FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants
FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants
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DOI：
10.1038/gim.2017.75
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发表时间：
2018-01-01
影响因子：
8.8
通讯作者：
Brockmann, Knut
中科院分区：
文献类型：
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作者：
Mitter, Diana;Pringsheim, Milka;Brockmann, Knut
目的：本研究旨在扩大FOXG1综合征的临床和遗传谱，并评估FOXG1变异导致的基因型-表型关联。方法：我们收集了30例新的和53例报道的FOXG1杂合致病性或可能致病性变异患者。我们根据变异的类型和位置对患者进行分组。采用Fisher精确检验和非参数多变量检验对分子和临床数据进行统计分析。结果：在30例新患者中，我们鉴定出19种新的FOXG1变体。在83例患者中，共有54种变异：移码型20例（37%），错义型17例（31%），无义型15例（28%），帧内型2例（4%）。移码和无义变体分布在所有FOXG1蛋白结构域；错义变体聚集在保守叉头域内。我们发现了比先前描述的更高的表型变异性。基因型-表型关联显示FOXG1基因型组在精神运动发育和神经功能方面存在显著差异。更严重的表型与在n端结构域和叉头结构域（除了保守位点1）截断FOXG1变异相关，而较轻的表型与叉头保守位点1的错义变异相关。结论：这些数据可能有助于改善新的FOXG1序列变异的解释和有充分根据的遗传咨询。
Purpose: The study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.Methods: We compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.Results: Among the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotypephenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.Conclusions: These data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.