Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis
Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis
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DOI：
10.1136/jmg.2009.071688
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发表时间：
2010-03-01
影响因子：
4
通讯作者：
Hofstra, Robert M. W.
中科院分区：
文献类型：
--
作者：
Vos, Yvonne J.;de Walle, Hermien E. K.;Hofstra, Robert M. W.
目的开发一个全面的突变分析系统，具有较高的检出率，开发一种工具，以预测检测到突变的机会在L1 CAM基因，并寻找基因型-表型相关性的X连锁隐性遗传疾病，L1 syndrome.Methods的DNA从367转介患者进行了分析，在该基因的编码序列的突变。一个亚组的100例患者也进行了调查的突变调控序列和大的重复。结果在73例患者中检测到68种不同的基因突变。在具有三个或更多L1综合征临床特征的患者中，突变检测率为66%，而在特征较少的患者中，突变检测率为16%。有一名以上受影响亲属的家庭的检测率为51%，有一名受影响男性的家庭的检测率为18%。这两个因素的组合导致85%的检出率（OR 10.4，95% CI 3.6至30.1）。突变类型影响L1综合征的严重程度。截短突变的儿童更有可能在3岁之前死亡的错义突变（52%比8%; p=0.02）。结论我们开发了一个全面的突变检测系统，在特定的人群中，检测率几乎为20%，高达85%。利用患者的临床特征和家族史，临床医生可以准确地预测发现突变的机会。证实了基因型-表型相关性。证明了（母体）生殖系嵌合体的发生。
Objectives To develop a comprehensive mutation analysis system with a high rate of detection, to develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and to look for genotype-phenotype correlations in the X-linked recessive disorder, L1 syndrome.Methods DNA from 367 referred patients was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences and for large duplications. Clinical data for 106 patients were collected and used for statistical analysis.Results 68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 8%; p=0.02).Conclusions We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.