Hydrocephalus, Congenital, 3, With Brain Anomalies

A number sign (#) is used with this entry because of evidence that congenital hydrocephalus-3 with brain anomalies (HYC3) is caused by homozygous mutation in the WDR81 gene (614218) on chromosome 17p13.

For a discussion of genetic heterogeneity of congenital hydrocephalus, see 236600.

Clinical Features

Shaheen et al. (2017) reported 2 unrelated consanguineous Saudi families (families 13 and 26) in which at least 5 patients, including a pair of twins, had hydrocephalus apparent in utero. In the first family, the twin gestation was terminated at 18 weeks based on prenatal findings of severe hydrocephalus, a second conception showed significantly enlarged ventricles and hypoplastic cerebellum, and a third pregnancy resulted in delivery of a similarly affected fetus at age 28 weeks due to preeclampsia; this infant died 2 hours after birth. In the second family, the mother had a history of stillbirth associated with polyhydramnios, hydranencephaly, and absent cerebellum. A subsequent pregnancy resulted in delivery of a male infant with holoprosencephaly, absent cerebellum, Dandy-Walker malformation, hydrocephaly, brain atrophy, and dysmorphic facial features.

Inheritance

The transmission pattern of HYC3 in the families reported by Shaheen et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated patients, each conceived of consanguineous Saudi parents (families 13 and 26), with congenital hydrocephalus, Shaheen et al. (2017) identified homozygous mutations in the WDR81 gene (Q1096X, 614218.0003 and G282E, 614218.0004). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Segregation of the disorder with the genotype was demonstrated for 1 family. Both families had histories of additional similarly affected pregnancies, but DNA from those patients was not available. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated a loss-of-function effect. The patients were part of a large genetic study of 27 consanguineous Saudi families with congenital hydrocephalus.