Genetic and ultrasound assessment in recurrent fetal malformations: a case report on TUBA1A gene variation

Abstract

To elucidate the etiology of recurrent fetal brain developmental malformations accompanied by other structural ultrasound anomalies in a Chinese non-consanguineous couple, we performed a comprehensive evaluation of prenatal ultrasound phenotypes across their two consecutive pregnancies. Copy number variation sequencing and exome sequencing were applied to the amniotic fluid sample obtained from the affected pregnancy. One copy number variation and four candidate missense variants in three genes identified in the initial analysis were reassessed and reclassified according to current clinical and genetic evidence. Our results demonstrated that a maternal mosaic c.7G>A(p.Glu3Lys) variant in the tubulin alpha 1a (TUBA1A) gene was the underlying cause of the couple’s recurrent adverse pregnancy outcomes. These findings enrich the database of pathogenic TUBA1A variants, expand the spectrum of associated prenatal ultrasound phenotypes, and provide valuable insights into the underlying pathogenic mechanisms.

Keywords

TUBA1A / tubulinopathy / prenatal phenotype / parental mosaicism / case report

References

[1] Keays DA,Tian G,Poirier K.et al. Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans Cell. 2007 128 45 57

[2] Aiken J,Buscaglia G,Bates EA,Moore JK. The α-tubulin gene TUBA1A in brain development: a key ingredient in the neuronal isotype blend J Dev Biol. 2017 5 8 PMC5648057

[3] Schröter J,Popp B,Brennenstuhl H.et al. Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies Eur J Hum Genet. 2022 30 298 306 PMC8904761

[4] Schröter J,Döring JH,Garbade SF.et al. Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies Genet Med. 2021 23 516 23 PMC7935713

[5] Brar BK, Thompson MG, Vora NL, et al.; Fetal Sequencing Consortium. Prenatal phenotyping of fetal tubulinopathies: a multicenter retrospective case series Prenat Diagn. 2022 42 1686 93 PMC9805891

[6] Ramirez DA,Anninger WV,Scoles D. Optic nerve hypoplasia and bilateral persistent fetal vasculature due to tuba1a tubulinopathy Retin Cases Brief Rep. 2025 19 264 6

[7] Richards S, Aziz N, Bale S, et al.; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Genet Med. 2015 17 405 24 PMC4544753

[8] Wilcox EH, Webb RF, Tshering KC, et al.; ClinGen RASopathy Expert Panel. Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels Genet Med Open. 2025 3 103430 PMC12151217

[9] Tavtigian SV, Greenblatt MS, Harrison SM, et al.; ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI). Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework Genet Med. 2018 20 1054 60 PMC6336098

[10] Tavtigian SV,Harrison SM,Boucher KM,Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines Hum Mutat. 2020 41 1734 7

[11] Abou Tayoun AN, Pesaran T, DiStefano MT, et al.; ClinGen Sequence Variant Interpretation Working Group (ClinGen SVI). Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion Hum Mutat. 2018 39 1517 24 PMC6185798

[12] Brandt T,Sack LM,Arjona D.et al. Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants Genet Med. 2020 22 336 44

[13] Riggs ER,Andersen EF,Cherry AM.et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) Genet Med. 2020 22 245 57

[14] Belvindrah R,Natarajan K,Shabajee P.et al. Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration J Cell Biol. 2017 216 2443 61 PMC5551700

[15] Leca I,Phillips AW,Ushakova L,Cushion TD,Keays DA. Codon modification of Tuba1a alters mRNA levels and causes a severe neurodevelopmental phenotype in mice Sci Rep. 2023 13 1215 PMC9867703

[16] Hoff KJ,Aiken JE,Gutierrez MA,Franco SJ,Moore JK. TUBA1A tubulinopathy mutants disrupt neuron morphogenesis and override XMAP215/Stu2 regulation of microtubule dynamics Elife. 2022 11 e76189 9236607

[17] Aiken J,Moore JK,Bates EA. TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity Hum Mol Genet. 2019 28 1227 43 PMC6452179

[18] Cabet S,Karl K,Garel C.et al. Two different prenatal imaging cerebral patterns of tubulinopathy Ultrasound Obstet Gynecol. 2021 57 493 7

[19] Hebebrand M,Hüffmeier U,Trollmann R.et al. The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy Orphanet J Rare Dis. 2019 14 38 PMC6371496

[20] Gardner JF,Cushion TD,Niotakis G.et al. Clinical and functional characterization of the recurrent TUBA1A p.(Arg2His) mutation Brain Sci. 2018 8 145 PMC6119949

[21] Yokoi S,Ishihara N,Miya F.et al. TUBA1A mutation can cause a hydranencephaly-like severe form of cortical dysgenesis Sci Rep. 2015 5 15165 PMC4615979

[22] Myers KA,Bello-Espinosa LE,Kherani A,Wei XC,Innes AM. TUBA1A mutation associated with eye abnormalities in addition to brain malformation Pediatr Neurol. 2015 53 442 4

[23] Shimojima K,Narita A,Maegaki Y,Saito A,Furukawa T,Yamamoto T. Whole-exome sequencing identifies a de novo TUBA1A mutation in a patient with sporadic malformations of cortical development: a case report BMC Res Notes. 2014 7 465 PMC4118784

[24] Okumura A,Hayashi M,Tsurui H.et al. Lissencephaly with marked ventricular dilation, agenesis of corpus callosum, and cerebellar hypoplasia caused by TUBA1A mutation Brain Dev. 2013 35 274 9

[25] Sohal AP,Montgomery T,Mitra D,Ramesh V. TUBA1A mutation-associated lissencephaly: case report and review of the literature Pediatr Neurol. 2012 46 127 31

[26] Lecourtois M,Poirier K,Friocourt G.et al. Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype Acta Neuropathol. 2010 119 779 89

[27] Fallet-Bianco C,Loeuillet L,Poirier K.et al. Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1A Brain. 2008 131 2304 20

[28] Monaghan KG, Leach NT, Pekarek D, Prasad P, Rose NC.; ACMG Professional Practice and Guidelines Committee. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG) Genet Med. 2020 22 675 80

[29] Walsh N,Cooper A,Dockery A,O'Byrne JJ. Variant reclassification and clinical implications J Med Genet. 2024 61 207 11

[30] Li LS,Li DZ. Ongoing reanalysis of prenatal exome sequencing data leads to higher diagnostic yield Ultrasound Obstet Gynecol. 2022 59 833 4

[31] Jansen AC,Oostra A,Desprechins B.et al. TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria Neurology. 2011 76 988 92

[32] ClinGen Sequence Variant Interpretation Recommendation for de novo Criteria (PS2/PM6) - Version 1.1. Available from: https://www.clinicalgenome.org/site/assets/files/3461/svi_proposal_for_de_novo_criteria_v1_1.pdf. [Last accessed on 12 Mar 2026]

[33] ClinGen Sequence Variant Interpretation Recommendation for PM2 - Version 1.0. Available from: https://www.clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf. [Last accessed on 12 Mar 2026]