Genotype-phenotype correlations for SLC26A4-related deafness

Abstract

Pendred syndrome (PS) and non-syndromic enlarged vestibular aqueduct (EVA) are two recessive disorders characterized by the association of sensorineural hearing loss (SNHL) with inner ear malformations that range from isolated EVA to Mondini Dysplasia, a complex malformation that includes a cochlear dysplasia and EVA. Mutations in the SLC26A4 gene, coding for the protein pendrin, have been implicated in the pathophysiology of both disorders. In order to determine whether SLC26A4 genotypes can be correlated to the complexity and severity of the phenotypes, we ascertained 1,506 deaf patients. Inner ear abnormalities were present in 474 patients (32%). Mutation screening of SLC26A4 detected two mutations in 16% of patients, one mutation in 19% of patients and zero mutation in 65% of patients. When the distribution of SLC26A4 genotypes was compared across phenotypes, a statistically significant difference was found between PS patients and non-syndromic EVA-Mondini patients (P = 0.005), as well as between EVA patients and Mondini patients (P = 0.0003). There was a correlation between phenotypic complexity of inner ear malformations and genetic heterogeneity--PS patients have the most severe phenotype and the most homogeneous etiology while EVA patients have the least severe phenotype and the most heterogeneous etiology. For all patients, variability in the degree of hearing loss is seen across genotypes implicating other genetic and/or environmental factors in the pathogenesis of the PS-Mondini-EVA disease spectrum.

Figure 1:

Phenotype-genotype correlation for CT scan abnormalities and SLC26A4 mutations. a). Distributions of number of mutated alleles among EVA and Mondini groups (Fisher’s exact test p=0.0003). b) Distribution of the number of mutated alleles among PS and Non syndromic EVA-Mondini (NS) patients. Patients with PS are more likely to carry biallelic mutations. The proportion of zero mutation is much higher in the NS group (p=0.005).

Figure 2:

Prevalence of unilateral and bilateral hearing loss in patients with unilateral or bilateral inner ear malformations. Bi: bilateral; Uni: unilateral, HL: hearing loss.

Figure 3:

Degree of hearing loss in patients with zero, one or two mutations. Mutations of SLC26A4 were associated with a wide spectrum of hearing loss phenotypes. The degree of hearing loss distribution in patients with CT scan anomalies and two SLC26A4 mutations is not statistically different from that in patients with only one or zero mutation. (Fisher’s exact test p>0.05)

Figure 4:

Schematic illustration of the interaction of genetic and environmental factors in the etiology of EVA, Mondini and PS. Genetic heterogeneity is more pronounced in the lesser severe phenotype; EVA where the environment is believed to play a bigger role. In the other side of the spectrum, PS is more homogeneous genetically with a lesser environment influence.