1. RESULTS
Burden of rare variants in OTOF gene in familial Meniere disease
P Roman-Naranjo1, CA Jimenez-Ruiz1, MC Moleon2, A Gallego-Martinez1, JA Lopez-Escamez1,2
1 Otology & Neurotology Group CTS495, Department of Genomic Medicine, GENYO - Centre for Genomics and Oncological Research – Pfizer/University of Granada/ Junta de Andalucía, PTS, Granada, Spain.
2 Department of Otolaryngology, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Universitario Virgen de las Nieves, Granada, Spain.
MATERIALS & METHODS
MAF < 0.001
40% cases carried 1
or more rare variants
in SNHL genes
http://compbio.charite.de/PhenIX/
Figure 1: GATK Best practices and PhenIX pipeline Figure 2: Workflow followed in SRVA and GBA
Single Rare Variant Analysis
MAF < 0.001
CADD > 15
MAF < 0.05
Exonic &
nonsynonymous
variants
Quality
control
Extract
SNHL genes variants
100.000
variants/exome
28.995 variants
in SNHL
26.870 variants
in SNHL
514 variants
330 rare
variants
225 rare likely
pathogenic
variants
100 rare likely
pathogenic
variants
We recruited 72 familial MD cases to perform whole-exome sequencing. Variant calling was performed with the Genome Analysis Tool Kit (GATK).
Candidate genes were prioritized based on predicted variant pathogenicity and phenotypic information of diseases associated with the genes harboring
these variants using the PhenIX pipeline (Figure 1). A single rare variant analysis (SRVA) focused on SNHL genes was performed to identify rare
variants using as a cutoff a minor allele frequency (MAF) <0.001. A gene burden analysis (GBA) focused on SNHL genes was performed to analyze the
interaction of multiple common and rare variants increasing the MAF up to > 0.05 (Figure 2). We studied and compared the relationship between rare
variants and common variants which modulate gene expression according GTEx Portal. Two independent datasets were used as reference to compare
the observed MAF in familial MD and estimate odds ratios in a case-control design: Non-Finnish European population (NFE) from the Exome
Aggregation Consortium (ExAC) database and the Collaborative Spanish Variant Server (CSVS) database. Besides, IBS population from 1000Genomes
was used for studying the relationship between variants.
Gene Position REF ALT Variant Function CADD MAF (ExAC-NFE) MAF (CSVS) # Cases
DIABLO chr12:122701379 G C Nonsyn SNV 26.7 - - 3
TECTA chr11:121028725 T C Nonsyn SNV 23.5 1.2x10-4 1.0x10-3 3
MYH14 chr19:g.50785088 A G Nonsyn SNV 28.9 - - 3
DIAPH1 chr5:140953259 G A Nonsyn SNV 23.4 2.0x10-5 - 3
Gene # Variants Odd ratio ExAC (CI) p-value cor. ExAC Odd ratio CSVS (CI) p-value cor. CSVS
OTOF 14 2.9 (2-4.2) 3.0x10-4 2.3 (1.6-3.5) 8.3x10-4
OTOG 11 2.6 (1,7-4) 1.0x10-4 2.3 (1.5-3.6) 1.9x10-3
MYH14 6 3.6 (2.3-5.7) 1.9x10-4 2.6 (1.6-4.2) 6.4x10-4
OTOF
OTOF
OTOF
PhenIX pipeline showed that 40% of familial MD cases carried, at least, a novel or ultrarare variant in genes related with SNHL. These variants are likely
pathogenic according to its Combined Annotation Dependent Depletion (CADD) value since it is higher than 15. One hundred rare likely pathogenic
variants were selected following the SRVA pipeline (Table 1). A total of 225 rare likely pathogenic variants were retrieved with the GBA. After Bonferroni
correction, OTOF gene was the gene with a higher enrichment of rare likely pathogenic variants (Table 2 & Figure 3). The intronic variant rs34796712,
which modulate the OTOF expression, showed a lower frequency in MD cases when it is associated to a rare variant (RV) compared with 1000 Genomes
Spanish (IBS) controls (Table 3 & Figure 4).
Table 1: Highlighted variants obtained through single rare variant analysis
Table 2: Genes with a significant accumulation of rare variants in familial MD cases
Figure 3: OTOF gene showed an accumulation of variants in its coiled-coil domain.
INTRODUCTION
Meniere disease (MD) is a rare inner ear disorder characterized by vertigo, sensorineural hearing loss (SNHL) and tinnitus with a prevalence of 75 cases
in 100,000 people. Although most cases are considered sporadic, familial aggregation exists among 10% of MD cases, supporting a genetic background
for this disease. Several genes have been described in familial MD such as DTNA, FAM136A, PRKCB, DPT and SEMA3D genes, showing genetic
heterogeneity. Thus, the goal of this study is to define new candidate genes for familial MD.
CONCLUSIONS
1.- At least a novel or ultrare variant in
SNHL genes was found in 40% of familial MD
cases, suggesting a strong effect of these
genes in MD phenotype.
2.- OTOF gene showed a significant
accumulation of rare variants.
3.- The intronic variant rs34796712 could play
a protective role in MD patients with rare
variants in OTOF gene
Figure 4: These rare variants are related with the intronic variant rs34796712, which
regulates OTOF expression according to GTEx Portal.
FUNDING
Supported by the Luxembourg National Research
Fund INTER/Mobility/17/11772209 and EF-0247-2017
from Andalusian Health Government to JALE.
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Table 3: The occurrence of rs34796712 + RV is less common in MD population
than IBS controls population.
Common variant Rare variants Cases (MD) IBS (1000G) Odd ratio p-value cor
rs34796712 RV 7 26 0.29 (0.12-0.7) 0.024
- 76 81
rs939814 RV 25 31 1.06 (0.56-1.98) .
- 30 50
rs6547079 RV 25 33 0.97 (0.52-1.8) .
- 35 57
rs884390 RV 11 20 0.66 (0.3-1.48) .
- 72 87
