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

Abstract

Structured Abstract 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.

Genomic imbalances in craniofacial microsomia

“…However, it is not clear whether CMA can contribute to etiological diagnosis for all CFM patients. In fact, individuals presenting additional major features should be investigated by CMA, but for individuals with only features within the CFM spectrum, a multifactorial etiology is the most supported (Rengasamy Venugopalan et al, 2019).…”

“…However, none of the patients from this study had a clinical diagnosis of Treacher Collins or any other syndromic diagnosis associated with CFM. Recently, mutations in other genes, including the MYT1 , ZIC3 , and AMIGO2 were described as a genetic cause of CFM (Lopez et al, 2016; Rengasamy Venugopalan et al, 2019; Trimouille et al, 2020). Nevertheless, for most CFM patients, the genetic cause remains unknown.…”

“…In and AMIGO2 were described as a genetic cause of CFM (Lopez et al, 2016;Rengasamy Venugopalan et al, 2019;Trimouille et al, 2020). Nevertheless, for most CFM patients, the genetic cause remains unknown.…”

Recurrent constellations of embryonic malformations re‐conceptualized as an overlapping group of disorders with shared pathogenesis

“…Finally, some studies reported discreet copy number variants or single nucleotide polymorphisms that might contribute to the features of the RCEM in question (Lombardi et al, 2011;Lopez et al, 2016;Rengasamy Venugopalan et al, 2019;Steiner, Vengoechea, & Collins 2nd., 2013). However, none of these have been recurrent across cohorts of affected individuals, suggesting that these are more likely to be either coincidental or predisposition rather than causal variants.…”

Description of a family with X‐linked oculo‐auriculo‐vertebral spectrum associated with polyalanine tract expansion in ZIC3

“…A genetic origin of OAVS is supported by the description of familial forms, 2 along with the existence of several causative copy number variations, 3,4 and more recently the description of deleterious variants in MYT1 5,6 and AMIGO2 7 genes. However, pathogenic variants in known genes or copy number variations only explain a small number of OAVS cases, and the molecular basis of this spectrum remains elusive.…”