A novel EFTUD2 splicing variant causing mandibulofacial dysostosis with microcephaly: a case report.

Background: Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant disorder caused by pathogenic variants in the EFTUD2 gene, presenting with craniofacial anomalies, microcephaly, and systemic abnormalities. Despite several reported cases, the genetic and molecular mechanisms underlying MFDM remain inadequately understood. This case study identifies and analyzes a previously unreported EFTUD2 splice variant (NM_004247.4:c.492+1del), investigates its clinical phenotype, and analyzes genotype-phenotype correlations to improve early recognition and diagnosis of MFDM.

Case description: The patient had facial abnormalities (micrognathia, high-arched palate, microtia, and preauricular tags), a small head-to-body ratio, sensorineural hearing loss, delayed speech development, and cognitive impairment. Exome sequencing identified a splice variant, NM_004247.4:c.492+1del, in the EFTUD2 gene, which was classified as pathogenic according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). AlphaFold 2 predictions indicated that this variant had a significant impact on the protein structure. RNA-sequencing (RNA-seq) further demonstrated that the NM_004247.4:c.492+1del variant led to a pronounced splicing abnormality, causing exon 6 skipping during the transcription process of the EFTUD2 gene.

Conclusions: This study reported a novel EFTUD2 splice variant in a child with MFDM, expanding its variant spectrum. Utilizing RNA-seq, we demonstrated the variant's pathogenicity and contributed to the understanding of MDFM's genotype-phenotype relationship, enriching the disease's variant spectrum with molecular insights.