Introduction: Less than 20% of congenital hypothyroidism (CH) has a known genetic aetiology; thyroid transcription factor mutations (PAX8, Nkx2.1, Nkx2.5, FOXE1) or biallelic TSHR mutations cause <5% of thyroid dysgenesis (TD), whereas mutations in genes mediating thyroid hormone biosynthesis (TPO, TG, DUOX2, DUOXA2, IYD, SLC5A5, SLC26A4) account for most dyshormonogenesis cases. Increased CH frequency in consanguineous populations, relatives of TD cases, and in conjunction with extrathyroidal anomalies suggests involvement of hitherto unidentified genes.
Although genetic diagnosis is not routinely undertaken, establishing the molecular basis of CH may inform treatment, anticipate extrathyroidal features and confirm recurrence risk to facilitate genetic counselling. Prediction of genetic basis from clinical phenotype is unreliable, precluding implementation of selective candidate gene analysis; accordingly, a comprehensive genetic screening strategy has been developed.
Method: Compared to conventional sequencing, next generation sequencing (NGS) technologies increase sequencing capacity and speed, with molecular barcodes enabling multiplex analysis of samples, to improve throughput and efficiency. 11 known and 20 putative CH-associated genes were screened using NGS in 49 families. This genetic diagnostic strategy aimed to identify mutations in known and predicted CH-associated genes and to delineate a mutation-negative cohort in whom novel genetic causes can be sought.
Results: Ten families harboured mutations in known causative genes, of which five were known (DUOX2: Q686X, R354W, TPO: R665Q, R491H, TG R277X) and six were novel (DUOX2: Q570L, TG: S509X, R140X W1031L, C707Y, T1397RfsX30, c.638+5 G>A); two families harboured compound TG mutations.
Conclusion: NGS enables efficient screening of multiple genes simultaneously, facilitating genetic diagnosis in CH. Such comprehensive screening will identify mutations in known genes associated with atypical clinical phenotypes, and in putative CH-associated genes identified from animal models. Identification of mutation-negative cases defines a population in whom whole exome sequencing may identify novel genetic aetiologies for CH, elucidating novel pathways in thyroid development and physiology.
13 Nov 2013
British Society for Paediatric Endocrinology and Diabetes