Clinical and molecular characterization of craniofrontonasal syndrome: new symptoms and 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 We have recruited and screened a female cohort affected with CFNS. Our primary finding was the description of monozygotic twins, i.e., patients 5 and 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 several 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 and 6 harboring 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.

Case report: Craniofrontonasal syndrome caused by a novel variant in the EFNB1 gene in a Colombian woman

“…About 123 variants in the EFNB1 gene, almost all missense, non-sense, and frameshift, have been reported in patients with CFNS ( Bukowska-Olech et al, 2021 ), with the majority of them located at exons 2 and 3 (of the five exons this gene has) that code for the extracellular ephrin domain and thus, affecting the interaction between the ephrin-B1 protein and the Eph receptors ( Darling and Lamb, 2019 ; Gürsoy et al, 2021 ). Accordingly, the variant c.374A>C (p.Glu125Ala) reported in our patient is located at exon 2, changing a polar (glutamic acid) for a non-polar aminoacid (alanine) and probably affecting the receptor-binding domain of the protein, leading to the clinical manifestations described in this proband.…”

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects

“…Interestingly, based on the medical literature, the EFNB1 gene is usually reported as the sixth most commonly affected gene in CS ( Paumard-Hernandez et al, 2015 ; Miller et al, 2017 ; Lee et al, 2018 ). However, we postulate that a very characteristic disease, i.e., craniofrontonasal dysplasia (CFND) resulting from pathogenic variants of the EFNB1 , should be considered a standalone genetic disorder in which features other than CS guide the proper diagnosis ( Bukowska-Olech et al, 2021 ). Moreover, CFND represents a classic viscerocranium defect, whereas CS is a neurocranium abnormality.…”