染色体微阵列分析技术在489例生长发育迟缓／智力低下患儿中的应用

Application of chromosome microarray analysis in 489 children with developmental delay/intellectual disability

目的应用染色体微阵列分析（chromosome microarray analysis，CMA）分析不明原因的生长发育迟缓（developmental delay，DD）／智力低下（intellectual disability，ID）患儿的遗传学病因。方法收集染色体核型结果正常的DD／ID伴或不伴其他异常的患儿489例。分为3组：单纯性DD／ID组（n=358），DD／ID合并癫痫组（n=49），DD／ID合并其他结构畸形组（n=82）。进一步行CMA检测，并通过配套的CHAS软件及相关的生物信息学分析检测结果。结果CMA在126例患儿中检测到致病性拷贝数变异片段（copynumber variants，CNVs），检出率为25．8％（126／489），其中单纯性DD／ID组、DD／ID合并癫痫组以及DD／ID合并其他结构畸形组的致病性CNVs检出率差异无统计学意义。在这些致病性CNVs中，79例（62．7％，79／126）为微缺失／微重复综合征，其中较常见者综合征76例，包括Angelman／Prader—Willi综合征、Williams—Beuren综合征、22q11．2微缺失／微重复综合征、Wolf-Hirschhorn综合征、16p11．2微缺失／微重复综合征、1p36微缺失综合征、17p11．2微缺失／微重复综合征、2q37单体综合征、Rubinstein-Taybi综合征；而罕见综合征3例，包括15q24微缺失综合征、Xq28微重复综合征以及眼脑肾综合征。47例（37．3％，47／126）为新发的致病性片段，片段大小在153kb到7．93Mb之间。其中，16p13．2区域的ABAT和PMM2基因，Xp11．23p11．22区域的FTSJ1基因，14q32．31q32．33区域的DYNC1H1基因以及18q12．3q21．1区域的SETBP1基因为DD／ID可疑致病性基因。结论CMA显著提高DD／ID患儿遗传学病因的检出率，检测出核型分析不能识别的微缺失／微重复综合征和拷贝数变异片段，为具有表型异质性的罕见综合征性DD／ID患者的遗传病学诊断提供了分子水平的检测手段。同时CMA还具有发现新的可疑致病性基因的能力。为疾病的诊断、咨询、治疗、预后评估以及疾病的再发风险评估提供了遗传学依据。

Objective To assess the value of chromosome microarray analysis （CMA） for identifying the etiology of developmental delay/intellectual disability （DD/ID）. Methods A total of 489 children referred for DD/ID with or without other abnormalities were recruited. All patients showed a normal karyotype. DNA was extracted and hybridized with Affymetrix CytoScan 750K array by following the manufacturer＇s protocol. The data was analyzed with CHAS v2.0 software. Results The children were classified as with isolated DD/ID （n=358）, DD/ID with epilepsy （n=49）, and DD/ID with other structural anomalies （n = 82）. Pathogenic copy number variants （CNVs） were identified in 126 cases （25.8 % ）, which included 89 （24.9%, 89/358） of whose with isolated DD/ID, 13 （26.5%, 13/49） of those with DD/ID and epilepsy, and 24 （29.3%, 24/82） of whose with DD/ID and other structural anomalies[P=0. 064 （24.9 % vs. 26.5%）, P=0.679 （24.9% vs. 29.3%）, andP=0.113 （26.5% vs. 29.3%）, respectively]. Among the 126 cases, 79 were identified as microdeletion/microduplication syndromes, which included 15q24microdeletion syndrome, Xq28 mieroduplication syndrome, and Lowe syndrome. Forty seven cases had de novo pathogenic CNVs. ABAT, PMM2, FTSJ1, DYNCIH1 and SETBP1 were considered as candidate genes for DD/ID. Conclusion CMA is an effective method for identifying the etiology of DD/ID and is capable of identifying microdeletion/microduplication syndromes as well as de novo pathogenic CNVs which may be missed by conventional karyotyping. Based on the results, candidate genes for DD/ID may be identified.