Identification and investigation of a gene involved in monogenic forms of Goldenhar syndrome – GOLDGEN

Goldenhar syndrome belongs to the heterogeneous spectrum of oculoauriculovertebral dysplasia (OAVS, OMIM 164210). Several chromosomal abnormalities have been described associated with this spectrum, and furthermore mutations in different genes of development cause abnormalities of the jaw or facial asymmetries in human or mouse. To date, no gene has been identified as formally involved in the genesis of the OAVS, despite evidence of familial cases, mostly with autosomal dominant inheritance.
The aim of this study is to find one or several genes involved in the Goldenhar syndrome.
We have recruited a cohort of 120 patients affected with OAVS, whose phenotype is finely characterized by a clinical questionnaire, photos, and radiographs. All these patients were analyzed using an oligonucleotide array-CGH pangenomic approach (funding GIS Maladies Rares 2007-2009), and to date this work led to 4 publications. A study by exome sequencing (Next Generation Sequencing) is now conducted in 5 patients, as well as their unaffected parents, affected with a "complete" form of OAVS or Goldenhar syndrome, combining ear anomalies (microtia and préauricular tags), hemifacial microsomia (with bones hypoplasia), vertebral anomalies, ocular anomalies (coloboma of eyelid or epibulbar dermoid), and +/-facial cleft, renal and cardiac anomalies (funding GIS Maladies Rares 2011). This study should identify variants de novo present in one or several candidate genes, due to genetic heterogeneity and oligogenism suspected in this syndrome. If one (or more) new gene (s) is (are) identified, its (their) study would be performed in the OAVS cohort, and in controls, by Sanger sequencing. Then different functional approaches will be undertaken on the gene(s) identified: studies of expression during ontogeny, research of allelic expression imbalance (possible epigenetic modification), cell models, animal models (existing or construction). This work is expected to identify new signaling pathways in the process of embryonic development especially for the craniofacial region. It will also study the pathophysiological mechanisms involved in Goldenhar syndrome, in the OAVS and microtia.
The identification of the gene (s) will be of precious help to the diagnosis and the genetic counseling in this disorder that represents the second most common cause of embryonic anomaly of the head and neck. Finally, this work could lead to the identification of other candidate genes for diseases whose phenotype is overlapping with that of Goldenhar (Treacher-Collins, BOR, or Nager syndromes).