Damaging variants in FOXI3 cause microtia and craniofacial microsomia

Area of Science:

• Genetics
• Developmental Biology
• Craniofacial Abnormalities

Background:

• Craniofacial microsomia (CFM) encompasses a range of developmental anomalies affecting facial structures.
• The genetic underpinnings of CFM are largely unidentified, hindering diagnosis and treatment.
• Microtia, a common feature of CFM, involves underdevelopment of the external ear.

Purpose of the Study:

• To investigate the genetic etiology of craniofacial microsomia (CFM) and microtia in families with unknown genetic causes.
• To identify specific genes and mutations responsible for CFM phenotypes.
• To functionally characterize the impact of identified genetic variants.

Main Methods:

• Genome sequencing and linkage analysis were employed in affected families.
• Functional studies involved in vitro expression of wild-type and mutant FOXI3 proteins.
• Analysis included assessment of protein localization and loss-of-function effects.

Main Results:

• A pathogenic missense variant in the FOXI3 gene (p.Arg236Trp) was identified as the cause of disease in a 5-generation family.
• Additional damaging variants in FOXI3 were found in 6 individuals from 3 other families with microtia-CFM spectrum phenotypes.
• Variants affecting FOXI3's nuclear localization sequence correlated with isolated microtia, while loss-of-function variants were associated with more severe CFM, indicating dosage sensitivity.

Conclusions:

• Mutations in FOXI3 are the second most frequent genetic cause of CFM, accounting for 1% of all cases and 13% of familial cases in the studied cohort.
• FOXI3, a regulator of ectodermal and neural crest development, plays a critical role in craniofacial morphogenesis.
• Understanding the genetic basis of CFM, particularly the role of FOXI3, is crucial for diagnosis and potential therapeutic strategies.