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Landa P.,North East Thames Regional Genetics Service Laboratory | Differ A.-M.,North East Thames Regional Genetics Service Laboratory | Rajput K.,Great Ormond Street Hospital for Children NHS Foundation Trust | Jenkins L.,North East Thames Regional Genetics Service Laboratory | And 2 more authors.
BMC Medical Genetics | Year: 2013

Background: Pendred syndrome is a common autosomal recessive disorder causing deafness. Features include sensorineural hearing impairment, goitre, enlarged vestibular aqueducts (EVA) and occasionally Mondini dysplasia. Hearing impairment and EVA may occur in the absence of goitre or thyroid dyshormonogensis in a condition known as non-syndromic EVA. A significant number of patients with Pendred syndrome and non-syndromic EVA show only one mutation in SLC26A4. Two genes, KCNJ10, encoding an inwardly rectifying potassium channel and FOXI1, a transcriptional factor gene, are thought to play a role in the disease phenotypes.Methods: Using Polymerase Chain Reaction and Sanger sequencing, sixty-eight patients with monoallelic mutations of SLC26A4 were tested for mutations in KCNJ10 and FOXI1.Results: Two variants were observed in the KCNJ10 gene, p.Arg271Cys in three patients and p.Arg18Gln in one patient; only one variant, p.Arg123Trp was observed in the FOXI1 gene in a single patient. Both p.Arg271Cys and p.Arg18Gln are likely to be polymorphisms as judged by their frequency in the general population.Conclusion: Therefore we found no evidence for a significant association between mutations of KCNJ10 and FOXI1 with SLC26A4. It was also observed that the variant, p.Arg271Cys in KCNJ10, previously thought to have a protective effect against seizure susceptibility, was found in a patient with Pendred syndrome with co-existing epilepsy. © 2013 Landa et al.; licensee BioMed Central Ltd.

Soh L.M.,William Harvey Research Institute | Druce M.,William Harvey Research Institute | Grossman A.B.,William Harvey Research Institute | Grossman A.B.,University of Oxford | And 5 more authors.
European Journal of Endocrinology | Year: 2015

Design: Patients with Pendred syndrome have genotypic and phenotypic variability, leading to challenges in definitive diagnosis. Deaf children with enlarged vestibular aqueducts are often subjected to repeated investigations when tests for mutations in SLC26A4 are abnormal. This study provides genotype and phenotype information from patients with suspected Pendred syndrome referred to a single clinical endocrinology unit. Methods: A retrospective analysis of 50 patients with suspected Pendred syndrome to investigate the correlation between genetic, perchlorate discharge test (PDT) and endocrine status. Results: Eight patients with monoallelic SLC26A4 mutations had normal PDT. Of the 33 patients with biallelic mutations, ten of 12 patients with O30% discharge developed hypothyroidism. In our cohort, c.626GOT and c.3-2AOG result in milder clinical presentations with lower median perchlorate discharge of 9.3% (interquartile range 4-15%) compared with 40% (interquartile range 21-60%) for the remaining mutations. Eight novel mutations were detected. All patients with PDT <30% remained euthyroid to date, although the majority are still under the age of 30. There was a significant correlation between PDT and goitre size (R=0.61, P=0.0009) and the age of onset of hypothyroidism (R=-0.62, P=0.0297). In our population, the hazard of becoming hypothyroid increased by 7% per percentage point increase in PDT (P<0.001). Conclusion: There is a correlation between SLC26A4 genotype and thyroid phenotype. If results hold true for larger patient numbers and longer follow-up, then for patients with monoallelic mutations, PDT could be unnecessary. Patients with biallelic mutations and PDT discharge >30% have a high risk of developing goitre and hypothyroidism, and should have lifelong monitoring. © 2015 European Society of Endocrinology Printed in Great Britain.

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