15q11.2-13.2微重复四倍体综合征1例并文献复习

目的 采用分子遗传学技术分析1例常规染色体核型拟诊为21/22三体的发育迟缓伴孤独症患儿，明确遗传学诊断。方法 收集患儿及其父母的外周血标本，常规提取基因组DNA，应用高分辨染色体核型分析（400-550带）检测患儿及其父母的染色体数目及结构，微阵列比较基因组杂交技术(array-CGH)筛查患儿的全基因组拷贝数变异，以荧光原位杂交技术（FISH）对异常的基因拷贝进行染色体精确定位和定量。结果 女，2岁，发育迟缓伴孤独症样表现。外侧眼角下垂、内眦赘皮。常规染色体核型检查（320带）分别为47,XX,+22和47,XX,+21。高分辨染色体核型分析显示，该患儿携带额外标记染色体（SMC），核型为47，XX，+mar dn，尚不能确定是否为21/22三体携带者，患儿父亲高分辨率核型染色体分析提示为46,XY，母亲为46,XX，提示患儿携带SMC为新生突变。array-CGH检测显示15q11.2-13.2区域微重复（chr15:22684529-30730543，8.0 Mb，hg19）。FISH验证该SMC来源于15号染色体，由15q11.2-13.2区域二倍体及双着丝粒组成。患儿最终诊断为15q11.2-13.2微重复四倍体综合征。复习文献报道的15q11.2-13.2拷贝数增加病例的临床表型，微重复四倍体综合征的主要表型有智力低下/发育迟缓（100％）、肌张力低下（92.9％）、孤独症/孤独症样表现（71.4％）和癫痫（61.5％）等。结论 15q11.2-13.2微重复四倍体综合征是患儿发生精神发育迟滞伴孤独症的遗传学基础，array-CGH能够快速、准确地检测基因组的微小失衡。

A case of 15q11.2-13.2 tetraploid microduplication syndrome and literature review

Objective To identify the underlying genetic causes with multiple molecular genetic techniques in a female patient with neuro-developmental delay and autism, who has ever been diagnosed as 21/22 trisomy with conventional karyotype analysis.Methods The peripheral blood was collected from the patient and her parents. Genomic DNA was extracted by phenol-chloroform method. The high-resolution karyotype analysis (400-550 bands) was performed to check the chromosome′s number and structure, and the array comparative genomic hybridization (array-CGH) was used to detect the whole genomic copy number variation.The fluorescent in situ hybridization was employed to localize and quantify the abnormal genomic copy numbers.Results A 2-year-old girl suffered from neuro-developmental delay and autism with downslanting of the palpebral fissures and epicanthic folds. The result of conventional karyotype analysis (320 bands) was 47,XX,+22 or 47,XX,+21.The high-resolution karyotype analysis (400-550 bands) detected a supernumerary marker chromosome(SMC) and her karyotype was 47,XX,+mar dn, which had ever been misdiagnosed as 21/22 trisomy.Her parents′ karyotype was 46,XY and 46,XX, respectively. The SMC was de novo. About 8.0 Mb duplication in the 15q11.2-13.2 region (chr15:22684529-30730543, 8.0 Mb,hg19) was found in the patient by array-CGH. FISH confirmed that the SMC was originated from chromosome 15, and consisted of two copies of the centromerics and 15q11.2-13.2 interval. The 15q11.2-13.2 tetraploid microduplication syndrome or Idic(15) syndrome was established after all. A literature review of the clinical phenotypes of the 15q11.2-13.2 microduplication was performed, which showed that intellectual disability/ developmental retardation, hypotpnia, autism/autism-like symptoms and epilepsy were the key clinical phenotypes in the Idic(15) syndrome.Conclusion The de novo tetrasomy 15q11.2-13.2 is a genetic basis for neuro-developmental delay and autism in this case. The array-CGH can detect genomic micro-imbalance quickly and precisely.