Sotos综合征的临床表型及遗传学分析

Clinical phenotypes and a genetic analysis of patients with Sotos syndrome

摘要:

3例男性患儿，年龄7~13个月，均以运动发育迟缓、智力落后就诊，均有前额突出、眼距宽或者下颌尖长等特殊面容，身长和头围方面仅病例1的头围超过2 SD，其中2例患儿的骨龄超前、1例患儿脑电图异常，3例患儿头部CT均显示脑室扩大。全基因组芯片分析发现1例患儿染色体5q35.2区域缺失一个1.75 Mb大小的拷贝，其中包括NSD1基因；荧光定量PCR方法对拷贝数异常区域进行验证：NSD1基因拷贝数减半。高通量测序分析发现另2例患儿的NSD1基因分别存在c.1157T > G杂合突变和c.1177G > T杂合突变，其中c.1157T > G杂合突变未见报道，但生物信息学分析提示该位点突变具有致病性。因此，3例患儿均确诊为Sotos综合征。Sotos综合征是常染色体显性遗传的先天性生长过度症，70%~90%的患者存在NSD1基因突变，约10%存在染色体5q35区域（包括NSD1基因）缺失。

Abstract:

Three boys aged 7-13 months visited the hospital due to unusual facies (prominent forehead, hypertelorism, or long mandible), motor developmental delay, and mental retardation. As for body length and head circumference, only one patient had a head circumference of > 2 SD. Two patients had an advanced bone age, one had electroencephalographic abnormalities, and 3 had enlarged ventricles on head CT. The whole-genome microarray analysis showed the deletion of a copy with a size of 1.75 Mb in the chromosomal region 5q35.2 in one patient, which contained the NSD1 gene. Quantitative real-time PCR was performed for the validation of the region with copy number variation, and the results showed that the copy number of the NSD1 gene in this patient was reduced by half. High-throughput sequencing identified two heterozygous mutations, c.1157T > G and c.1177G > T, in the NSD1 gene in two patients. c.1157T > G mutations had not been reported before, but the bioinformatics analysis showed that this mutation had pathogenicity. All three boys were diagnosed with Sotos syndrome. Sotos syndrome is a congenital overgrowth syndrome with autosomal dominant inheritance; 70%-90% of patients have NSD1 gene mutations, and about 10% of patients have depletion in the 5q35 region (containing the NSD1 gene).