儿童Mowat-Wilson综合征的临床特点及基因变异和遗传情况

Clinical characteristics,genetic variation,and inheritance of Mowat-Wilson syndrome in children

目的总结儿童Mowat-Wilson综合征(MWS)的临床特点,了解本病的基因变异和遗传情况。方法回顾性分析2017年1月—2022年12月南京医科大学附属南京儿童医院收治的8例MWS患儿的临床资料。结果8例患儿均有发育迟缓、特殊面容及先天性畸形(如先天性心脏病、骨骼发育畸形、先天性巨结肠、肾脏异常等)。患儿1的ZEB2基因上存在c.2350_c.2351insT(p.S784F*11)杂合移码变异,其父母均无该基因变异,为新生变异;患儿2的ZEB2基因上存在c.1150C>T(p.Q384*,831)杂合无义变异,其父母均无该基因变异,为新生变异;患儿3和患儿6的ZEB2基因均存在c.2073G>A(p.W691*,524)杂合无义变异,2例患儿父母均无该基因变异,为新生变异;患儿4的ZEB2基因上存在c.3179G>A(p.C1060Y)杂合错义变异,其父母均无该基因变异,为新生变异;患儿5的ZEB2基因上存在c.904C>T(p.R302*,913)杂合无义变异,其父母均无该基因变异,为新生变异;患儿7的ZEB2基因上存在c.2467(exon8)C>T(p.Q823*,392)杂合无义变异,其父母均无该基因变异,为新生变异;患儿8的ZEB2基因上存在c.1961A>C(p.D654A)杂合错义变异,变异来源尚不明确。有3种变异(p.C1060Y、p.D654A、p.Q823*,392)此前未见报道。按照ACMG指南,2种错义突变分别被评估为可能致病性变异(p.C1060Y)和意义不明变异(p.D654A),其余6种变异均被评级为致病性变异。结论MWS患儿的临床特点为智力发育迟缓、特殊面容、癫痫、矮小症及各种先天性畸形,慢性肾脏病表型为首次报道;遗传学特点为患儿ZEB2基因上存在杂合变异,多数变异为新生变异,少数变异来源不明确。

Objective To summarize the clinical characteristics of Mowat-Wilson syndrome(MWS)in children,and to understand the genetic variation and inheritance of the disease.Methods The clinical data of 8 children with MWS admitted to Nanjing Children's Hospital Affiliated to Nanjing Medical University from January 2017 to December 2022 were analyzed retrospectively.Results Eight patients had developmental delay,unusual facies and congenital malformations(such as congenital heart disease,skeletal malformation,congenital megacolon,renal abnormalities,etc.).Patient 1 carried a de novo heterozygous frameshift variant of ZEB2 gene[c.2350_c.2351insT(p.S784F*11)],which was not found in his parents;patient 2 carried a de novo heterozygous nonsense variant in the ZEB2 gene[c.1150C>T(p.Q384*,831)],which was not found in his parents;a same heterozygous nonsense variant of ZEB2 gene was detected in patients 3 and 6[c.2073G>A(p.W691*,524)],while it was not found in their parents;patient 4 carried a de novo heterozygous missense variant in the ZEB2 gene[c.3179G>A(p.C1060Y)],which was not found in his parents;patient 5 carried a de novo heterozygous nonsense variant in the ZEB2 gene[c.904C>T(p.R302*,913)],which was not found in his parents;patient 7 carried a de novo heterozygous nonsense variant in the ZEB2 gene[c.2467C>T(p.Q823*,392)],which was not found in his parents;patient 8 had a heterozygous missense variation in the ZEB2 gene[c.1961A>C(p.D654A)],and the source of the variation was not clear.Three variants had not been reported previous-ly(p.C1060Y,p.D654A,and p.Q823*,392).According to the ACMG guidelines,two missense mutations were evaluat-ed as likely pathogenic(p.C1060Y)variants with unknown significance(p.D654A),while the remaining six variants were rated as pathogenic variants.Conclusions MWS patients are characterized by mental retardation,special facies,epilepsy,short stature and various congenital malformations.The phenotype of chronic kidney disease is reported for the first time.The genetic characteristics are heterozygous variations on ZEB2 gene,most of the variants are neonatal variants,and the origin of a few variants is unclear.