Whole-Exome Sequencing Revealed a Novel De Novo Pathogenic EFTUD2 Variant in Mandibulofacial Dysostosis, Guion-Almeida Type: Reinforcing Links to Choanal and Oesophageal Atresia.

Mandibulofacial dysostosis type Guion-Almeida (MFDGA) is a rare autosomal dominant disorder characterized by malar and mandibular hypoplasia, microcephaly and diverse craniofacial and extracranial malformations, caused by pathogenic variants in the EFTUD2 gene. This study investigates a 12-year-old boy presenting with congenital microcephaly, choanal atresia, recurrent respiratory infections, moderate hearing loss and typical MFDGA features, born to healthy non-consanguineous Iranian parents. Whole-exome sequencing (WES) was employed, with variants filtered and prioritized using the Phenomizer algorithm based on Human Phenotype Ontology terms. A novel de novo frameshift variant in EFTUD2 (c.1237delC; p.Arg413Alafs*53) was identified and validated by Sanger sequencing. This variant was absent in the parents and healthy brother but detected in an aborted sibling with oesophageal atresia, reinforcing a genotype-phenotype correlation. Paternity and segregation analyses confirmed the biological relationships and de novo nature of the variant, likely arising from germline mosaicism. This finding links the variant to choanal atresia and oesophageal atresia and supports the use of Phenomizer as supplementary aids in validating gene-phenotype correlations during WES analysis, particularly in disorders with variable clinical presentations.