耳-腭-指综合征1型新生儿围产期临床特征和遗传特点分析

doi:10.3969/j.issn.1673-8640.2022.08.002

检验医学 ›› 2022, Vol. 37 ›› Issue (8): 710-714.DOI: 10.3969/j.issn.1673-8640.2022.08.002

耳-腭-指综合征1型新生儿围产期临床特征和遗传特点分析

赵旭亮¹, 田瑞霞², 李旭³, 贾建安⁴, 俞敏², 朱复希¹()

1.安徽医科大学第一附属医院妇产科生殖医学中心,安徽合肥 230022
2.中国人民解放军联勤保障部队第901医院妇产科,安徽合肥 230031
3.安徽省儿童医院磁共振室,安徽合肥 230051
4.中国人民解放军联勤保障部队第901医院检验科,安徽合肥 230031

收稿日期:2021-02-25 修回日期:2022-05-18 出版日期:2022-08-30 发布日期:2022-09-16
通讯作者: 朱复希
作者简介:朱复希,E-mail： fxzhu@163.com。
赵旭亮,男,1987年生,学士,主管技师,主要从事遗传缺陷和分子诊断研究。
基金资助:
安徽省自然科学基金资助项目(1908085J28)

Analysis of perinatal clinical features and genetic characteristics of a neonate with otopalatodigital syndrome type 1

ZHAO Xuliang¹, TIAN Ruixia², LI Xu³, JIA Jian'an⁴, YU Min², ZHU Fuxi¹()

1. Reproductive Medicine Center,Department of Obstetrics,the First Affiliated Hospital of Anhui Medical University,Hefei 230022,Anhui,China
2. Department of Obstetrics and Gynecology,the No. 901 Hospital of the Joint Service of the People's Liberation Army,Hefei 230031,Anhui,China
3. Magnetic Resonance Imaging Room,Anhui Provincial Children's Hospital,Hefei 230051,Anhui,China
4. Department of Clinical Laboratory,the No. 901 Hospital of the Joint Service of the People's Liberation Army,Hefei 230031,Anhui,China

Received:2021-02-25 Revised:2022-05-18 Online:2022-08-30 Published:2022-09-16
Contact: ZHU Fuxi

摘要/Abstract

摘要：

目的对1例耳-腭-指综合征1型（OPD1）患儿围产期的临床特征和遗传特点进行分析,提高临床对此类罕见病的认识。方法收集1例OPD1患儿的临床资料,对患儿及其父母进行全外显子家系测序（Trio-WES）。采用Sanger测序对变异位点进行验证。采用生物信息学分析评估变异位点的危害性。结合文献对细丝蛋白A（FLNA）基因热点变异患儿的临床特征进行回顾性分析。结果产前超声提示患儿小下颌、鼻梁塌陷、脊椎排列异常、双足第2趾长,出生后患儿具有眼距较宽、眼睑裂倾斜、鼻梁塌陷、下颌后缩、耳位低且右耳可见副耳、双足第2趾明显长于其余4趾的体貌特征。基因检测结果提示患儿FLNA基因发生杂合变异（c.620C>T/p.Pro207Leu）,患儿母亲存在该位点变异,父亲基因型为野生型。文献回顾分析结果显示,FLNA基因c.620C>T/p.Pro207Leu是导致OPD1的热点变异,携带该变异的患者可表现为眼距宽、眼睑裂倾斜、小下颌、腭裂、不同类型的指（趾）骨畸形、听力下降等临床特征。结论 FLNA基因c.620C>T/p.Pro207Leu变异可导致OPD1的发生。结合家系资料分析、产前超声检查和家系基因分析是诊断耳-腭-指谱系障碍（OPDSD）并进一步分型的有效方法。

关键词: 细丝蛋白A, 耳-腭-指综合征1型, 耳-腭-指谱系障碍

Abstract:

Objective To investigate the perinatal clinical features and genetic characteristics of a neonate with otopalatodigital syndrome type 1（OPD1）,and to improve the clinical understanding of such rare diseases. Methods The clinical data of a neonate with OPD1 was collected. The genes of the neonate and his parents were determined by trio-whole exome sequencing（Trio-WES）. Variation sites were verified by Sanger sequencing. The biohazard of gene mutation was analyzed by relevant prediction software. The clinical features of the neonate with filamin A（FLNA） gene hot spot mutation were analyzed retrospectively. Results Prenatal ultrasound showed that the fetal had clinical manifestations such as micrognathia,nasal collapse,abnormal spinal alignment and the length of the second toes of both feet. After birth,the case had a special appearance of ocular hypertelorism,collapsed nasal bridge and wide nasal root,small mandible and backward retraction,low ear position and accessory ear. The results of gene test showed that the FLNA gene had heterozygous mutation（c.620C>T/p.Pro207Leu）,his mother carried the same variant,and his father has wild type. Literature reviewing showed that FLNA gene c.620C>T/p.Pro207Leu was the hot spot variant causing to OPD1. The high frequency phenotypes of the mutation was ocular hypertelorism,eyelid cleft,micrognathia,cleft palate,different types of finger（toe） deformity and hearing loss. Conclusions OPD1 is caused by FLNA gene hot spot variant c.620C>T/p.Pro207Leu. The combination of family datum analysis,prenatal ultrasound and family gene analysis is an effective method for the diagnosis and further typing of otopalatodigital spectrum disorder（OPDSD）.

Key words: Filamin A, Otopalatodigital syndrome type 1, Otopalatodigital spectrum disorder

中图分类号:

R446.1

赵旭亮, 田瑞霞, 李旭, 贾建安, 俞敏, 朱复希. 耳-腭-指综合征1型新生儿围产期临床特征和遗传特点分析[J]. 检验医学, 2022, 37(8): 710-714.

ZHAO Xuliang, TIAN Ruixia, LI Xu, JIA Jian'an, YU Min, ZHU Fuxi. Analysis of perinatal clinical features and genetic characteristics of a neonate with otopalatodigital syndrome type 1[J]. Laboratory Medicine, 2022, 37(8): 710-714.

图/表 5

图1 患儿母亲孕40+2周产前超声影像注：（a）胎儿正常下颌的反“S”线征消失,下颌小且后缩,鼻梁塌陷;（b）胎儿脊柱胸椎第3~5椎体,正常椎体和椎弓骨化中心形成的前后平行排列的2条强回声带失去正常形态,排列紊乱;（c）胎儿足部第2趾明显长于其余4趾。

图2 患儿出生后的典型体貌特征注：（a）眼距较宽、眼睑裂倾斜、鼻梁塌且鼻根宽、下颌小且后缩;（b）低耳位,出现副耳;（c）足第2趾明显长于其余4趾。

图3 患儿FLNA基因变异位点Sanger测序验证结果注：患儿FLNA基因发生杂合变异c.620C>T/p.Pro207Leu,母亲携带该杂合变异,父亲基因型为野生型;红色箭头所指为变异位点。

图4 FLNA基因c.620C>T/p.Pro207Leu变异位点危害性分析注：（a）FLNA蛋白第207号脯氨酸在不同物种间高度保守（蓝色箭头）;（b）FLNA蛋白二聚体结构简图,N-端肌动蛋白结合域由钙调节蛋白同源结构域（calponin homology domain,CHD）1及CHD2组成,可与F-肌动蛋白结合,并具有信号转导功能;本例患儿变异位点c.620C>T/p.Pro207Leu位于CHD2区域,可与第203号天冬氨酸（Asp-203）残基形成氢键,进而对结构稳定性产生局部影响。

表1 FLNA基因c.620C>T/p.Pro207Leu杂合变异患者及胎儿临床特征

病例	性别	确诊时间	眼距较宽	眼睑裂倾斜	鼻梁塌	低耳位	小下颌	腭裂	指（趾）骨畸形	脊椎侧弯	听力下降
本例患儿	男	出生1 d	+	+	+	+	+	-	+	+
病例1^[5]	男	孕36周	+	+	+	+	+	-	+	-
病例2^[5]	男	孕22周	+	+	+	+	+	-	+	+
病例3^[6]	男	6个月	+	-	-	-	-	-	+	-	+
病例4^[6]	男	1个月	+	+	-	-	-	+	+	-	+
病例5^[7]	男	11岁	+	-	+	+	-	+	+	-	+
病例6^[7]	男	出生1 d	+	+	+	+	-	+	+	-	+

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耳-腭-指综合征1型新生儿围产期临床特征和遗传特点分析

Analysis of perinatal clinical features and genetic characteristics of a neonate with otopalatodigital syndrome type 1

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