染色体微阵列分析在胎儿颅面畸形遗传病因诊断中的应用

doi:10.12280/gjszjk.20230489

摘要/Abstract

摘要：

目的：利用染色体微阵列分析（chromosomal microarray analysis，CMA）技术明确胎儿颅面畸形（craniofacial malformations，CFMs）遗传病因。方法：选取2017年1月—2023年3月于福建省泉州市妇幼保健院（儿童医院）进行遗传学病因诊断的CFMs胎儿72例作为研究对象，其中46例为孤立性CFMs，其余26例合并其他结构异常（非孤立性CFMs）。72例CFMs胎儿的检测样本中，有45例为羊水标本，27例为流产组织标本。所有样本均进行了CMA检测，45例羊水标本还进行了核型分析。结果：在45例进行核型分析的病例中，2例诊断为染色体非整倍体（18-三体综合征和47,XXY），异常检出率为4.44%（2/45）。CMA分析检出4例染色体非整倍体、3例致病性拷贝数变异和11例临床意义不明拷贝数变异，阳性检出率为（9.72%，7/72）。非孤立性CFMs组的阳性检出率（26.92%，7/26）显著高于孤立性CFMs组（0.00%，P<0.001）。结论：产前超声提示胎儿CFMs，进一步行CMA检测有助于明确遗传病因。

关键词: 颅面畸形, 染色体微阵列分析, 核型分析, 病因诊断, DNA拷贝数变异

Abstract:

Objective: To explore the etiological genetics diagnosis of fetuses with craniofacial malformations (CFMs) using chromosomal microarray analysis (CMA). Methods: Enrolled in this study were 72 pregnancies with fetal CFMs who came to Quanzhou Women′s and Children′s Hospial for etiology diagnosis from January 2017 to March 2023. Among them, 46 cases had the isolated CFMs and 26 cases also had other structural anomalies. In addition, 45 cases performed amniocentesis and carried out karyotype analysis and CMA, and the rest 27 cases only conducted CMA using fetal abortive tissue. Results: In the 45 cases that performed karyotype analysis, a trisomy 18 and a 47,XXY were diagnosed, with an abnormal detection rate of 4.44% (2/45). In the total 72 enrolled subjects that conducted CMA, 4 cases of aneuploid, 3 cases of pathogenic copy number variants (pCNVs), and 11 cases of variants of unknown significance were diagnosed, with an abnormal detection rate of 9.72% (7/72). In addition, the sub-group study indicated that the abnormal detection rate in the non-isolated CFMs group was significantly higher than that in the isolated CFMs group (26.92% vs. 0.00%，P<0.001). Conclusions: For those fetuses with CFMs indicated by prenatal ultrasound, the subsequent CMA would be helpful to clarify the genetic etiology of CFMs.

Key words: Craniofacial malformations, Chromosomal microarray analysis, Karyotyping, Etiological diagnosis, DNA copy number variations

庄建龙, 许伟雄, 陈文莉, 江矞颖. 染色体微阵列分析在胎儿颅面畸形遗传病因诊断中的应用[J]. 国际生殖健康/计划生育杂志, 2024, 43(2): 95-100.

ZHUANG Jian-long, XU Wei-xiong, CHEN Wen-li, JIANG Yu-ying. Etiological Genetics Diagnosis of Fetal Craniofacial Malformations Using Chromosomal Microarray Analysis[J]. Journal of International Reproductive Health/Family Planning, 2024, 43(2): 95-100.

图/表 5

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超声异常	例数
口面裂	32
唇腭裂	27
腭裂	3
唇裂	2
颅骨畸形	8
小头畸形	3
颅骨形状异常	2
柠檬头型	2
草莓头型	1
耳畸形	7
眼畸形	6
鼻异常	6
颜面部异常	5
小下颌	4
前额异常	3
舌头异常	1

超声异常	例数
口面裂	32
唇腭裂	27
腭裂	3
唇裂	2
颅骨畸形	8
小头畸形	3
颅骨形状异常	2
柠檬头型	2
草莓头型	1
耳畸形	7
眼畸形	6
鼻异常	6
颜面部异常	5
小下颌	4
前额异常	3
舌头异常	1

序号	CMA结果	片段大小	来源	致病性判读	超声结果	妊娠结局随访
1	arr[GRCh37]13q31.3q34 (92,396,250-115,107,733)×4	22.7 Mb	/	致病	左侧眼球小并左侧晶状体增粗，胼胝体发育不良，小脑发育不良并蚓部缺失，双侧手指姿势异常固定	终止妊娠
2	arr[GRCh37]11q23.3q25(116,683, 755-134,937,416)×3,22q11.1q11.21 (16,888,900-20,312,661)×3	18.2 Mb； 3.4 Mb	/	致病	唇腭裂，室间隔缺损，颈部褶皱，小下颌，右侧面颊部肌性小突起	终止妊娠
3	arr[GRCh37]11p15.5p15.4 (230,751-9,983,403)×2 hmz	9.7 Mb	/	致病	口舌姿势异常，肠道强回声，心包少量积液，双肾偏大，右肾肾柱过长	终止妊娠

序号	CMA结果	片段大小	来源	致病性判读	超声结果	妊娠结局随访
1	arr[GRCh37]13q31.3q34 (92,396,250-115,107,733)×4	22.7 Mb	/	致病	左侧眼球小并左侧晶状体增粗，胼胝体发育不良，小脑发育不良并蚓部缺失，双侧手指姿势异常固定	终止妊娠
2	arr[GRCh37]11q23.3q25(116,683, 755-134,937,416)×3,22q11.1q11.21 (16,888,900-20,312,661)×3	18.2 Mb； 3.4 Mb	/	致病	唇腭裂，室间隔缺损，颈部褶皱，小下颌，右侧面颊部肌性小突起	终止妊娠
3	arr[GRCh37]11p15.5p15.4 (230,751-9,983,403)×2 hmz	9.7 Mb	/	致病	口舌姿势异常，肠道强回声，心包少量积液，双肾偏大，右肾肾柱过长	终止妊娠

序号	CMA结果	片段大小	来源	致病性判读	超声结果	妊娠结局随访
1	arr[GRCh37]17q11.2(29,104,296-30,249,530)×3	1.1 Mb	/	VOUS	唇腭裂	继续妊娠
2	arr[GRCh37]13q31.1q31.3(87674122-90306265)×3	2.6 Mb	/	VOUS	眼距宽，FGR，左手大拇指短，颅缝早闭，小耳畸形，室间隔缺损	终止妊娠
3	arr[GRCh37]6q22.1q22.31(118,049,152-119,335,244)×3	1.2 Mb	/	VOUS	唇腭裂，全前脑，喙鼻	终止妊娠
4	arr[GRCh37]16p13.12p12.3(14,764,953-16,858,332)×1	2.0 Mb	新发	VOUS	唇腭裂	终止妊娠
5	arr[GRCh37]14q13.2q21.3(35,428,813-49,221,239)×2 hmz	13.7 Mb	/	VOUS	耳廓异常，室间隔缺损，胎儿生长发育受限，羊水偏多	终止妊娠
6	arr[GRCh37]8q24.11(118,225,220-118,884,779)×3	659.5 Kb	/	VOUS	小下颌	继续妊娠
7	arr[GRCh37]9q33.1q34.11(118,633,242-130,783,340)×2 hmz	12.1 Mb	/	VOUS	唇裂	终止妊娠
8	arr[GRCh37]2q13(110,873,835-110,980,295)×1	106.4 Kb	/	VOUS	唇腭裂	终止妊娠
9	arr[GRCh37]13q31.3(92,045,579-94,558,980)×3	2.5 Mb	/	VOUS	唇腭裂	终止妊娠
10	arr[GRCh37]14q11.2(23,264,097-23,520,626)×1	256.5 Kb	/	VOUS	双侧耳廓异常	继续妊娠
11	arr[GRCh37]2p16.1p15(60,273,431-62,216,924)×3,7p14.1 (39,593,488-40,397,573)×3	1.9 Mb； 804.0 Kb	/	VOUS	颜面轮廓稍扁平；胎儿冠状静脉窦增宽，永存左上腔静脉	终止妊娠