IL10RA及DUOX2复合杂合变异致极早发炎症性肠病1例患儿的遗传学分析

Analysis of a child with Very early onset inflammatory bowel disease due to compound heterozygous variants of IL10RA and DUOX2 genes

目的探讨1例新生儿期起病的极早发炎症性肠病(VEOIBD)患儿的遗传学病因。方法收集1例因"生后6 d以腹泻、发热起病"于2018年5月23日就诊于复旦大学附属儿科医院的VEOIBD患儿的临床及随访资料。对其进行家系全外显子测序(WES),对可疑致病变异进行Sanger测序及PCR验证。结果患儿为4.5岁女性,主要表现为腹泻、发热、生长发育迟缓、直肠阴道瘘、甲状腺功能低下,3.5月龄时因严重的肠粘连及肠梗阻而行肠造瘘术。根据其临床表现、消化内镜、组织病理学检查结果诊断为VEOIBD。该患儿合并先天性甲状腺功能减低症,1月龄起予左旋甲状腺素替代治疗。家系WES发现该患儿DUOX2基因存在c.2654G>T及c.505C>T复合杂合错义变异及IL10RA基因存在c.301C>T杂合错义变异,进一步数据分析发现该患儿IL10RA基因的第1外显子存在333 bp的片段缺失。根据美国医学遗传学与基因组学学会变异评级相关指南(ACMG),该患儿IL10RA:c.301C>T被评级为致病性变异(PS1+PM3+PP3+PP4),DUOX2:c.2654G>T变异判定为可能致病性变异(PS3+PM3+PM5),DUOX2:c.505C>T判定为意义未明变异(PM2_Supporting+PM3+PP4)。结论对新生儿期起病的极早发炎症性肠病患儿应尽早行基因检测。合并DUOX2基因变异可能加重了该患儿的临床症状。该结果可为患儿家系的遗传咨询和产前诊断提供帮助,并进一步增加临床医生对该罕见病的认识。

Objective To explore the genetic basis of a child with Very early onset inflammatory bowel disease(VEOIBD).Methods A female child who had presented at the Children′s Hospital of Fudan University on May 23,2018 due to occurrence of diarrhea and fever 6 days after birth was selected as the study subject.Clinical data of the child was collected.Family-based whole-exome sequencing(WES)was carried out.Candidate variant was verified by Sanger sequencing and PCR of the patient and her parents.Results The child had developed the symptoms 6 days after birth,with main manifestations including diarrhea,fever,failure to thrive,rectovestibular fistula and hypothyroidism.An enterostomy was performed at the age of 3.5 months due to severe intestinal adhesion and obstruction.Based on her clinical manifestations,colonoscopic finding,and results of biopsies,she was diagnosed with VEOIBD in conjunct with congenital hypothyroidism.Replacement treatment of levothyroxine was given since one month of age.Family-based WES revealed that the child has harbored compound heterozygous variants of the DUOX2 gene,namely c.2654G>T(p.R885L)and c.505C>T(p.R169W),in addition with a heterozygous c.301C>T(p.R101W)variant of the IL10RA gene.Re-analysis of the WES data revealed that the patient also had a 333 bp deletion spanning exon 1 of the IL10RA gene(Chr11:117857034_117857366).Conclusion For patients with VEOIBD,genetic testing is recommended.Presence of additional DUOX2 gene variants might have exacerbated the clinical symptoms in this patient.Above finding has facilitated genetic counseling and prenatal diagnosis for this family,and raised clinicians′awareness of this rare disease.