Abstract:
BACKGROUND:The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A. RESULTS:In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication. CONCLUSIONS:With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.
journal_name
Orphanet J Rare Disjournal_title
Orphanet journal of rare diseasesauthors
Hebebrand M,Hüffmeier U,Trollmann R,Hehr U,Uebe S,Ekici AB,Kraus C,Krumbiegel M,Reis A,Thiel CT,Popp Bdoi
10.1186/s13023-019-1020-xsubject
Has Abstractpub_date
2019-02-11 00:00:00pages
38issue
1issn
1750-1172pii
10.1186/s13023-019-1020-xjournal_volume
14pub_type
杂志文章,评审abstract:BACKGROUND:Phenylketonuria (PKU) is an inherited deficiency in the enzyme phenylalanine hydroxylase (PAH), which, when poorly-managed, is associated with clinical features including deficient growth, microcephaly, seizures, and intellectual impairment. The management of PKU should start as soon as possible after diagno...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-019-1153-y
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abstract:BACKGROUND:It is unknown whether the neonatal tetrahydrobiopterin (BH4) loading test is adequate to diagnose long-term BH4 responsiveness in PKU. Therefore we compared the predictive value of the neonatal (test I) versus the 48-h BH4 loading test (test II) and long-term BH4 responsiveness. METHODS:Data on test I (>199...
journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
doi:10.1186/s13023-016-0394-2
更新日期:2016-01-29 00:00:00
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journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
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journal_title:Orphanet journal of rare diseases
pub_type: 已发布勘误
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journal_title:Orphanet journal of rare diseases
pub_type: 临床试验,杂志文章
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journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
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journal_title:Orphanet journal of rare diseases
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journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
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journal_title:Orphanet journal of rare diseases
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journal_title:Orphanet journal of rare diseases
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journal_title:Orphanet journal of rare diseases
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journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
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journal_title:Orphanet journal of rare diseases
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journal_title:Orphanet journal of rare diseases
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journal_title:Orphanet journal of rare diseases
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journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
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journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章,评审
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journal_title:Orphanet journal of rare diseases
pub_type: 杂志文章
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pub_type: 杂志文章,评审
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