2. Academic Validation
  3. Novel compound heterozygous frameshift variants in WDR81 associated with congenital hydrocephalus 3 with brain anomalies: First Chinese prenatal case confirms WDR81 involvement

Novel compound heterozygous frameshift variants in WDR81 associated with congenital hydrocephalus 3 with brain anomalies: First Chinese prenatal case confirms WDR81 involvement

  • Mol Genet Genomic Med. 2021 Apr;9(4):e1624. doi: 10.1002/mgg3.1624.
Jiasun Su 1 2,  Weiliang Lu 1 2,  Mengting Li 1 2,  Qiang Zhang 1 2,  Fei Chen 1 2,  Shang Yi 1 2,  Qi Yang 1 2,  Sheng Yi 1 2,  Xunzhao Zhou 1 2,  Limei Huang 1 2,  Yiping Shen 1 2 3,  Jingsi Luo 1 2,  Zailong Qin 1 2
Affiliations

Affiliations

  • 1 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.
  • 2 Genetic and Metabolic Central Laboratory, Guangxi Birth Defects Research and Prevention Institute, Nanning, China.
  • 3 Department of Genetics, Harvard Medical School, Boston, MA, USA.
PMID: 33724704 DOI: 10.1002/mgg3.1624
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords

WDR81; compound heterozygous frameshift variants; congenital hydrocephalus 3 with brain anomalies; prenatal.

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