Exploring genotype‐phenotype relationships in the CDKL5 deficiency disorder using an international dataset,Clinical Genetics

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Exploring genotype‐phenotype relationships in the CDKL5 deficiency disorder using an international dataset
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-10-12 , DOI: 10.1111/cge.13862
Conor I MacKay ₁ , Kingsley Wong ₁ , Scott T Demarest _{2,

3} , Tim A Benke _{2,

4} , Jenny Downs _{1,

5} , Helen Leonard ₁

Affiliation

Characterized by early‐onset seizures, global developmental delay and severe motor deficits, CDKL5 deficiency disorder is caused by pathogenic variants in the cyclin‐dependent kinase‐like 5 gene. Previous efforts to investigate genotype‐phenotype relationships have been limited due to small numbers of recurrent mutations and small cohort sizes. Using data from the International CDKL5 Disorder Database we examined genotype‐phenotype relationships for 13 recurrent CDKL5 variants and the previously analyzed historic variant groupings. We have applied the CDKL5 Developmental Score (CDS) and an adapted version of the CDKL5 Clinical Severity Assessment (CCSA), to grade the severity of phenotype and developmental outcomes for 285 individuals with CDKL5 variants. Comparisons of adapted CCSA and CDS between recurrent variants and variant groups were performed using multiple linear regression adjusting for age and sex. Individuals with the missense variant, p.Arg178Trp, had the highest mean adapted CCSA and lowest mean developmental scores. Other variants producing severe phenotypes included p.Arg559* and p.Arg178Gln. Variants producing milder phenotypes included p.Arg134*, p.Arg550*, and p.Glu55Argfs*20. There are observed differences in phenotype severity and developmental outcomes for individuals with different CDKL5 variants. However, the historic variant groupings did not seem to reflect differences in phenotype severity or developmental outcomes as clearly as analyzed by individual variants.

中文翻译：

使用国际数据集探索 CDKL5 缺乏症的基因型-表型关系

CDKL5 缺乏症的特点是早发性癫痫、全面发育迟缓和严重的运动障碍，是由细胞周期蛋白依赖性激酶样 5 基因的致病变异引起的。由于复发突变数量少和队列规模小，之前研究基因型-表型关系的努力受到限制。使用来自国际 CDKL5 疾病数据库的数据，我们检查了 13 种复发性CDKL5变异和先前分析的历史变异分组的基因型-表型关系。我们已应用 CDKL5 发育评分 (CDS) 和 CDKL5 临床严重程度评估 (CCSA) 的改编版本，对 285 名CDKL5患者的表型和发育结果的严重程度进行分级变种。使用针对年龄和性别调整的多元线性回归，对复发变体和变体组之间的适应 CCSA 和 CDS 进行比较。具有错义变异 p.Arg178Trp 的个体具有最高的平均适应 CCSA 和最低的平均发育分数。其他产生严重表型的变体包括 p.Arg559* 和 p.Arg178Gln。产生较温和表型的变体包括 p.Arg134*、p.Arg550* 和 p.Glu55Argfs*20。具有不同 CDKL5 变异的个体在表型严重程度和发育结果方面观察到差异。然而，历史变异分组似乎并没有像单个变异所分析的那样清楚地反映表型严重程度或发育结果的差异。

更新日期：2020-10-12

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