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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

Authors :
Yiping Shen
Weiliang Lu
Mengting Li
Shang Yi
Zailong Qin
Limei Huang
Sheng Yi
Qi Yang
Xunzhao Zhou
Fei Chen
Jingsi Luo
Jiasun Su
Qiang Zhang
Source :
Molecular Genetics & Genomic Medicine, Molecular Genetics & Genomic Medicine, Vol 9, Iss 4, Pp n/a-n/a (2021)
Publication Year :
2021

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.<br />We identified a fetus with a Novel compound heterozygous frameshift variants in WDR81(c.146_147insG (p.Thr52fs) and c.673delC (p.Leu225fs)) presented with the main Congenital hydrocephalus 3 with brain anomalies (HYC3). This was a first Chinese prenatal case with HYC3 phenotype carried the WDR81 pathogenic variants detected by whole‐exon sequencing.

Details

ISSN :
23249269
Volume :
9
Issue :
4
Database :
OpenAIRE
Journal :
Molecular geneticsgenomic medicine
Accession number :
edsair.doi.dedup.....cf77858be37a01e79e16966c7ad885fa