Intrafamilial Variability of the Deafness and Goiter Phenotype in Pendred Syndrome Caused by a T416P Mutation in the SLC26A4 Gene

Abstract

Pendred syndrome (PS) is the most common cause of syndromic deafness, accounting for more than 5% of all autosomal-recessive hearing loss cases. It is characterized by bilateral sensorineural hearing loss and by goiter with or without hypothyroidism. Mutations in the SLC26A4 gene cause both classical PS and deafness associated with an enlarged vestibular aqueduct without goiter. To investigate a possible genotype-phenotype correlation in PS, we performed a detailed clinical and genetic study in three adult German sibs with typical PS caused by a common homozygous SLC26A4 mutation, T416P. An audiological long-term follow-up of 23 yr showed that the mutation T416P is associated with a distinct type of hearing loss in each of the three sibs: moderate-to-profound progressive deafness, profound nonprogressive deafness, and a milder but more rapidly progressing form. We show that these phenotypic differences are not caused by either different degrees of inner ear malformations or sequence variations in the GJB2/connexin 26 gene. Because the thyroid phenotype was also highly variable within the family, with thyroid sizes ranging from normal to large goiters requiring thyroidectomy, this study leads to the conclusion that other environmental and/or genetic factors have an impact on the PS phenotype.

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

“…However the analysis could be started with exons 4, 10, 14 and 11 + 12, where we found the majority of pathogenic mutations. The most common mutation in our cohort, p.Val138Phe (18% of all pathogenic alleles), was also found in some familial cases in Germany (Borck et al, 2003) and was shown to be a founder mutation in the Central European area as was the mutation p.Thr416Pro (found twice -5.9% -in our study) also described in Germany (Napiontek et al, 2004).…”

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

“…Intrafamilial and interfamilial phenotypic variability, mostly in terms of presence/absence and severity of thyroid and inner ear malformations, have been reported by other groups (12)(13)(14)32). In the family tested in the present work, the extreme variability can not only be found in the degree of hearing impairment, but also in the time of onset for the thyroid alterations.…”

“…Mutations of this gene have been associated, in compound heterozygosity or in homozygosity, with Pendred syndrome (PS), an autosomal recessive disorder first described in 1896 and characterized by the association of sensorineural hearing loss (SNHL) and goiter (10). The phenotype of PS is highly variable with regard to deafness, goiter, and thyroid function (12)(13)(14)(15). Sensorineural deafness is congenital, and in most cases has a progressive course.…”

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

“…P endred syndrome (PS) (OMIM#274600) (1) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) (2) to Mondini malformation (3), combined with deficient iodide organification in the thyroid gland, as demonstrated by the positive perchlorate discharge test in affected individuals (4)(5)(6)(7). Another form of SNHL associated with EVA, however, showing normal thyroid function, is called nonsyndromic EVA (ns-EVA) (OMIM#600791).…”