Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, 91054, Erlangen, Germany.
Department of Pediatrics, Division of Neuropediatrics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Orphanet J Rare Dis. 2019 Feb 11;14(1):38. doi: 10.1186/s13023-019-1020-x.
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.
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.
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.
TUBA1A 相关的微管蛋白病在临床上具有异质性，其主要临床特征为脑畸形、小头症、发育迟缓伴癫痫。它是一种常染色体显性遗传病，主要由 TUBA1A 中的新生变异引起。
通过外显子组测序，我们在 3 名发育迟缓的个体中发现了 TUBA1A 的杂合新生错义变异。虽然 c.1307G>A，p.(Gly436Asp) 变异是新发现的，但两个变异 c.518C>T，p.(Pro173Leu)和 c.641G>A，p.(Arg214His) 之前已有报道。我们将这些个体的可变表型与当前文献的仔细回顾进行了比较，并鉴定了 166 名个体，包括 146 名出生个体和 20 名胎儿，这些个体均携带 TUBA1A 变异。在 107 例有可用临床信息的病例中，我们根据人类表型本体论对报告的表型进行了标准化。最常报道的特征是发育迟缓（98%）、胼胝体异常（96%）、小头症（76%）和无脑回畸形（无脑回-巨脑回）（70%），尽管不同研究中的报道并不完整。我们总共鉴定了 121 个特定变异，包括 15 个高频变异。错义变异聚集在 C 末端，靠近最常受影响的氨基酸位置 Arg402（13.3%）。在三维蛋白模型中，包括 C 末端区域的所有致病变异的 38.6%，预计会影响微管相关蛋白或马达蛋白的结合。对高频变异的基因型-表型分析表明，某些临床特征存在过表达。然而，携带这些变异的个体通常在同一篇文献中报道。
我们纳入了 166 名个体，提供了最全面的 TUBA1A 变异临床解释的表型和基因型标准化综合分析。尽管数量相当可观，但由于报告中的研究间变异性较大，详细的基因型-表型特征仍受到限制。
