Department of Neurology, The Carol and James Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Boston, MA, USA.
Eur J Hum Genet. 2012 May;20(5):510-5. doi: 10.1038/ejhg.2011.241. Epub 2011 Dec 21.
Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder, which affects 1 in 6000 people. About half of these patients are affected by mental retardation, which has been associated with TSC2 mutations, epilepsy severity and tuber burden. The bimodal intelligence distribution in TSC populations suggests the existence of subgroups with distinct pathophysiologies, which remain to be identified. Furthermore, it is unknown if heterozygous germline mutations in TSC2 can produce the neurocognitive phenotype of TSC independent of epilepsy and tubers. Genotype-phenotype correlations may help to determine risk profiles and select patients for targeted treatments. A retrospective chart review was performed, including a large cohort of 137 TSC patients who received intelligence assessment and genetic mutation analysis. The distribution of intellectual outcomes was investigated for selected genotypes. Genotype-neurocognitive phenotype correlations were performed and associations between specific germline mutations and intellectual outcomes were compared. Results showed that TSC1 mutations in the tuberin interaction domain were significantly associated with lower intellectual outcomes (P<0.03), which was also the case for TSC2 protein-truncating and hamartin interaction domain mutations (both P<0.05). TSC2 missense mutations and small in-frame deletions were significantly associated with higher IQ/DQs (P<0.05). Effects related to the mutation location within the TSC2 gene were found. These findings suggest that TSC2 protein-truncating mutations and small in-frame mutations are associated with distinctly different intelligence profiles, providing further evidence that different types and locations of TSC germline mutations may be associated with distinct neurocognitive phenotypes.
结节性硬化症复合征（TSC）是一种常染色体显性、多系统紊乱，影响 6000 人中的 1 人。这些患者中有大约一半受到智力迟钝的影响，智力迟钝与 TSC2 突变、癫痫严重程度和结节负担有关。TSC 人群中双模态智力分布表明存在具有不同病理生理学的亚组，这些亚组仍有待确定。此外，尚不清楚 TSC2 中的杂合性种系突变是否可以在没有癫痫和结节的情况下产生 TSC 的神经认知表型。基因型-表型相关性可能有助于确定风险概况并选择患者进行靶向治疗。进行了回顾性图表审查，包括接受智力评估和基因突变异分析的 137 名 TSC 患者的大型队列。研究了选定基因型的智力结果分布。进行了基因型-神经认知表型相关性分析，并比较了特定种系突变与智力结果之间的关联。结果表明，结节素相互作用域中的 TSC1 突变与较低的智力结果显著相关（P<0.03），TSC2 蛋白截断和错构素相互作用域突变也是如此（均 P<0.05）。TSC2 错义突变和小框内缺失与较高的智商/发育商显著相关（P<0.05）。发现与 TSC2 基因内突变位置有关的效应。这些发现表明，TSC2 蛋白截断突变和小框内突变与明显不同的智力特征相关，进一步证明不同类型和位置的 TSC 种系突变可能与不同的神经认知表型相关。
