A novel nonsense substitution identified in the AMIGO2 gene in an Occulo-Auriculo-Vertebral spectrum patient.

OBJECTIVE: Craniofacial microsmia is the second most common congenital disorder with mostly unilateral defects of ear, temporomandibular joint, mandible, and muscles of facial expression and mastication. The objective of this study was to identify, if there were any, de novo germline or somatic variants in a patient with Occulo-Auriculo-Vertebral Spectrum (OAVS) using whole-exome sequencing. SETTINGS AND SAMPLE POPULATION: Trio/Family-based study of an OAVS proband. MATERIALS AND METHODS: Children's Mercy Hospital Institutional Review Board approved this study and a request-to-rely was procured from the University of Missouri Kansas City IRB. Informed assent/consent was obtained for all family members prior to any research activities. The peripheral blood/affected side tissues from corrective surgery of the proband and peripheral blood samples from unaffected parents were collected. The isolated genomic DNA were enriched for exomes and sequenced on an Illlumina HiSeq 2500 instrument yielding paired-end 125 nucleotide reads (84X coverage). Gapped alignment to reference sequences (GRCh37.p5) was performed with BWA and the GATK and analysis completed using custom-developed software. RESULTS: Analyses revealed that the proband carried a de novo germ line nonsense substitution (c.901C>T) in AMIGO2 gene, and missense substitutions in ZCCHC14 (c.1198C>T), and in SZT2 genes (c.2951C>T). CONCLUSIONS: The nonsense substitution in AMIGO2 gene introduces a premature stop codon possibly rendering the gene non-functional via nonsense-mediated pathway decay-therefore considered a stronger candidate. Further functional studies are required to confirm whether loss-of-function variants in AMIGO2 can cause OAVS.