A Homozygous Nonsense Thyroid Peroxidase Mutation (R540X) Consistently Causes Congenital Hypothyroidism in Two Siblings Born to a Consanguineous Family

Journal of Clinical Research in Pediatric Endocrinology
Hakan CangulDuran Üstek

Abstract

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, and mutations in the thyroid peroxidase (TPO) gene have been reported to cause the disease. Our aim in this study was to determine the genetic basis of CH in two affected children coming from a consanguineous family. First, we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in the linked gene by Sanger sequencing. By using next-generation sequencing, we also checked if any other mutation was present in the remaining 10 causative CH genes. The family showed potential linkage to the TPO gene, and we detected a homozygous nonsense mutation (R540X) in both cases. The two patients had total iodide organification defect (TIOD). Both the microsatellite marker haplotypes and the mutation segregated with the disease status in the family, i.e. all healthy subjects were either heterozygous carriers or homozygous wild-type, confirming the pathogenic nature of the mutation. Neither was the mutation present in any of the 400 control chromosomes nor were there any other mutations in the remaining causative CH genes. This study proves the pathogenicity of R540X mutation and d...Continue Reading

Methods Mentioned

BETA
electrophoresis
PCR

Software Mentioned

NextGENe Report
NextGENe Variant Comparison Tool
Gene Mapper
TruSeq Amplicon Workflow
Illumina MiSeq System
SoftGenetics NextGENe
Illumina Design Studio
MiSeq Reporter
Chromas
Exon Primer

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