全外显子组序列分析新生儿FGFR2基因相关疾病1例

Exploring the utility of whole-exome sequencing as a diagnostic tool in a newborn with FGFR2 gene related disorder

目的通过对1例新生儿期特殊面容、神经系统结构畸形患儿进行全外显子组序列检测分析,旨在为该患儿寻找潜在的致病原因。方法纳入1例在复旦大学附属儿科医院(我院)新生儿病房住院期间未能明确诊断的多发畸形患儿,主要临床表型为前额突出、腭弓高、耳位低、枕部较平,双侧脑室扩大、透明隔部分缺如、胼胝体发育异常,采用Sure Selct Human All Exon捕获试剂盒和Illumina Hi Seq2000测序平台,行全外显子组序列检测。数据分析采用复旦大学附属儿科医院转化中心所建立的高通量测序数据分析流程。采用Sanger测序进行验证。结果患儿全外显子组序列检测数据,共检测到79 064个变异,经过质量控制筛选、变异频率筛选、变异分类筛选,剩余645个变异。在进一步分析中,645个变异中有159个其所在基因在OMIM数据库及HGMD数据库与疾病相关。从3个已经报道的突变位点中锁定致病突变为FGFR2基因(NM_000141)c.C1040G,p.S347C。Sanger测序在家系内验证该位点为新发(de novo)突变。结论采用全外显子组序列检测,明确诊断FGFR2相关疾病1例。并且结合我院已经建立的高通量测序数据分析和临床诊断流程,为新生儿多发畸形寻找潜在的致病基因提供了快速、高效的方法。

Objective In this study,the whole-exome sequencing was used to identify pathogenic mutations in a newborn with frontal bossing,high-arched palate,low set ear,ventriculomegaly,absent septum pellucidum and agenesis of the corpus callosum.M ethods The exome targets of the patient's DNA were captured with the Sure Selct Human All Exon kit followed by sequencing with the Illumina Hi Seq2000 platform. The data analysis pipeline of the Children's Hospital of Fudan University was used for the annotation and variant calling. The detected variant was confirmed with Sanger direct sequencing. Results Whole-exome sequencing identified total 79064 variants in the proband. After filtering of quality,frequency criteria and classification,645 rare variants were identified. Among these rare variants,159 variants were mapped to disease-related genes in HGMD or OMIM database. Manual analysis revealed a reported heterozygous mutation( c. C1040 G,p. S347C) in FGFR2 gene. Sanger direct sequencing confirmed that it was a de novo mutation in the proband. Conclusion We present a patient with FGFR2 related disorder detected by whole-exome sequencing. This study clearly shows the efficacy of Whole-exome sequencing and our data analysis pipeline for rapid genetic diagnosis of multiple congenital malformations in newborn with an unknown cause.