Hypoparathyroidism Panel

Hypoparathyroidism is an abnormality of calcium metabolism characterized by hypocalcemia and hyperphosphatemia due to inadequate (absent or markedly reduced) secretion of parathyroid hormone (Garfield et al. 2001; De Sanctis et al. 2012; Al-Azem et al. 2012; Kim et al. 2015). Hypoparathyroidism can be inherited (commonly seen in children) or acquired (usually in adults). Clinical manifestations of pediatric hypoparathyroidism include bronchospasm, laryngospasm, tetany and seizures in the neonatal period; and confusion, fatigue, muscle cramping, paraesthesia, twitching and arrhythmia in older children. Congenital hypoparathyroidism caused by genetic aberration can be syndromic or isolated.

Isolated hypoparathyroidism can be inherited in autosomal dominant (AP2S1, CASR, GNA11, PTH and GCM2), autosomal recessive (PTH and GCM2) or X-linked manner (SOX3) (Kim et al. 2015; De Sanctis et al. 2012; Mannstadt et al. 2013). Syndromic hypoparathyroidism is commonly seen in chromosome 22q11.2 microdeletion syndrome, but can be also caused by defects in single genes such as AIRE (polyglandular autoimmune syndrome, autosomal recessive), TBCE (hypoparathyroidism-retardation-dysmorphism syndrome, autosomal recessive), FAM111A (Kenny-Caffey syndrome, autosomal dominant), GATA3 (hypoparathyroidism-deafness-renal dysplasia syndrome, autosomal dominant), PTH1R (Blomstrand chondrodysplasia, autosomal recessive), GNAS and STX16 (pseudohypoparathyroidism, autosomal dominant) or HADHA and HADHB (trifunctional protein deficiency, autosomal recessive). Mitochondrial genome defects have been also associated with syndromic hypoparathyroidism such as Kearns-Sayre syndrome. The mutation spectrum throughout these genes includes all types of variants.

See individual gene test descriptions for information on molecular biology of gene products.

In a cohort study of 37 pediatric hypoparathyroidism patients in Korea (Kim et al. 2015), 22 cases (59.5%) had 22q11.2 microdeletion syndrome. Other genetic defects were found in GATA3 (5/37, 13.5%), AIRE (1, 2.7%), FAM111A (1, 2.7%) and mitochondrial genome (1, 2.7%). The remaining 7 (18.9%) patients were classified as idiopathic hypoparathyroidism cases.

The cause of nonsurgical isolated hypoparathyroidism remains unknown in about 90% of sporadic cases and 30% of familial cases (Lambert et al. 2014).

No large deletions or duplications have been reported yet in these genes: FAM111A, AP2S1, GNA11, PTH, PTH1R, and TBCE. Deletions or duplications have been reported in these genes, but are uncommon: AIRE, CASR, GATA3, GCM2, HADHA, HADHB, and STX16. Deletions or duplications have been commonly reported in SOX3 and GNAS.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).