1q21.1远端微缺失/微重复综合征合并先天性心脏病4例临床及遗传学分析

doi:10.12280/gjszjk.20240304

摘要/Abstract

摘要：

目的：探讨染色体拷贝数变异测序（copy number variation sequencing，CNV-seq）诊断1q21.1远端微缺失/微重复综合征合并先天性心脏病（congenital heart disease，CHD）的临床应用价值，并对此类患者进行临床及遗传学分析。方法：回顾性分析4例就诊于甘肃省妇幼保健院，经CNV-seq诊断为1q21.1微缺失/微重复综合征合并CHD患儿的临床及遗传学特征。结果：4例1q21.1微缺失/微重复综合征合并CHD患儿染色体CNV重叠区域为chr1:g.146520000-147840000，包含心脏相关的基因有CAJ5、CAJ8、PPKAB2、CHD1L和BCL9等。1例1q21.1微重复患儿还表现为小下颌、舌后坠、上颌腭裂的多发畸形和泌尿系统的发育异常，3例1q21.1微缺失患儿中有2例表现出严重的生长发育迟缓（其中1例伴有严重的智力障碍、肌张力减低和小阴茎，1例特殊面容），1例患儿已行CHD手术，预后良好。结论：CHD合并发育迟缓和（或）特殊面容是1q21.1微缺失/微重复综合征低龄患儿的重要表型，此类表型患儿有必要做染色体CNV-seq检测，为进一步临床诊治提供理论依据。

关键词: DNA拷贝数变异, 全基因组测序, 染色体缺失, 染色体重复, 心脏缺损, 先天性

Abstract:

Objective: To analyze the clinical and genetic characteristics of 1q21.1 distal microdeletion/microduplication syndrome combined with congenital heart disease (CHD) using chromosome copy number variation sequencing (CNV-seq). Methods: Retrospective analysis was conducted on the four pediatric patients diagnosed with 1q21.1 microdeletion/microduplication syndrome and CHD using CNV-seq at Gansu Provincial Maternity and Child Care Hospital. Results: The chromosomal CNV overlap region of 4 cases was identified as chr1:g.1465200000-147840000, the heart-related genes included CAJ5, CAJ8, PPKAB2, CHD1L, BCL9, etc. One child with microduplication displayed various concurrent anomalies including micromandible malformations, retrolingual fall, maxillary clefts as well as aberrant urinary system development. In three children with microdeletion, two out of three experienced significant growth retardation (one presenting severe intellectual impairment along with hypotonia and micropenis while another exhibited distinctive facial features), and one child underwent surgery for CHD during follow-up with a favorable prognosis. Conclusions: CHD in combination with developmental delay and/or distinctive facial features, represents a significant phenotype in young children affected by 1q21.1 microdeletion/duplication syndrome. It is imperative to identify chromosomal CNV in these individuals to provide theoretical basis for subsequent clinical diagnosis and treatment.

Key words: DNA copy number variations, Whole genome sequencing, Chromosome deletion, Chromosome duplication, Heart defects, congenital

何静, 王静, 蔺鹏武, 贾春暘, 朱韶华, 郝胜菊, 冯暄. 1q21.1远端微缺失/微重复综合征合并先天性心脏病4例临床及遗传学分析[J]. 国际生殖健康/计划生育杂志, 2024, 43(6): 462-466.

HE Jing, WANG Jing, LIN Peng-wu, JIA Chun-yang, ZHU Shao-hua, HAO Sheng-ju, FENG Xuan. Clinical and Genetic Analysis of 4 Cases of 1q21.1 Distal Microdeletion/Microduplication Syndrome Complicated with Congenital Heart Disease[J]. Journal of International Reproductive Health/Family Planning, 2024, 43(6): 462-466.

图/表 4

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病例	性别	就诊年龄	生长发育	认知/行为特征	心脏超声	其他	随访
1	男	1 d	多发畸形	-	卵圆孔未闭，房间隔缺损，动脉导管未闭，大动脉水平左向右分流、三尖瓣少量返流	左右肾超声异常、硬腭裂、新生儿肺炎、明显三凹征	要求出院，3 d后夭折
2	男	4岁10个月	小头畸形、严重生长发育迟缓、阴茎短小	重度智力障碍、言语简单	房间隔缺损	全身四肢肌张力减低明显，原始神经反射减弱	CHD未治疗、瘫痪、重度智力障碍
3	女	5 d	正常	未见异常	室间隔缺损、房间隔缺损	右肾肾盂分离5 mm	1岁时行室间隔和房间隔缺损修补术，预后良好
4	女	11个月	生长发育迟缓、小头畸形、特殊面容	未见异常	卵圆孔未闭，房间隔缺损	无	CHD未治疗、发育迟缓

病例	性别	就诊年龄	生长发育	认知/行为特征	心脏超声	其他	随访
1	男	1 d	多发畸形	-	卵圆孔未闭，房间隔缺损，动脉导管未闭，大动脉水平左向右分流、三尖瓣少量返流	左右肾超声异常、硬腭裂、新生儿肺炎、明显三凹征	要求出院，3 d后夭折
2	男	4岁10个月	小头畸形、严重生长发育迟缓、阴茎短小	重度智力障碍、言语简单	房间隔缺损	全身四肢肌张力减低明显，原始神经反射减弱	CHD未治疗、瘫痪、重度智力障碍
3	女	5 d	正常	未见异常	室间隔缺损、房间隔缺损	右肾肾盂分离5 mm	1岁时行室间隔和房间隔缺损修补术，预后良好
4	女	11个月	生长发育迟缓、小头畸形、特殊面容	未见异常	卵圆孔未闭，房间隔缺损	无	CHD未治疗、发育迟缓

病例	CNV-seq结果	片段大小	变异类型	覆盖区域	变异来源
1	seq[hg19]dup(1)(q21.1-q21.2)	1.32 Mb	重复	约97% 1q21.1	未知
	chr1:g.146520000-147840000			微重复综合征
2	seq[hg19]del(1)(q21.1-q21.2)	2.74 Mb	缺失	1q21.1微缺失综	未知
	chr1:g.146500000-149240000			合征全部区域
3	seq[hg19]del(1)(q21.1q21.2)	1.34 Mb	缺失	约97% 1q21.1	自发突变
	chr1:g.146500001-147840000			微缺失综合征
4	seq[hg19]del(1)(q21.1q21.2)	2.12 Mb	缺失	约97% 1q21.1	未知
	chr1:g.145720000-147840000			微缺失综合征

病例	CNV-seq结果	片段大小	变异类型	覆盖区域	变异来源
1	seq[hg19]dup(1)(q21.1-q21.2)	1.32 Mb	重复	约97% 1q21.1	未知
	chr1:g.146520000-147840000			微重复综合征
2	seq[hg19]del(1)(q21.1-q21.2)	2.74 Mb	缺失	1q21.1微缺失综	未知
	chr1:g.146500000-149240000			合征全部区域
3	seq[hg19]del(1)(q21.1q21.2)	1.34 Mb	缺失	约97% 1q21.1	自发突变
	chr1:g.146500001-147840000			微缺失综合征
4	seq[hg19]del(1)(q21.1q21.2)	2.12 Mb	缺失	约97% 1q21.1	未知
	chr1:g.145720000-147840000			微缺失综合征