Ofd1, the gene responsible for Oral-Facial-Digital syndrome type I, encodes a protein essential for primary cilia formation and left-right asymmetry establishment. It also plays roles in multiple biological processes such as proteome balance, as it was the first example of a ciliopathy protein controlling both protein expression and autophagic/proteasomal degradation [2]. Additionally, it is involved in cell-extracellular matrix (ECM) interactions in melanocytes and may be related to autophagy regulation [5,6].

Mutations in Ofd1 result in a variety of phenotypes. In humans, these range from multiorgan-involved disorders like OFD type I and Joubert syndromes, to single-tissue-related conditions such as retinitis pigmentosa and primary ciliary dyskinesia. The inheritance patterns vary from X-linked dominant male-lethal to X-linked recessive [1,3]. For instance, in a Chinese boy with Joubert syndrome, a novel frameshift mutation in Ofd1 was identified, expanding the genotype-phenotype spectrum [4]. Also, in three male patients with primary ciliary dyskinesia, hemizygous pathogenic variants in Ofd1 were found, suggesting that PCD is part of the OFD1-related disorder spectrum [3].

In conclusion, Ofd1 is crucial for primary cilia-related functions and is involved in proteome balance, cell-ECM interactions, and autophagy. Its mutations are associated with a wide range of ciliopathies, including OFD type I, Joubert syndromes, retinitis pigmentosa, and primary ciliary dyskinesia. Understanding the role of Ofd1 through human case studies helps in genetic testing and timely management of these related disorders [1,3,4].