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Major brain malformations: corpus callosum dysgenesis, agenesis of septum pellucidum and polymicrogyria in patients with BCORL1-related disorders

Journal of Human Genetics volume 67, pages 95–101 (2022)Cite this article

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Abstract

Objective

BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations.

Methods and results

We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients’ charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development.

Conclusions

We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis.

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Data availability

Data available on request from the authors.

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Acknowledgements

We would like to thank members and affiliates of the International Research Consortium for the Corpus Callosum and Cerebral Connectivity (IRC5, https://www.irc5.org) for their collaboration and input.

Author information

Author notes

  1. These authors contributed equally: Michal Gafner, Marina Michelson

Authors and Affiliations

  1. Department of Pediatrics B, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

    Michal Gafner

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Michal Gafner, Marina Michelson, Keren Yosovich, Ronen Hady-Cohen, Dorit Lev, Yael Michaeli-Yosef, Tally Lerman-Sagie & Lubov Blumkin

  3. Magen Center for Rare Diseases, Wolfson Medical Center, Holon, Israel

    Marina Michelson, Keren Yosovich, Ronen Hady-Cohen, Dorit Lev, Yael Michaeli-Yosef, Tally Lerman-Sagie & Lubov Blumkin

  4. The Rina Mor Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel

    Marina Michelson & Dorit Lev

  5. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    Emanuela Argilli, Elliott H. Sherr & Kendall C. Parks

  6. Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA

    Emanuela Argilli, Elliott H. Sherr & Kendall C. Parks

  7. Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel

    Keren Yosovich

  8. Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Eleina M. England

  9. Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel

    Ronen Hady-Cohen, Yael Michaeli-Yosef, Tally Lerman-Sagie & Lubov Blumkin

  10. Fetal Neurology Clinic, Wolfson Medical Center, Holon, Israel

    Zvi Leibovitz

  11. Obstetrics-Gynecology Ultrasound Unit, Rappaport Faculty of Medicine, Bnai-Zion Medical Center, The Technion, Haifa, Israel

    Zvi Leibovitz

  12. Pediatric Movement Disorders Service, Wolfson Medical Center, Holon, Israel

    Lubov Blumkin

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  1. Michal Gafner
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Contributions

All authors contributed to the study conception and design. All authors read and approved the final paper and agree to be accountable for all aspects of the work. MG—data curation; writing—original draft. MM—data curation; writing—original draft. EA—data curation. KY—formal genetic analysis. EHS—data curation. KCP—data curation. EME—data curation. RHC—conceptualization. ZL—conceptualization. DL—conceptualization, formal genetic analysis. YMY—conceptualization, formal genetic analysis. TLS—conceptualization, writing—review and editing, supervision. LB—Conceptualization, writing—review and editing, supervision.

Corresponding author

Correspondence to Lubov Blumkin.

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Informed consent for publication was obtained from participants and their parents.

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The study was approved by the institutional review board [0075-17WOMC]. Informed consent to participate in the study was obtained from legal guardians.

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Gafner, M., Michelson, M., Argilli, E. et al. Major brain malformations: corpus callosum dysgenesis, agenesis of septum pellucidum and polymicrogyria in patients with BCORL1-related disorders. J Hum Genet 67, 95–101 (2022). https://doi.org/10.1038/s10038-021-00971-5

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