A novel 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 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 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 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 gene.

CONCLUSIONS

This study reported a novel 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.