2.1 Results of genetic testing
The patient and their parents underwent fifteen genetic testing for hereditary deafness, and the results are shown in Figure.1.
The patient and her mother c.1174A>T heterozygous mutation in the SLC26A4 gene, the father is wild-type at fifteen locus. Because the patient’s mother was pregnant again, in order to find out the cause of the patient’s hearing abnormalities, the Proband performed whole-exome sequencing and verified his parents using Sanger sequencing. At the same time, the patient’s father performed the first-generation sequencing of the whole SLC26A4 gene. The results of the proband are shown in Table.1, and the first-generation sequencing verification results are shown in Figures.2 and Figures.3.
2.2 The pathogenicity rating of the variant site
According to American College of Medical Genetics and Genomics (ACMG) guidelines, SLC26A4:NM_000441.2:exon10:c.1174A>T:p.N392Y is classified as pathogenic by fulfilling the standard PM3_VeryStrong, PM1, PP3, PP4, PS3_Supporting, PM2_Supporting.
Table.1 The results of whole-exome sequencing and Sanger sequencing
gene
|
Mutation location
|
Gene subregion
|
HGVS
|
Heterozygosity
|
SLC26A4
|
chr7:107690148-107690148
|
exon10
|
NM_000441.2 :c.1174 A>T:p.N392Y
|
Proband:Heterozygous
Father:wild
Mother:Heterozygous
|
SLC26A4
|
chr7:107704365-107704365
|
exon18
|
NM_000441.2:c.2069 T>A:p.V690E
|
Proband:Heterozygous
Father:Heterozygous
Mother:wild
|
According to the literature, Pathogenic or probable pathogenic variants detected in translocations of variants in 3 individuals with deafness[6] (PM3_VeryStrong). The variant occurred in the functional structure of SLC26A/SulP transporter domain (PM1). Predicted by multiple statistical methods (REVEL), the results show that the mutation has harmful effects on genes or gene products (PP3). The corresponding disease of the variant is consistent with the phenotype of this case (PP4). It is reported in the literature that immunofluorescence experiments have confirmed that this mutation causes gene function damage[7] (PS3_Supporting). This mutation is in the China Genome Database, the Human Exome Database (ExAC), the reference population Thousand Genome (1000G) and the Population Genome Mutation Frequency Database (gnomAD) are 0.00071531, 8.24198466990851e-06, 0.000199681 and 0.00019253, respectively. This known variant is assessed as pathogenic in the ClinVar database. This known variant is assessed as DM in the HGMD database[8]-[11] (PM2_Supporting).
According to the ACMG guidelines, SLC26A4:NM_000441.2:exon18:c.2069T>A:p.V690E is classified as likely pathogenic by fulfilling the criteria PM1, PM2, PM3, PP3, PP4.
The mutation occurred in the functional domain of the STAS domain (PM1). The mutation is in the China Genome Database, the Human Exome Database (ExAC), the Reference Population Thousand Genome (1000G) and the Population Genome Mutation Frequency Database (gnomAD) are not found (PM2). This variant forms a compound heterozygosity with the c.1174A>T mutation site in the SLC26A4 gene (PM3). Predicted by a variety of statistical methods (REVEL), the results show that the variant is Genes or gene products cause harmful effect (PP3). The corresponding disease of the variant matches the EVA phenotype of this case (PP4).