Novel FOXE1 mutation associated with the rare Bamforth-Lazarus syndrome in an Omani family

We present here the first case report of Bamforth-Lazarus syndrome (BLS) in two siblings from Oman, with a novel mutation, p.Phe89Leu (F89L) in the FOXE1 gene. This study utilized an in-silico functional assessment strategy for use in extremely rare disorders such as BLS to assess the pathogenicity of novel variant. First, all previously reported germline pathogenic mutations in the FOXE1 gene were mapped and found to be located within the DNA-binding Forkhead domain critical to the transcription factor binding function of the FOXE1 protein. It was observed that no germline pathogenic mutations had been reported in association with BLS in other regions of the FOXE1 coding sequence. This was a strong indication that the novel mutation, F89L reported in our patients, and located mid-region of the FOXE1 DNA-binding Forkhead domain, is likely to be deleterious for protein function. Based on family segregation analysis, bioinformatic analyses and protein modelling, sufficient evidence was accrued to classify the novel F89L mutation as being pathogenic according to ACMG guidelines.