Dataset Information

Identification of potential pathogenic mutations in Chinese children with first branchial cleft anomalies detected by whole-exome sequencing.

ABSTRACT:

Importance

First branchial cleft anomalies (FBCAs) are rare congenital malformations, accounting for < 8% of all branchial cleft anomalies. However, little is currently known about the cause of FBCAs at the molecular level.

Objective

To identify genomic alterations related to the genetic etiology of FBCAs in Chinese children.

Methods

We performed whole-exome sequencing of samples from 10 pediatric patients with FBCAs. Data analysis was carried out using the Burrow-Wheeler Alignment software package, and the dbSNP database for comparisons. Rare variants were further validated by Sanger sequencing. Insertion/deletions (indels) were examined using the Genome Analysis Toolkit.

Results

We identified 14 non-synonymous mutations in seven potential FBCA-susceptibility genes (TRAPPC12, NRP2, NPNT, SH3RF2, RHPN1, TENM4, and ARMCX4). We also detected 133 shared small indels in 125 genes. Gene Ontology analysis indicated that most of the identified genes played critical roles in development and differentiation pathways involved in regulating organ development.

Interpretation

We characterized the mutational landscape in pathways involved in development and differentiation in Chinese children with FBCA. The results identified potential pathogenic genes and mutations related to FBCA, and provide molecular-level support for the branchial theory of FBCA pathogenesis.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8458719 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo describe the prevalence and significance of first branchial cleft anomalies in children with congenital aural atresia.MethodsRetrospective cohort study and case series. Patients were included if they had ICD-10 code Q16.0, Q16.1, Q16.9, Q17.2, or Q17.9 in their medical record and were seen at UCSF Benioff Children's Hospital from 2012 to 2020 for aural atresia. Children were categorized as having aural atresia and first branchial cleft anomalies if the presence of a first branchial cleft anomaly was noted in otolaryngology provider notes; otherwise, they were categorized as aural atresia alone. Patients with aural atresia and first branchial cleft anomalies were included in the case series.ResultsAmong 125 children with congenital aural atresia, 5 (4%) were identified with first branchial cleft anomalies. In all cases, an epithelialized tract was noted to originate from the inferior aspect of the middle ear cleft, exiting the temporal bone in an inferomedial position adjacent to the stylomastoid foramen, with a cutaneous exit point inferior to the expected location of the native ear canal. There was no association with sex, microtia grade, or laterality of atresia; however, children with aural atresia and first branchial cleft anomalies were significantly more likely to have syndromes such as Goldenhar and Treacher Collins (p = .04) than those with aural atresia alone.3/5 (60%) children with aural atresia and first branchial cleft anomalies presented with cholesteatoma compared with 1/120 (0.8%) children with aural atresia alone, a significant difference (p < .001). All four children over the age of two have undergone surgical management. In two of these, excision of the branchial cleft anomaly could be combined with atresiaplasty, with normal hearing results in both cases.ConclusionsAural atresia can be associated with comorbid anomalies of the head and neck. First branchial cleft anomalies can be suspected based on characteristic clinical appearance and confirmed with computed tomography showing a typical course through the temporal bone. When present in the context of congenital aural atresia, first branchial cleft anomalies are associated with a significantly increased risk for cholesteatoma, often necessitating surgical management with favorable hearing outcomes.Level of evidence4.