10.1016/j.ajhg.2025.05.014. PMID: 39606420 Free PMC article. Updated. Preprint.

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Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach

Affiliations

Genomic rare variant mechanisms for congenital cardiac laterality defect: A digenic model approach

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

LinkOut - more resources

Full Text Sources

Medical

Research Materials