Congenital Hypothyroidism (Thyroid Dysgenesis) via the PAX8 Gene

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. It occurs in one of every 3,000-4,000 newborns and is twice as common in females as in males. Without early and adequate treatment, CH is characterized by growth failure, developmental delay, and permanent intellectual disability. Current newborn screening primarily detects the elevated thyroid stimulating hormone (TSH) level at birth in response to decreased or absent thyroid hormone production and can identify over 90% of CH cases. Most CH patients grow and develop normally after treatment with thyroxine (Park and Chatterjee. 2005; Rose et al. 2006). CH is usually a sporadic disorder, but growing evidence confirms several genetic mechanisms together account for at least 5% of cases. The majority of CH cases (~80%) are due to developmental defects of the thyroid gland known as thyroid dysgenesis, including thyroid agenesis, hypoplasia, and ectopy. The remaining ~15% are caused by defects in one of the steps of thyroid hormone biosynthesis (thyroid dyshormonogenesis). Other less common causes are central hypothyroidism (impaired hypothalamic-pituitary-thyroid axis), thyroid hormone transporter defects, and thyroid hormone resistance (Peter and Muzsnai 2011; Nettore et al. 2013; Weber et al. 2013).

PAX8-related CH is an autosomal dominant disorder with incomplete penetrance. The familial cases show variable clinical phenotypes, ranging from subclinical CH to severe thyroid dysgenesis. PAX8, encoded by the PAX8 gene, is a transcription factor directly regulating transcription of thyroid-specific genes and the survival of thyroid cell precursors (Macchia et al. 1998; Nettore et al. 2013). Over 20 PAX8 pathogenic variants have been reported, including missense, nonsense, and small deletions/insertions. Haploinsufficiency of the PAX8 gene is thought to be a common mechanism for most reported disease-causing variants, although a few pathogenic variants with dominant negative activity have also been reported. No clear genotype-phenotype correlations have been suggested (Hermanns et al. 2013; Narumi et al. 2012; Nettore et al. 2013).

Congenital hypothyroidism (CH) is normally a sporadic disease, but in about 5% of cases a genetic cause has been demonstrated. Pathogenic variants in multiple genes from several molecular mechanisms are associated with CH. Clinical sensitivity of PAX8 mutation analysis is unknown, but is expected to be low. Over 20 PAX8 pathogenic variants have been reported in sporadic and familial cases of CH (Nettore et al. 2013). No gross deletion and duplication variants affecting the PAX8 gene have been reported so far.

This test provides full coverage of all coding exons of the PAX8 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).