Zhang Liming, Wu Xue, Yang Jianwei, Sun Hongqi, Yang Junmei, Chen Yongxing
Department of Endocrine Genetics and Metabolism, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450018, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Mar 10;42(3):343-348. doi: 10.3760/cma.j.cn511374-20240229-00131.
To explore the clinical features, genetic characteristics in a child with Miller-McKusick-Malvaux syndrome (3MS) type 1 caused by CUL7 gene variant.
A child diagnosed with 3MS type 1 at the Children's Hospital Affiliated to Zhengzhou University in February 2021 was selected as the subject of this study. Peripheral blood samples were collected from the child and her parents for genomic DNA extraction. Whole exome sequencing (WES) was performed on the child, and Sanger sequencing was used to validate the candidate variants and analyze their pathogenicity. A literature search was conducted using the keywords "3M syndrome" in the China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and PubMed databases from inception to December 2024. The clinical data of Chinese children with 3MS reported in the literature were summarized. This study was approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University (Ethics No. 2024-K-020).
The child was a 6-year-old and 2-month-old female with facial dysmorphism, skeletal abnormalities, and growth and developmental delay. WES revealed compound heterozygous variants in the CUL7 gene: c.2686G>T (p.E896*) and c.1200delT (p.R401Gfs66). Sanger sequencing confirmed that these two variants were inherited from the child's father and mother, respectively. According to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants, c.2686G>T (p.E896) was classified as a pathogenic (PVS1+PM2_Supporting+PM3), and c.1200delT (p.R401Gfs*66) was classified as a likely pathogenic (PVS1+PM2_Supporting). Based on the literature search strategy, 18 relevant articles were identified, including a total of 32 Chinese cases of 3MS, of which 8 were fetuses. A total of 32 Chinese 3MS cases were included in the literature review, of which 8 were fetuses. The majority of these cases carried variants in the CUL7 gene (20/32, 62.5%) and OBSL1 gene (12/32, 37.5%). The main clinical manifestations included intrauterine or postnatal growth and developmental delay (32/32, 100.0%), triangular facies (27/32, 84.3%), and skeletal abnormalities (21/32, 65.6%).
The compound heterozygous variants c.2686G>T (p.E896*) and c.1200delT (p.R401Gfs*66) in the CUL7 gene are likely the genetic cause of 3MS type 1 in the child. For children presenting with facial dysmorphism, skeletal abnormalities, and intrauterine or postnatal growth and developmental delay, 3MS should be considered as a differential diagnosis.
探讨1型米勒-麦库西克-马尔沃克斯综合征（3MS）患儿由CUL7基因变异引起的临床特征及遗传特点。
选取2021年2月在郑州大学附属儿童医院诊断为1型3MS的一名患儿作为本研究对象。采集患儿及其父母的外周血样本用于提取基因组DNA。对患儿进行全外显子组测序（WES），并采用桑格测序法验证候选变异位点并分析其致病性。使用关键词“3M综合征”在中国知网、万方数据知识服务平台和PubMed数据库中进行检索，检索时间从建库至2024年12月。总结文献中报道的中国3MS患儿的临床资料。本研究经郑州大学附属儿童医院医学伦理委员会批准（伦理编号：2024-K-020）。
该患儿为6岁2个月女童，有面部畸形、骨骼异常及生长发育迟缓。WES显示CUL7基因存在复合杂合变异：c.2686G>T（p.E896*）和c.1200delT（p.R401Gfs66）。桑格测序证实这两个变异位点分别遗传自患儿的父亲和母亲。根据美国医学遗传学与基因组学学会（ACMG）序列变异解读标准与指南，c.2686G>T（p.E896）被分类为致病性变异（PVS1+PM2_Supporting+PM3），c.1200delT（p.R401Gfs*66）被分类为可能致病性变异（PVS1+PM2_Supporting）。基于文献检索策略，共鉴定出18篇相关文章，包括32例中国3MS病例，其中8例为胎儿。文献综述共纳入32例中国3MS病例，其中8例为胎儿。这些病例中大多数携带CUL7基因变异（20/32，62.5%）和OBSL1基因变异（12/32，37.5%）。主要临床表现包括宫内或出生后生长发育迟缓（32/32，100.0%）、三角形面容（27/32，84.3%）和骨骼异常（21/32，65.6%）。
CUL7基因中的复合杂合变异c.2686G>T（p.E896*）和c.1200delT（p.R401Gfs*66）可能是该患儿1型3MS的遗传病因。对于出现面部畸形、骨骼异常及宫内或出生后生长发育迟缓的患儿，应考虑将3MS作为鉴别诊断。
