BBSOAS is molecularly defined by the presence of a disease causing mutation in NR2F1 gene or a deletion of the NR2F1 gene on chromosome 5q15, consistent with an autosomal dominant inheritance pattern. The reported mutations are loss-of-function mutations and missense mutations. Pathogenic missense mutations are mainly located in the DNA-binding domain, and few are reported to be located in the ligand binding domain. The majority of the individuals reported to date present the disorder as a result of a de novo mutation in NR2F1. However, transmission from an affected parent have been reported (Chen et al., 2016).
Individuals with deletions of NR2F1 may present with similar phenotypes although the phenotypic spectrum and severity, may be confounded by the concurrent deletion of other genes.
NR2F1 encodes a conserved orphan nuclear receptor and transcriptional regulator. The ligand of NR2F1 remains unknown. Similar to most nuclear receptors, NR2F1 contains DNA-binding domain, formed by two zinc-finger domains, and a putative ligand-binding domain.
Molecular confirmation is necessary for a definitive diagnosis. Most of the affected individuals have been diagnosed through SNP array or whole exome sequencing, perhaps due to the relatively unspecific facial and general clinical findings. Targeted Sanger sequencing can also be used for the detection of pathogenic variants when the phenotype is suggestive, as well as the presence of a variant that has previously been identified in other affected family members.
Prenatal testing may be considered for pregnancies at increased risk, in families in which the pathogenic mutation has been identified.