Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series

doi:10.1002/pd.6269

Review

. 2022 Dec;42(13):1686-1693.

doi: 10.1002/pd.6269. Epub 2022 Nov 28.

Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series

Bobby K Brar¹, Marisa Gilstrop Thompson², Neeta L Vora³, Kelly Gilmore³, Karin Blakemore¹, Kristen A Miller¹, Jessica Giordano⁴, Andreas Dufke⁵, Beatrix Wong⁶, Samantha Stover⁷, Billie Lianoglou⁸, Ignatia Van den Veyver⁹, Esther Dempsey¹⁰, Mara Rosner¹, Karen Chong¹¹, David Chitayat¹¹, Teresa N Sparks¹², Mary E Norton¹², Ronald Wapner⁴, Kristin Baranano¹³, Angie C Jelin¹; Fetal Sequencing Consortium

Affiliations

¹ Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
² Department of Obstetrics and Gynecology, Christiana Care Medical Center, Newark, Delaware, USA.
³ Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁴ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, USA.
⁵ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
⁶ Division of Human Genetics, Cincinnati Children's Hospital Center, Cincinnati, Ohio, USA.
⁷ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁸ Department of Surgery, University of California, San Francisco, California, USA.
⁹ Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.
¹⁰ St George's University of London, Molecular and Clinical Sciences Research Institute, London, UK.
¹¹ The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹² Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California, USA.
¹³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 36403095
PMCID: PMC9805891
DOI: 10.1002/pd.6269

Review

Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series

Bobby K Brar et al. Prenat Diagn. 2022 Dec.

. 2022 Dec;42(13):1686-1693.

doi: 10.1002/pd.6269. Epub 2022 Nov 28.

Authors

Affiliations

¹ Department of Gynecology and Obstetrics, Division of Maternal-Fetal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
² Department of Obstetrics and Gynecology, Christiana Care Medical Center, Newark, Delaware, USA.
³ Department of Obstetrics and Gynecology, Division of Maternal - Fetal Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
⁴ Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, New York, USA.
⁵ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
⁶ Division of Human Genetics, Cincinnati Children's Hospital Center, Cincinnati, Ohio, USA.
⁷ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁸ Department of Surgery, University of California, San Francisco, California, USA.
⁹ Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.
¹⁰ St George's University of London, Molecular and Clinical Sciences Research Institute, London, UK.
¹¹ The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹² Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California, USA.
¹³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

PMID: 36403095
PMCID: PMC9805891
DOI: 10.1002/pd.6269

Abstract

Objective: Tubulinopathies refer to conditions caused by genetic variants in isotypes of tubulin resulting in defective neuronal migration. Historically, diagnosis was primarily via postnatal imaging. Our objective was to establish the prenatal phenotype/genotype correlations of tubulinopathies identified by fetal imaging.

Methods: A large, multicenter retrospective case series was performed across nine institutions in the Fetal Sequencing Consortium. Demographics, fetal imaging reports, genetic screening and diagnostic testing results, delivery reports, and neonatal imaging reports were extracted for pregnancies with a confirmed molecular diagnosis of a tubulinopathy.

Results: Nineteen pregnancies with a fetal tubulinopathy were identified. The most common prenatal imaging findings were cerebral ventriculomegaly (15/19), cerebellar hypoplasia (13/19), absence of the cavum septum pellucidum (6/19), abnormalities of the corpus callosum (6/19), and microcephaly (3/19). Fetal MRI identified additional central nervous system features that were not appreciated on neurosonogram in eight cases. Single gene variants were reported in TUBA1A (13), TUBB (1), TUBB2A (1), TUBB2B (2), and TUBB3 (2).

Conclusion: The presence of ventriculomegaly with cerebellar abnormalities in conjunction with additional prenatal neurosonographic findings warrants additional evaluation for a tubulinopathy. Conclusive diagnosis can be achieved by molecular sequencing, which may assist in coordination, prognostication, and reproductive planning.

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Conflict of interest statement

Conflicts of Interest:

The authors report no conflicts of interest. Our data is original and is not being considered for publication in any other journal.

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References

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1. Cabet S, Karl K, Garel C, et al. Two different prenatal imaging cerebral patterns of tubulinopathy. Ultrasound Obstet Gynecol 2021;57(3):493–497. (In eng). DOI: 10.1002/uog.22010. - DOI - PubMed
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[1] Romero DM, Bahi-Buisson N, Francis F. Genetics and mechanisms leading to human cortical malformations. Semin Cell Dev Biol 2018;76:33–75. (In eng). DOI: 10.1016/j.semcdb.2017.09.031. - DOI - PubMed

[2] Romero DM, Bahi-Buisson N, Francis F. Genetics and mechanisms leading to human cortical malformations. Semin Cell Dev Biol 2018;76:33–75. (In eng). DOI: 10.1016/j.semcdb.2017.09.031. - DOI - PubMed

[3] Brock S, Stouffs K, Scalais E, et al. Tubulinopathies continued: refining the phenotypic spectrum associated with variants in TUBG1. Eur J Hum Genet 2018;26(8):1132–1142. (In eng). DOI: 10.1038/s41431-018-0146-y. - DOI - PMC - PubMed

[4] Brock S, Stouffs K, Scalais E, et al. Tubulinopathies continued: refining the phenotypic spectrum associated with variants in TUBG1. Eur J Hum Genet 2018;26(8):1132–1142. (In eng). DOI: 10.1038/s41431-018-0146-y. - DOI - PMC - PubMed

[5] Bahi-Buisson N, Maillard C. Tubulinopathies Overview. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993. - PubMed

[6] Bahi-Buisson N, Maillard C. Tubulinopathies Overview. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2022, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993. - PubMed

[7] Cabet S, Karl K, Garel C, et al. Two different prenatal imaging cerebral patterns of tubulinopathy. Ultrasound Obstet Gynecol 2021;57(3):493–497. (In eng). DOI: 10.1002/uog.22010. - DOI - PubMed

[8] Cabet S, Karl K, Garel C, et al. Two different prenatal imaging cerebral patterns of tubulinopathy. Ultrasound Obstet Gynecol 2021;57(3):493–497. (In eng). DOI: 10.1002/uog.22010. - DOI - PubMed

[9] Hung KL, Lu JF, Su DJ, Hsu SJ, Wang LC. Tubulinopathy Presenting as Developmental and Epileptic Encephalopathy. Children (Basel) 2022;9(8) (In eng). DOI: 10.3390/children9081105. - DOI - PMC - PubMed

[10] Hung KL, Lu JF, Su DJ, Hsu SJ, Wang LC. Tubulinopathy Presenting as Developmental and Epileptic Encephalopathy. Children (Basel) 2022;9(8) (In eng). DOI: 10.3390/children9081105. - DOI - PMC - PubMed

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Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series

Affiliations

Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series

Authors

Affiliations

Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

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