X-Linked Hypoparathyroidism via the Interstitial Deletion-Insertion Involving Chromosomes 2p25.3 and Xq27.1, Near SOX3

Hypoparathyroidism (HPT) is an abnormality of calcium metabolism characterized by hypocalcemia and hyperphosphatemia due to inadequate (absent or markedly reduced) secretion of parathyroid hormone (PTH) (Garfield et al. 2001. PubMed ID: 11504667; De Sanctis et al. 2012. PubMed ID: 23128574; Al-Azem et al. 2012. PubMed ID: 22863393; Kim et al. 2015. PubMed ID: 26384470). HPT can occur as part of a complex congenital syndrome or isolated. Males with X-linked recessive HPT have deficiency of circulating immunoreactive PTH due to parathyroid agenesis. If untreated, patients suffer from neonatal or infantile onset of hypocalcemic seizures (Bowl et al. 2005. PubMed ID: 16167084; Taylor et al. 2015. PubMed ID: 25985138).

X-Linked hypoparathyroidism is caused by the interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1 and affecting expression of the SOX3 gene. Two similar interstitial deletion-insertions have been reported in two related Missouri kindreds and an unrelated individual. The variant reported in the Missouri kindreds consisted of the insertion of 304 kb from chromosome 2p25 within a 23-25 kb deletion located 67 kb downstream of the SOX3 gene on chromosome X. This variant was shown to affect the expression of the SOX3 gene, which is important for the embryonic development of the parathyroid glands (Bowl et al. 2005. PubMed ID: 16167084). The second interstitial deletion-insertion in an unrelated affected individual consisted of the insertion of 47 kb from chromosome 2p25.3 within a 1.4 kb deletion located 82 kb downstream of the SOX3 gene on chromosome X (Taylor et al. 2015. PubMed ID: 25985138). This test detects the complex rearrangement described by Taylor et al. (2015), but not the complex rearrangement described in the Missouri kindreds by Bowl et al. (2005).

The interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1 detectable with this assay has been reported in only a single individual with X-Linked hypoparathyroidism (Bowl et al. 2005. PubMed ID: 16167084) Therefore, the prevalence of this complex rearrangement event in a larger cohort of patients with X-Linked hypoparathyroidism is unknown. Overall, interstitial deletion-insertions involving chromosomes 2p25.3 and Xq27.1 have been reported in only two unrelated kindreds (Bowl et al. 2005. PubMed ID: 16167084; Taylor et al. 2015. PubMed ID: 25985138).

This test involves amplification of patient DNA with several sets of specific PCR primers that flank the interstitial deletion-insertion junction point. In a patient with this rearrangement allele, two separate primer sets amplify across the insertion boundary resulting in 490 bp and 331 bp products. Other control primers are used to detect the normal allele. Sanger sequencing of this rearrangement allele will also be done to confirm the breakpoint positions at the insertion boundary. This test permits the identification of patients with normal genotypes, male patients who are hemizygous for this rearrangement allele, and heterozygous female carriers.