A hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome.

Otofaciocervical syndrome (OFCS) is an autosomal recessively inherited disorder characterized by facial dysmorphism, external ear anomalies with preauricular pits and hearing impairment, branchial cysts or fistulas, anomalies of the vertebrae and the shoulder girdle, and mild intellectual disability. In a large consanguineous family with OFCS from Turkey, we performed whole-exome sequencing (WES) of a single pooled DNA sample of four affected individuals. Filtering for variants with a percentage of alternate reads ≥ 90 % and a coverage of at least five reads identified only a single novel homozygous variant, c.497G>T, located in PAX1 that co-segregated with the disease in the family. PAX1 encodes a transcription factor with a critical role in pattern formation during embryogenesis in vertebrates. The mutation is predicted to substitute the glycine at position 166 to valine (p.G166V) within the highly conserved paired-box domain of the PAX1 protein. We performed a dual luciferase reporter assay to examine the transactivation of a regulatory sequence in the Nkx3-2 promoter region, which is a direct target of mouse Pax1 transcriptional regulation. We observed a significantly reduced transactivation in HEK293T cells overexpressing Pax1(G157V) in comparison to Pax1(WT) expressing cells, indicating a reduced DNA-binding affinity of the mutant protein. Taken together, our results show that the strategy of pooling DNA is a powerful, cost-effective application for WES in consanguineous families and establish PAX1 as a new disease-causing gene for OFCS and as part of the EYA-DACH-SIX-PAX network, important in early embryogenesis.

Unusual route of a bullet: From scapula to eye.

Herein, an awkward case of globe perforation with a bullet-entering from the right posterior scapular region and leaving the body from the right orbit through the eye - is reported. Route of the bullet could be devastating - as it passed through the neck and the maxillofacial region-however by chance no vital damage occurred. Its path was assessed by plain radiography and computed tomography scans. Sometimes prediction of the trajectory is very difficult without additional radiological investigations. Especially, in the case of any high velocity projectile wounding, physician must be aware of the fact that the bullet's course will not be a linear but most probably a complicated one. Prognosis of the injury depends on the path of the bullet or shrapnel fragment, close clinical observation, an open-minded approach, and the multidisciplinary care. Moreover, even the crime investigation might be needed.