Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• Mandibulofacial dysostosis with microcephaly (MFDM) is a rare genetic disorder.
• It is characterized by microcephaly, craniofacial anomalies, and hearing loss.
• The condition results from haploinsufficiency of the spliceosomal GTPase U5-116 kDa/EFTUD2.

Purpose of the Study:

• To review the molecular basis of MFDM.
• To report new mutations in the EFTUD2 gene.
• To consolidate data from previously reported and new cases.

Main Methods:

• Literature review of MFDM cases.
• Genetic analysis of new individuals with MFDM.
• Compilation of pathogenic EFTUD2 variants.

Main Results:

• The study includes 107 individuals from 94 kindreds with MFDM.
• 76 distinct mutations and 7 microdeletions in EFTUD2 were identified.
• Stop-gain (38%) and splicing (43%) mutations are more common than missense substitutions (18%).
• Clinical features include microcephaly (nearly universal), craniofacial malformations, and hearing loss; esophageal atresia occurs in ~27%.

Conclusions:

• EFTUD2 mutations are the primary cause of MFDM.
• The spectrum of clinical features is broad, with some anomalies like microcephaly showing age-dependent changes.
• A comprehensive database of EFTUD2 mutations is available for research.