The First Description of Monozygotic Twin Females Discordant for the Craniofrontonasal Syndrome Phenotype and the Report of Four Novel Pathogenic Variants in the EFNB1 Gene

Abstract Background: Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder that results from pathogenic variants in the EFNB1 gene. The syndrome paradoxically presents with greater severity of the symptoms in heterozygous females than hemizygous males.Results: Our primary finding was the description of monozygotic twins, i.e., patients 5 & 6, discordant for the CFNS phenotype. Intriguingly, patient 5 presented classical CFNS gestalt, whereas patient 6 manifested only very subtle craniofacial features, not resembling CFNS. Besides, we have expanded the mutational spectrum of the EFNB1 gene through reporting four novel pathogenic variants – p.(Trp12*), p.(Cys64Phe), p.(Tyr73Metfs*86), p.(Glu210*). All those alterations were found applying either targeted NGS of a custom gene panel or PCR followed by Sanger sequencing and evaluated using in silico predictors. Lastly, we have also expanded the CFNS phenotypic spectrum by describing in patient 3 novel features of the syndrome, such as bifid hallux, bicornuate uterus, and abnormal right ovary segmented into six parts Conclusions: We have described the unreported so far differences of the clinical phenotype in the monozygotic twin patients 5 & 6 harbouring an identical p.(Glu210*) variant located in the EFNB1 gene. With our finding, we have pointed to an unusual phenomenon of mildly affected females with CFNS, who may not manifest features suggestive of the syndrome. Consequently, this study may be valuable for geneticists consulting patients with craniofacial disorders.