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Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations

European Journal of Human Genetics volume 29, pages 1654–1662 (2021)Cite this article

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Abstract

Genetic alterations in COL4A2 are less common than those of COL4A1 and their fetal phenotype has not been described to date. We describe a three-generation family with an intragenic deletion in COL4A2 associated with a prenatal diagnosis of recurrent fetal intracerebral hemorrhage (ICH), and a myriad of cerebrovascular manifestations. Exome sequencing, co-segregation analysis, and imaging studies were conducted on eight family members including two fetuses with antenatal ICH. Histopathological evaluation was performed on the terminated fetuses. An intragenic heterozygous pathogenic in-frame deletion; COL4A2, c.4151_4168del, (p.Thr1384_Gly1389del) was identified in both fetuses, their father with hemiplegic cerebral palsy (CP), as well as other family members. Postmortem histopathological examination identified microscopic foci of heterotopias and polymicrogyria. The variant segregated in affected individuals demonstrating varying degrees of penetrance and a wide phenotypic spectrum including periventricular venous hemorrhagic infarction causing hemiplegic CP, polymicrogyria, leukoencephalopathy, and lacunar stroke. We present radiographic, pathological, and genetic evidence of prenatal ICH and show, for what we believe to be the first time, a human pathological proof of polymicrogyria and heterotopias in association with a COL4A2 disease-causing variant, while illustrating the variable phenotype and partial penetrance of this disease. We highlight the importance of genetic analysis in fetal ICH and hemiplegic CP.

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Fig. 1: Pedigree of the family.
Fig. 2: Fetal ultrasound.
Fig. 3: Histopathological evaluation of fetuses with COL4A2 intragenic deletion at 26 weeks of gestation.
Fig. 4: Brain MRI of patients with COL4A2 intragenic deletion.

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Acknowledgements

We are grateful to the patients for consenting to participate in this study. Variantyx Genomic Intelligence® is thanked for their assistance in the interpretation of the genetic analysis. Esther Eshkol is thanked for editorial assistance.

Funding

This study was funded by the Brain Center at Tel Aviv Sourasky Medical Center.

Author information

Author notes

  1. These authors contributed equally: Gustavo Malinger, Aviva Fattal-Valevski

Authors and Affiliations

  1. Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Moran Hausman-Kedem & Aviva Fattal-Valevski

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

    Moran Hausman-Kedem, Liat Ben-Sira, Debora Kidron, Shay Ben-Shachar, Rachel Straussberg, Daphna Marom, Penina Ponger, Gustavo Malinger & Aviva Fattal-Valevski

  3. Radiology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Liat Ben-Sira

  4. Pathology Institute, Meir Medical Center, Kfar-Saba, Israel

    Debora Kidron

  5. Schneider Children’s Medical Center, Petah Tikva, Israel

    Shay Ben-Shachar & Rachel Straussberg

  6. Clalit Research Institute, Ramat Gan, Israel

    Shay Ben-Shachar

  7. Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Daphna Marom, Penina Ponger & Anat Bar-Shira

  8. Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Gustavo Malinger

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  1. Moran Hausman-Kedem
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Correspondence to Moran Hausman-Kedem.

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The authors declare no competing interests.

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All experiments were performed in accordance with relevant guidelines and regulations. The study protocols were reviewed and approved by the Institutional Review Board. Informed consent was obtained from all participants prior to genetic testing.

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Hausman-Kedem, M., Ben-Sira, L., Kidron, D. et al. Deletion in COL4A2 is associated with a three-generation variable phenotype: from fetal to adult manifestations. Eur J Hum Genet 29, 1654–1662 (2021). https://doi.org/10.1038/s41431-021-00880-3

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