Rare Clinical Gene Variants of TUBA1A: Tubulinopathy-Related Brain Malformation Spectrum Disorder
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Tubulinopathies refer to complex brain malformations related to abnormal microtubule proteins necessary for neuronal migration. Among the most frequently reported gene mutations involves TUBA1A, which encodes tubulin alpha-1A protein. TUBA1A-related tubulinopathy is an autosomal dominant (AD) disorder characterized by brain anomalies including corpus callosum agenesis, cerebellar hypoplasia and cortical dysgenesis. Prenatal detection typically begins with fetal imaging and postnatally clinical presentation often involves developmental delay or epilepsy.
Two cases of similar tubulin variants are presented to illustrate the spectrum of prenatal brain findings. Specifically, prenatal exome sequencing (ES) detected missense TUBA1A variants resulting in deleterious structure and function of tubulin alpha-1A protein.
Case Presentation
Case 1: A 33-year-old G3P1 presents at 27 weeks for fetal posterior fossa anomalies (PFA).
Case 2: A 31-year-old G5P1 presents at 20 weeks for fetal bilateral ventriculomegaly.
Medical and family histories were unremarkable.
Diagnostic Workup
Both cases underwent aneuploidy screening with low-risk results prior to referral to fetal center. Families were offered detailed anatomy ultrasound (US), fetal magnetic resonance imaging (MRI) and diagnostic genetic testing.
In Case 1, fetal US reveled microcephaly, abnormal corpus callosum, and dilation of 4th ventricle and posterior fossa. Fetal MRI confirmed microcephaly, partial agenesis of corpus callosum and enlarged 4th ventricle and additionally characterized enlarged cisterna magna, cerebellar vermis hypoplasia and asymmetry of sylvian fissures and cerebral sulcation. Amniocentesis was declined and products of conception testing was pursued. Karyotype was normal (46, XY). ES revealed AD heterozygous TUBA1A variant with a diagnosis of TUBA1A-related brain malformations spectrum disorder. The missense mutation was a de novo pathogenic variant (c.344 T>C).
In Case 2, fetal US revealed bilateral ventriculomegaly with echogenic lining, abnormal corpus callosum, dilated 4th ventricle with cerebellar hypoplasia and scalp edema. Fetal MRI confirmed ventriculomegaly, partial agenesis of corpus callosum, dilated 4th ventricle, dysplastic cerebellar vermis, scalp edema and additionally characterized dysplastic brainstem. Amniocentesis revealed negative infection studies, normal karyotype (46, XX) and negative chromosomal microarray. Similarly, ES revealed AD heterozygous TUBA1A variant with the same diagnosis as Case 1. The missense mutation was a de novo pathogenic variant (c.167 C>T).
Treatment and Management
Management included multidisciplinary conference with genetics, maternal-fetal medicine and neurology subspecialists. Treatment options of ongoing fetal surveillance and medical interruption of pregnancy were discussed. Social work provided financial and emotional support resources. Pregnancy termination centers were contacted for care coordination at family request.
Outcome and Follow-Up
Ultimately, both patients elected pregnancy termination via dilation and evacuation. Families were counseled regarding <1% recurrence risk in future pregnancies given both cases involved de novo variants, however, germline mosaicism cannot be excluded.
Discussion
Current literature describes over 100 distinct TUBA1A mutations. The majority are characterized as deleterious, suggesting a critical role in neuronal function. Other case reports document brain malformations with the highest frequencies in cerebellar hypoplasia, cortical malformation and corpus callosum agenesis. These two cases identified cerebellar hypoplasia and abnormal corpus callosum, however they also presented with posterior fossa abnormalities. Case 1 identified cortical asymmetry, consistent with gestational ages approaching the third trimester. Importantly, this spectrum of anomalies remains nonspecific and compatible with other central nervous system disorders including PFA and dystroglycanopathies. In both scenarios, ES provided a diagnosis to counsel families on prognosis and future reproductive risks.
Conclusion
Prenatal counseling for rare genetic disorders with clinical heterogeneity remains difficult. While the severity of brain malformations identified on prenatal imaging is sufficient to make informed decisions for some families, other families desire more diagnostic certainty through genetic testing. Positive results on ES, such as TUBA1A gene variants, improve goals of care discussions and further genotype-phenotype characterization will be beneficial for prognostic counseling. Functional studies of cellular pathways involved in tubulin alpha-1 protein are potential areas of future research.
Tubulinopathies refer to complex brain malformations related to abnormal microtubule proteins necessary for neuronal migration. Among the most frequently reported gene mutations involves TUBA1A, which encodes tubulin alpha-1A protein. TUBA1A-related tubulinopathy is an autosomal dominant (AD) disorder characterized by brain anomalies including corpus callosum agenesis, cerebellar hypoplasia and cortical dysgenesis. Prenatal detection typically begins with fetal imaging and postnatally clinical presentation often involves developmental delay or epilepsy.
Two cases of similar tubulin variants are presented to illustrate the spectrum of prenatal brain findings. Specifically, prenatal exome sequencing (ES) detected missense TUBA1A variants resulting in deleterious structure and function of tubulin alpha-1A protein.
Case Presentation
Case 1: A 33-year-old G3P1 presents at 27 weeks for fetal posterior fossa anomalies (PFA).
Case 2: A 31-year-old G5P1 presents at 20 weeks for fetal bilateral ventriculomegaly.
Medical and family histories were unremarkable.
Diagnostic Workup
Both cases underwent aneuploidy screening with low-risk results prior to referral to fetal center. Families were offered detailed anatomy ultrasound (US), fetal magnetic resonance imaging (MRI) and diagnostic genetic testing.
In Case 1, fetal US reveled microcephaly, abnormal corpus callosum, and dilation of 4th ventricle and posterior fossa. Fetal MRI confirmed microcephaly, partial agenesis of corpus callosum and enlarged 4th ventricle and additionally characterized enlarged cisterna magna, cerebellar vermis hypoplasia and asymmetry of sylvian fissures and cerebral sulcation. Amniocentesis was declined and products of conception testing was pursued. Karyotype was normal (46, XY). ES revealed AD heterozygous TUBA1A variant with a diagnosis of TUBA1A-related brain malformations spectrum disorder. The missense mutation was a de novo pathogenic variant (c.344 T>C).
In Case 2, fetal US revealed bilateral ventriculomegaly with echogenic lining, abnormal corpus callosum, dilated 4th ventricle with cerebellar hypoplasia and scalp edema. Fetal MRI confirmed ventriculomegaly, partial agenesis of corpus callosum, dilated 4th ventricle, dysplastic cerebellar vermis, scalp edema and additionally characterized dysplastic brainstem. Amniocentesis revealed negative infection studies, normal karyotype (46, XX) and negative chromosomal microarray. Similarly, ES revealed AD heterozygous TUBA1A variant with the same diagnosis as Case 1. The missense mutation was a de novo pathogenic variant (c.167 C>T).
Treatment and Management
Management included multidisciplinary conference with genetics, maternal-fetal medicine and neurology subspecialists. Treatment options of ongoing fetal surveillance and medical interruption of pregnancy were discussed. Social work provided financial and emotional support resources. Pregnancy termination centers were contacted for care coordination at family request.
Outcome and Follow-Up
Ultimately, both patients elected pregnancy termination via dilation and evacuation. Families were counseled regarding <1% recurrence risk in future pregnancies given both cases involved de novo variants, however, germline mosaicism cannot be excluded.
Discussion
Current literature describes over 100 distinct TUBA1A mutations. The majority are characterized as deleterious, suggesting a critical role in neuronal function. Other case reports document brain malformations with the highest frequencies in cerebellar hypoplasia, cortical malformation and corpus callosum agenesis. These two cases identified cerebellar hypoplasia and abnormal corpus callosum, however they also presented with posterior fossa abnormalities. Case 1 identified cortical asymmetry, consistent with gestational ages approaching the third trimester. Importantly, this spectrum of anomalies remains nonspecific and compatible with other central nervous system disorders including PFA and dystroglycanopathies. In both scenarios, ES provided a diagnosis to counsel families on prognosis and future reproductive risks.
Conclusion
Prenatal counseling for rare genetic disorders with clinical heterogeneity remains difficult. While the severity of brain malformations identified on prenatal imaging is sufficient to make informed decisions for some families, other families desire more diagnostic certainty through genetic testing. Positive results on ES, such as TUBA1A gene variants, improve goals of care discussions and further genotype-phenotype characterization will be beneficial for prognostic counseling. Functional studies of cellular pathways involved in tubulin alpha-1 protein are potential areas of future research.
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