Duplicated Gene Found for Highly Prevalent Facial Anomaly

The genetic cause of a facial disorder known as hemifacial microsomia (HFM) or Goldenhar syndrome, the second-most common facial anomaly after cleft lip and palate, has been discovered.

While most HFM cases are sporadic, approximately 2% to 10% of cases are familial and occur in more than one generation, supporting the contribution of genetic risk factors which can be identified by whole-exome sequencing.

A team of scientists led by those at the Whitehead Institute for Biomedical Research (Cambridge, MA, USA) conducted a systematic analysis to identify an etiological variant of HFM and to increase the power of the investigation they focused on a large family with multiple affected individuals. The team studied the genomes of a five-year-old female member of the family, along with those of her mother, grandmother, and male cousin, who all exhibited traits of HFM. Later, the genetic information from the grandmother's Russian cousin, who resides in the Philadelphia area, was recruited to the study.

DNA was derived from collected whole blood with the investigators searching for a point mutation, but the five of the study participants held no such mutation in common. Next they looked for sections of the genome that are duplicated. All had an extra copy of one 1.3 megabase pair section of chromosome 14 and duplications this large are frequently detrimental.

Within this large piece of DNA, they identified eight candidate genes that could cause the type of HFM running in this family. They then used two algorithms to compare the molecular signatures of these eight genes to other genes known to be responsible for various facial malformations with features similar to HFM. The gene orthodenticle homeobox 2 (OTX2) emerged above the seven other candidates as the cause and it codes for a transcription factor.

The authors concluded that determining the causative gene for HFM can promote stratification of cases based on the molecular pathology, guide clinical care, offer reproductive alternatives to families that carry an OTX2 duplication, and facilitate definitive diagnosis, which is currently inadequate for HFM. Importantly, implicating OTX2 in this disorder can improve understanding of the basic molecular processes that underlie normal and pathological craniofacial development. They suggest clinicians be aware of the possibility of increased risk for medulloblastoma in HFM cases with OTX2 duplications. The study was published on May 9, 2014, in the journal Public Library of Science ONE.

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Whitehead Institute for Biomedical Research