Guangxi Health Commission Key Laboratory of Precise Diagnosis and Treatment of Genetic Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
Genetic and Metabolic Central Laboratory, Guangxi Birth Defects Research and Prevention Institute, Nanning, China.
Mol Genet Genomic Med. 2021 Apr;9(4):e1624. doi: 10.1002/mgg3.1624. Epub 2021 Mar 16.
Congenital hydrocephalus-3 with brain anomalies (HYC3, MIM 617967) is a rare form of congenital hydrocephalus characterized by severe hydrocephalus and cerebellar abnormalities, the onset of the disease occurs in utero even resulting in fetal death. A very limited spectrum of WDR81 pathogenic variants had been reported in three unrelated families with HYC3. This study aims at presenting novel compound heterozygous frameshift variants in WDR81 in a Chinese fetus.
Whole-exome sequencing (WES) was performed for a fetus with multiple congenital anomalies including sever hydrocephalus, cleft lip and palate, hydrops fetalis, hepatomegaly, and cerebellar hypoplasia. Sanger sequencing was performed to confirm the origin of the variants subsequently. Variants classification was based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.
Two novel heterozygous variants c.146_147insG (p.Thr52fs) and c.673delC (p.Leu225fs) in WDR81 were identified. Sanger sequencing revealed that the c.146_147insG mutation was maternal origin and the c.673delC mutation was paternal origin. Both variants were pathogenic according to the ACMG/AMP guidelines.
The present study expands the mutation spectrum of WDR81 and help further define the genotype-phenotype correlations of HYC3. WDR81-related HYC3 were highly clinical heterogeneity. We suggested that fetal hydrocephalus with extracerebral manifestations may be suggestive of WDR81 deficiency and WES is effective for achieving a conclusive diagnosis for disorder.
伴有脑畸形的先天性脑积水-3 型（HYC3，MIM 617967）是一种罕见的先天性脑积水形式，其特征为严重的脑积水和小脑异常，疾病的发病始于宫内，甚至导致胎儿死亡。在三个不相关的 HYC3 家族中，已经报道了非常有限的 WDR81 致病变异谱。本研究旨在报道一例中国胎儿中 WDR81 的新型复合杂合框移变异。
对一例伴有多种先天性异常的胎儿进行全外显子组测序（WES），这些异常包括严重的脑积水、唇腭裂、胎儿水肿、肝肿大和小脑发育不良。随后进行 Sanger 测序以确认变异的来源。变异分类基于美国医学遗传学与基因组学学院/分子病理学协会（ACMG/AMP）指南。
在 WDR81 中发现了两个新的杂合突变 c.146_147insG（p.Thr52fs）和 c.673delC（p.Leu225fs）。Sanger 测序显示 c.146_147insG 突变来自母体，c.673delC 突变来自父体。根据 ACMG/AMP 指南，这两个变异均为致病性的。
本研究扩展了 WDR81 的突变谱，并有助于进一步确定 HYC3 的基因型-表型相关性。WDR81 相关的 HYC3 具有高度的临床异质性。我们建议，伴有颅外表现的胎儿脑积水可能提示存在 WDR81 缺陷，WES 是实现该疾病明确诊断的有效方法。
