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

Area of Science:

• Genetics and Molecular Biology
• Rare Diseases
• Craniofacial Development

Background:

• Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant disorder.
• Pathogenic variants in the EFTUD2 gene cause MFDM, characterized by craniofacial anomalies, microcephaly, and systemic issues.
• Understanding the genetic and molecular basis of MFDM is crucial for diagnosis and management.

Observation:

• A patient presented with characteristic facial abnormalities, micrognathia, high-arched palate, microtia, preauricular tags, and a small head-to-body ratio.
• The patient also exhibited sensorineural hearing loss, delayed speech development, and cognitive impairment.
• Exome sequencing revealed a novel splice variant (NM_004247.4:c.492+1del) in the EFTUD2 gene, classified as pathogenic.

Findings:

• The identified NM_004247.4:c.492+1del variant in EFTUD2 was predicted by AlphaFold 2 to significantly impact protein structure.
• RNA-sequencing confirmed the variant causes exon 6 skipping in EFTUD2 mRNA, leading to splicing abnormalities.
• This novel splice variant expands the known spectrum of genetic alterations associated with MFDM.

Implications:

• This case study contributes to understanding the genotype-phenotype correlations in MFDM.
• The findings aid in the early recognition and diagnosis of MFDM by identifying a new pathogenic variant.
• Molecular insights from this study enrich the understanding of MFDM's genetic basis and variant spectrum.