背景:后颅窝畸形(PFM)是一种相对罕见的产前脑畸形。基因诊断方法,包括染色体核型分析,拷贝数变异(CNV)测试,和全外显子组测序(WES),已应用于几例胎儿结构畸形。然而,对不同类型的PFM采用适当的基因诊断方法的临床价值尚未得到证实.因此,在这项研究中,我们旨在分析不同的联合基因诊断方法对不同类型胎儿PFMs的价值。
方法:这项回顾性研究在北京妇产医院进行,首都医科大学,北京妇幼保健院.纳入从2017年1月1日至2022年12月31日在我院接受基因检测的51例被诊断为胎儿PFM的孕妇;排除了孤立的大水箱的妇女。根据其他异常的存在将所有参与者分为两组:孤立和非孤立的PFM组。不同的组合方法,包括核型分析,CNV测试,和基于三人的WES,用于遗传分析。核型分析的检出率,CNV测试,在分离和非分离组中测量WES。
结果:在孤立的PFMs中,4例检出致病性/可能致病性(P/LP)CNVs(36.36%,4/11),而G显带核型分析和WES显示阴性结果。在非孤立的PFMs中,序贯遗传学方法的检出率为47.5%(19/40);核型分析显示5例非整倍体(16.67%,5/30),CNV检测显示5例患者的P/LPCNVs(16.13%,5/31),和WES鉴定的P/LP变体(在基因CEP20,TMEM67,OFD1,PTPN11,ARID1A,和SMARCA4)在9例(40.91%,9/22)。WES在Joubert综合征胎儿中的检出率为83.33%(5/6)。只有6例患者(5例Blake囊囊肿和1例单侧小脑半球发育不良)存活。
结论:我们建议对具有分离的PFM的胎儿进行CNV检测。顺序遗传方法(核型分析,CNV测试,和WES)可能对具有非隔离的PFM的胎儿有益。特别是,我们推荐WES作为Joubert综合征的一线基因诊断工具.
BACKGROUND: Posterior fossa malformation (PFM) is a relatively uncommon prenatal brain malformation. Genetic diagnostic approaches, including chromosome
karyotyping, copy number variant (CNV) testing, and whole-exome sequencing (WES), have been applied in several cases of fetal structural malformations. However, the clinical value of appropriate genetic diagnostic approaches for different types of PFMs has not been confirmed. Therefore, in this study, we aimed to analyze the value of different combined genetic diagnostic approaches for various types of fetal PFMs.
METHODS: This retrospective study was conducted at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital. Fifty-one pregnant women diagnosed with fetal PFMs who underwent genetic testing in our hospital from January 1, 2017 to December 31, 2022 were enrolled; women with an isolated enlarged cisterna magna were excluded. All participants were categorized into two groups according to the presence of other abnormalities: isolated and non-isolated PFMs groups. Different combined approaches, including karyotype analysis, CNV testing, and trio-based WES, were used for genetic analysis. The detection rates of karyotype analysis, CNV testing, and WES were measured in the isolated and non-isolated groups.
RESULTS: In isolated PFMs, pathogenic/likely pathogenic (P/LP) CNVs were detected in four cases (36.36%, 4/11), whereas G-banding
karyotyping and WES showed negative results. In non-isolated PFMs, a sequential genetic approach showed a detection rate of 47.5% (19/40);
karyotyping revealed aneuploidies in five cases (16.67%, 5/30), CNV testing showed P/LP CNVs in five cases (16.13%, 5/31), and WES identified P/LP variants (in genes CEP20, TMEM67, OFD1, PTPN11, ARID1A, and SMARCA4) in nine cases (40.91%, 9/22). WES showed a detection rate of 83.33% (5/6) in fetuses with Joubert syndrome. Only six patients (five with Blake\'s pouch cyst and one with unilateral cerebellar hemisphere dysplasia) survived.
CONCLUSIONS: We recommend CNV testing for fetuses with isolated PFMs. A sequential genetic approach (
karyotyping, CNV testing, and WES) may be beneficial in fetuses with non-isolated PFMs. Particularly, we recommend WES as the first-line genetic diagnostic tool for Joubert syndrome.