Prenatal clinical manifestations in individuals with COL4A1/2 variants
Prenatal clinical manifestations in individuals with COL4A1/2 variants
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DOI：
10.1136/jmedgenet-2020-106896
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发表时间：
2021-08-01
影响因子：
4
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
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作者：
Itai, Toshiyuki;Miyatake, Satoko;Matsumoto, Naomichi
IV型胶原蛋白基因（COL4A1/2）的变异导致早发性脑血管疾病。大多数个体是在出生后被诊断出来的，COL4A1/2变异个体的产前特征尚不清楚。方法对218例疑似COL4A1/2相关脑缺陷患者进行COL4A1/2检测。在由COL4A1/2变异引起的病例中，我们将重点放在显示产前超声异常的个体上，并详细验证其产前和产后临床特征。结果56例（n=56/218, 25.7%）患者中检出致病性COL4A1/2变异，表现为脑孔畸形（n=29）、脑裂畸形（n=12）及其他畸形（n=15）。34个变异从头发生（n=34/56, 60.7%）。56例中有47例有胎儿信息，其中32例（n=32/47, 68.1%）有一个或多个胎儿异常。在最初的产前异常特征检测的中位胎龄为31周妊娠。只有14个人的特定产前发现强烈暗示了与COL4A1/2变异相关的特征。胎儿心室肿大是最常见的初始特征（n=20/ 32,62.5%）。后窝畸形，包括Dandy-Walker畸形，在产前观察到四个个体。关于脑外特征，16例胎儿生长受限，包括8例合并脑室肿大。结论对脑室肿大合并胎儿生长受限的产前观察，应进行彻底的超声检查，强烈怀疑致病变异时应考虑COL4A1/2基因检测。
Background Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. Methods We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. Results Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. Conclusions Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.