Aberrant Splicing Caused by Compound Heterozygous Variants in WDR35 Identified in a Fetus With Cranioectodermal...

Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is a rare autosomal recessive ciliopathy with significant involvement of the skeleton, ectoderm, retina, kidneys, liver, lungs, and occasionally the brain. Cranioectodermal dysplasia-2 (CED2) is caused by homozygous or compound heterozygous mutation in the WD repeat-containing protein 35 (WDR35). However, the current understanding of the CED2 prenatal phenotype is limited. Here, we describe the fetus at 12 + 4 weeks gestation from a Chinese family with healthy parents. The fetus presented with lymphedema, omphalocele, hydrops fetalis, abnormal posturing, hypoplasia of the ulna, hypoplasia of the radius, femoral bowing, short femur, ductus venosus agenesis, ventricular septal defect, and atrial septal defect. To our knowledge, apart from lymphedema and hydrop fetalis, no other phenotypes of the fetus described in this study have been reported in the CED2 prenatal phenotype. Compound heterozygous variants (c.3155-1G>A and c.215-8T>G) in the WDR35 were identified via trio-based exome sequencing and confirmed pathogenicity through mRNA splicing analysis in vivo. Collectively, we clarified the genetic diagnosis for the fetus with multiple ultrasound abnormalities, which is helpful for genetic counseling and early prenatal diagnosis. Meanwhile, a definitive genetic diagnosis could aid in assessing the risk of recurrence during reproduction and support further pre-implantation or prenatal diagnoses for the family. Additionally, the novel c.3155-1G>A variant expands the spectrum of WDR35 variants. The presence of omphaloceles, abnormal posturing, hypoplasia of the ulna, hypoplasia of the radius, femoral bowing, short femur, ductus venosus agenesis, ventricular septal defect, and atrial septal defect in fetus with WDR35 variants may expand the prenatal phenotypic spectrum of CED2.