Recurrent agnathia-otocephaly caused by DNA replication slippage in PRRX1

Area of Science:

• Genetics
• Developmental Biology
• Craniofacial Biology

Background:

• Agnathia-otocephaly is a rare, severe craniofacial malformation complex.
• Mutations in the PRRX1 gene have been implicated in this condition.

Observation:

• A family presented with a history of agnathia-otocephaly and severe retrognathia.
• Genetic analysis revealed a novel frameshift mutation (c.266_269dupAAAA) in the PRRX1 gene in the proband.
• The father carried a different in-frame duplication (c.267_269dupAAA) in the same gene.

Findings:

• Functional studies demonstrated loss of function for the frameshift PRRX1 mutation.
• SNP genotyping and family recurrence patterns indicated paternally derived germline mosaicism.
• This challenges the initial assumption of autosomal recessive inheritance.

Implications:

• Severe retrognathia and agnathia-otocephaly may represent a spectrum of PRRX1-related craniofacial malformations.
• Understanding PRRX1 mutation mechanisms is crucial for diagnosing and counseling families with these rare disorders.
• Germline mosaicism should be considered in the inheritance patterns of de novo mutations in craniofacial development.