Rauch Anita, Hoyer Juliane, Guth Sabine, Zweier Christiane, Kraus Cornelia, Becker Christian, Zenker Martin, Hüffmeier Ulrike, Thiel Christian, Rüschendorf Franz, Nürnberg Peter, Reis André, Trautmann Udo
Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Am J Med Genet A. 2006 Oct 1;140(19):2063-74. doi: 10.1002/ajmg.a.31416.
The underlying cause of mental retardation remains unknown in up to 80% of patients. As chromosomal aberrations are the most common known cause of mental retardation, several new methods based on FISH, PCR, and array techniques have been developed over recent years to increase detection rate of subtle aneusomies initially of the gene rich subtelomeric regions, but nowadays also genome wide. As the reported detection rates vary widely between different reports and in order to compare the diagnostic yield of various investigations, we analyzed the diagnostic yield of conventional karyotyping, subtelomeric screening, molecular karyotyping, X-inactivation studies, and dysmorphological evaluation with targeted laboratory testing in unselected patients referred for developmental delay or mental retardation to our cytogenetic laboratory (n = 600) and to our genetic clinic (n = 570). In the cytogenetic group, 15% of patients showed a disease-related aberration, while various targeted analyses after dysmorphological investigation led to a diagnosis in about 20% in the genetic clinic group. When adding the patients with a cytogenetic aberration to the patient group seen in genetic clinic, an etiological diagnosis was established in about 40% of the combined study group. A conventional cytogenetic diagnosis was present in 16% of combined patients and a microdeletion syndrome was diagnosed in 5.3%, while subtelomeric screening revealed only 1.3% of causes. Molecular karyotyping with a 10 K SNP array in addition revealed 5% of underlying causes, but 29% of all diagnoses would have been detectable by molecular karyotyping. In those patients without a clear diagnosis, 5.6% of mothers of affected boys showed significant (>95%) skewing of X-inactivation suggesting X-linked mental retardation. The most common diagnoses with a frequency of more than 0.5% were Down syndrome (9.2%), common microdeletion 22q11.2 (2.4%), Williams-Beuren syndrome (1.3%), Fragile-X syndrome (1.2%), Cohen syndrome (0.7%), and monosomy 1p36.3 (0.6%). From our data, we suggest the following diagnostic procedure in patients with unexplained developmental delay or mental retardation: (1) Clinical/dysmorphological investigation with respective targeted analyses; (2) In the remaining patients without an etiological diagnosis, we suggest conventional karyotyping, X-inactivation screening in mothers of boys, and molecular karyotyping, if available. If molecular karyotyping is not available, subtelomeric screening should be performed.
在高达80%的患者中，智力发育迟缓的根本原因仍不明确。由于染色体畸变是已知最常见的智力发育迟缓病因，近年来已开发出几种基于荧光原位杂交（FISH）、聚合酶链反应（PCR）和芯片技术的新方法，以提高最初对富含基因的亚端粒区域细微非整倍体的检测率，如今也可进行全基因组检测。由于不同报告中报道的检测率差异很大，为了比较各种检查的诊断效率，我们分析了在我们的细胞遗传学实验室（n = 600）和遗传诊所（n = 570）转诊来的发育迟缓或智力发育迟缓的未选择患者中，常规核型分析、亚端粒筛查、分子核型分析、X染色体失活研究以及伴有针对性实验室检测的畸形学评估的诊断效率。在细胞遗传学组中，15%的患者显示出与疾病相关的畸变，而在遗传诊所组中，畸形学检查后的各种针对性分析导致约20%的患者得到诊断。当将细胞遗传学异常的患者加入到遗传诊所就诊的患者组中时，联合研究组中约40%的患者确立了病因诊断。联合患者中有16%存在常规细胞遗传学诊断，5.3%被诊断为微缺失综合征，而亚端粒筛查仅发现1.3%的病因。此外，使用10 K单核苷酸多态性（SNP）芯片进行分子核型分析揭示了5%的潜在病因，但所有诊断中有29%可通过分子核型分析检测到。在那些没有明确诊断的患者中，受影响男孩的母亲中有5.6%显示X染色体失活明显（>95%）偏斜，提示X连锁智力发育迟缓。最常见的诊断且频率超过0.5%的是唐氏综合征（9.2%）、常见的22q11.2微缺失（2.4%）、威廉姆斯-博伦综合征（1.3%）、脆性X综合征（1.2%）、科恩综合征（0.7%）和1p36.3单体（0.6%）。根据我们的数据，我们建议对不明原因的发育迟缓或智力发育迟缓患者采用以下诊断程序：（1）进行临床/畸形学检查及相应的针对性分析；（2）在其余未明确病因诊断的患者中，我们建议进行常规核型分析、男孩母亲的X染色体失活筛查以及分子核型分析（如果可行）。如果无法进行分子核型分析，则应进行亚端粒筛查。
