Clinical features
EBF3-related HADD syndrome is a disorder characterized by low muscle tone (hypotonia), delayed development, impaired coordination, imbalance, facial dysmorphisms, behavioral features, and malformations of the brain and urogenital systems.
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 other 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 is caused by an EBF3 gene deletion or mutation affecting one copy of the gene. To date the majority of cases, result from an EBF3 deletion or variant that is not inherited from either parent. Most affected individuals represent a single occurrence in a family). Adults with EBF3-related HADDS have been identified who transmitted their gene mutation to similarly affected children. A few causes of parental mosaicism, where a small percentage of cells in the parent have the EBF3 mutation, 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 mosaicism in either the egg or sperm of one of the parents. Prenatal testing is technically feasible, but the likelihood of recurrence in families who have an affected child is low.