SLC26A4 Phenotypic Variability Influences Intra- and Inter-Familial Diagnosis and Management

Abstract

SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G>C), while the third family had compound heterozygous pathogenic variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management.

Keywords: DFNB4; Pendred syndrome; SLC26A4; enlarged vestibular aqueduct; hearing loss; heterogeneity.

Figure 1

Pedigrees of the three investigated Jordanian families (F1, F2, and F3) with variants in SLC26A4. Females are represented by circles and males are represented by squares. Filled symbols indicate affected individuals with hearing loss while empty symbols represent unaffected individuals. Arrows point to the proband of each family. The zygosity of the identified genotypes, validated using Sanger sequencing, was presented under the symbol of affected individuals and first-degree family members. Abbreviations: W: wild type, M1: mutation c.165-1G>C, M2: mutation (c.304G>A; p. Gly102Arg), and M3: mutation (c.1446G>A; p.Trp482*).

Figure 2

Audiograms of selected family members. Audiograms of F1: IV3 (c.165−1G>C) are shown in (A–C) at the age of 1 year and 7 months, 6 years, and 17 years, respectively. (D) for F1: IV-2 at the age of 3 years. Audiograms of F1: IV−5 are depicted in (E,F) before and after cochlear implant at the age of 4 and 5 years, respectively. (G) for F2 (p.Gly102Arg and p.Trp482*): IV−1 at the age of 7 years. (H) for F2: IV-3 at the age of 5 years. (I) for F3 (c.165−1G>C): V−4 at the age of 20 years. The symbols of the red circles and the blue crosses represent the readings of earphones unmasked air conduction of the right and left ear, respectively. Blue triangles for the masked air conduction readings of the right ear. The (<) and (>) symbols are used to represent the reading of the mastoid unmasked air conduction of the right and left ears, respectively. Arrows on any of the symbols represent no response.

Figure 3

Schematic representation of the location of the variants in SLC26A6. The upper pane represents the corresponding chromatograms of the identified variants. Variant locus is highlighted in yellow. Black peak, G base; blue peak, C base; red peak, T base; green peak, A base. Abbreviations: Hom: homozygous, Het: Heterozygous.

Figure 4

Temporal CT scan findings for F1: IV-3 and F1: IV-4. (A,B) Axial view of bilateral temporal bone CT scan for F1: IV-4 at the age of 17 years old post cochlear implantation where the blue lines represent the length of the EVA. The red circle shows the electrodes of the cochlear implant and the green rectangle shows the implanted cochlear device (A) for the right side and (B) for the left side. (B,C) Axial view of bilateral temporal bone CT scan for F1: IV-3 at the age of 25 years old showing features of incomplete partition II (Mondini Deformity) indicated by the blue circle (C) for the left side and (D) for the right side.