Clinical features
EBF3-related HADD syndrome is a syndromic neurodevelopmental disorder with multi-system involvement. It is characterized by hypotonia, developmental delay, impaired coordination, ataxia, facial dysmorphisms, behavioral features, congenital urogenital malformations, and cerebellar vermian hypoplasia.
Prevalence
EBF3-related HADDS was initially recognized in 2016 with 21 individuals reported across three studies (Chao et al. 2017; Harms et al. 2017; Sleven et al. 2017). Additional individuals were reported across three studies (Blackburn et al. 2017; Lopes et al. 2017; Tanaka et al. 2017). In a model of de novo mutations for autism spectrum disorder and intellectual disability, the statistical analysis identified EBF3 as one of ~1,000 genes that significant lack functional variation in non-ASD individuals but are enriched with de novo loss-of-function mutations in affected individuals (Samocha et al. 2017). More studies are needed to determine an unbiased prevalence of the syndrome.
Inheritance
EBF3-related HADDS, caused by an EBF3 gene deletion or variant, is inherited in an autosomal dominant manner. To date the majority of cases, result from a de novo EBF3 deletion or variant. Most affected individuals represent simplex cases (i.e. a single occurrence in a family). Adults with EBF3-related HADDS have been identified who transmitted their gene variant to similarly affected offspring. A few causes of parental mosaicism have also been identified. The recurrence risk for future pregnancies is low (<1%), but greater than that of the general population because of the possibility of germline mosaicism in one of the parents. Prenatal testing is technically feasible, but the likelihood of recurrence in families who have an affected child is low.