Novel EYA1 variants causing Branchio-oto-renal syndrome

Abstract

Introduction Branchio-oto-renal (BOR) syndrome is an autosomal dominant genetic disorder characterized by second branchial arch anomalies, hearing impairment, and renal malformations. Pathogenic mutations have been discovered in several genes such as EYA1, SIX5, and SIX1. However, nearly half of those affected reveal no pathogenic variant by traditional genetic testing. Methods and materials Whole Exome sequencing and/or Sanger sequencing performed in 10 unrelated families from Turkey, Iran, Ecuador, and USA with BOR syndrome in this study. Results We identified causative DNA variants in six families including novel c.525delT, c.979T>C, and c.1768delG and a previously reported c.1779A>T variants in EYA1. Two large heterozygous deletions involving EYA1 were detected in additional two families. Whole exome sequencing did not reveal a causative variant in the remaining four families. Conclusions A variety of DNA changes including large deletions underlie BOR syndrome in different populations, which can be detected with comprehensive genetic testing.

From clinical to molecular diagnosis: relevance of diagnostic strategy in two cases of branchio-oto-renal syndrome – case report

“…Au et al also described the presence of arthrogryposis in a patient with an otherwise clinical phenotype of typical BOR syndrome; they speculated that this characteristic feature, previously undescribed in patients with this microdeletion, may be related to the haploinsufficiency of the NCOA2 gene (OMIM * 601993), encoding the steroid receptor coactivator 2, involved in muscular differentiation [ 12 ]. Arthrogryposis, however, was not noted in our two cases nor in other described BOR patients with deletions involving NCOA2 [ 14 , 15 , 18 , 20 ]. This suggests that the deletion of NCOA2 may not be sufficient for arthrogryposis to develop.…”

Otological manifestations in branchiootorenal spectrum disorder: A systematic review and meta‐analysis

“…The flow diagram of the search process is provided in Figure 1. Ultimately, 40 articles met the inclusion criteria and could be included in the analysis 2,7,10,13‐15,17,20‐52 . One article fulfilled the inclusion criteria, but was not included in the analysis because the patient suffered from a second genetic disorder that could as well result in HL 53 .…”

Zmym4 is required for early cranial gene expression and craniofacial cartilage formation

“…Our long-standing interest in this quest has been to reveal the molecular interactions between the Six1 transcription factor and putative interacting partners that may account for variable craniofacial malformations found in Branchio-oto-renal syndrome (BOR) patients that include: the outer, middle, and inner ear; branchial fistulas and cysts; and in some cases renal abnormalities ( Moody et al, 2015 ; Smith, 2018 ). Approximately 5% of patients presenting with BOR have a mutation in SIX1 , and approximately 45% present with a mutation in EYA1 , which encodes a SIX1 co-factor that is required for transcriptional activation ( Buller et al, 2001 ; Ruf et al, 2004 ; Lee et al, 2007 ; Sanggaard et al, 2007 ; Patrick et al, 2009 ; Li et al, 2010 ; Moody and Saint-Jeannet, 2014 ; Moody and LaMantia, 2015 ; Klingbeil et al, 2017 ; Smith, 2018 ). We hypothesized that since nearly half of patients have a mutation in EYA1 , it is likely that unidentified SIX1 interacting proteins may be causative ( Moody et al, 2015 ).…”