We have previously sequenced the exomes of individuals from four families, where at least one member is affected with MBS. Each family unit consists of the affected individual(s), non-affected parents, and in some cases, non-affected siblings. We identified a few candidate genes (1-3) per family that have variants segregating with MBS (i.e. in affected family members and not in the non-affecteds). The genes identified do not overlap with any of the published candidate genes. Notably, we have not identified candidate genes in common across two or more of the four families studied. It is clear that interrogating more homogeneous subgroups of affected individuals based on detailed clinical phenotyping is required given the complexity and heterogeneity of this disorder to identify common genetic and potential environmental factors. In light of this, we established a new NHGRI protocol (14-HG-0055, ClinicalTrials.gov ID: NCT02055248); PI: Irini Manoli) dedicated to defining the phenotypes and the genetic factors associated with Moebius syndrome and other congenital facial weakness disorders. This protocol is partially funded by a competitive UO1 grant awarded in January 2014, 1U01HD079068-03 (coPIs: Jabs, Engle, Manoli, Brooks, Pierpaoli). Our goal is to enroll 24 patients and their family members each year, for 3 years. The affected individual(s) from each family undergoes standardized multisystem phenotyping at the NIH clinical research center. Specialists in ophthalmology, neurology, audiology, otolaryngology, dentistry, craniofacial surgery, speech pathology and rehabilitation medicine will evaluate the study participants. To date, we have enrolled 55 patients and their family members, as well as 16 healthy controls for brain imaging data analysis, for a total of 130 subjects. We have received several more inquiries at the 2016 Moebius Syndrome Foundation conference in Long Beach, CA. We have prioritized families with more than one affected individual, since we believe these will provide a better chance of identifying a causative germline mutation. Each of the three teams collaborating under the UO1 grant (NIH: Manoli/Brooks/Pierpaoli; MSMC: Jabs; BCH: Engle) analyzes the clinical and genetic data. We have created a database to enable sharing of the clinical phenotype information. The detailed phenotype information has already allowed us to categorize the affected individuals into more clearly defined subgroups, which will help inform and direct the genetic analyses that are currently in progress. The genetic data generated at the NIH is analyzed by all of the collaborating groups using various strategies and variants will be screened in the cohorts collected by our collaborators at MSMC and BCH. To date, we have identified 131 variants in 44 genes that segregate with affection status and are thus potential candidate causal variants. Additionally, we have phenotyped four individuals with Carey-Fineman-Ziter syndrome (CFZ; Facial weakness, Robin sequence, arthrogryposis, scoliosis, myopathy), enrolled through John Carey (University of Utah) and Elizabeth Engle (BCH). Candidate casual mutations have been previously identified (by Carey or Engle) in a gene that is common to all four individuals, and is some cases, the exact same mutation. In collaboration with Stephen Robertson (University of Otago, New Zealand) and Eric Olson (University of Texas Southwestern) we assessed and confirmed the functional relevance of these mutations in human myoblasts and the zebrafish model system. A manuscript describing the results of this work is currently under review at Nature Communications. We have received a body donation of an individual with classic Moebius syndrome. Postmortem brain imaging and high-resolution DTI revealed aberrant cranial nerve trajectory and highlights the utility of ex vivo micro-imaging approaches for describing abnormal neuroanatomy in human disorders, which is critical to understanding the pathophysiology of cranial nerve abnormalities in MBS. We have performed whole exome sequencing with lymphocyte DNA from this individual and will also sequence DNA extracted from disease-affected tissues to identify somatic mutations. We believe this collaborative approach of bringing together expert investigators from multiple sites to combine valuable resources/data, will maximize our capacity to identify germline or somatic genetic causes of the various syndromes associated with facial palsy.
| Telegrafi, Aida; Webb, Bryn D; Robbins, Sarah M et al. (2017) Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome. Am J Med Genet A 173:2763-2771 |
| Di Gioia, Silvio Alessandro; Connors, Samantha; Matsunami, Norisada et al. (2017) A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun 8:16077 |
