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An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism.

ABSTRACT: X-linked recessive hypoparathyroidism, due to parathyroid agenesis, has been mapped to a 906-kb region on Xq27 that contains 3 genes (ATP11C, U7snRNA, and SOX3), and analyses have not revealed mutations. We therefore characterized this region by combined analysis of single nucleotide polymorphisms and sequence-tagged sites. This identified a 23- to 25-kb deletion, which did not contain genes. However, DNA fiber-FISH and pulsed-field gel electrophoresis revealed an approximately 340-kb insertion that replaced the deleted fragment. Use of flow-sorted X chromosome-specific libraries and DNA sequence analyses revealed that the telomeric and centromeric breakpoints on X were, respectively, approximately 67 kb downstream of SOX3 and within a repetitive sequence. Use of a monochromosomal somatic cell hybrid panel and metaphase-FISH mapping demonstrated that the insertion originated from 2p25 and contained a segment of the SNTG2 gene that lacked an open reading frame. However, the deletion-insertion [del(X)(q27.1) inv ins (X;2)(q27.1;p25.3)], which represents a novel abnormality causing hypoparathyroidism, could result in a position effect on SOX3 expression. Indeed, SOX3 expression was demonstrated, by in situ hybridization, in the developing parathyroid tissue of mouse embryos between 10.5 and 15.5 days post coitum. Thus, our results indicate a likely new role for SOX3 in the embryonic development of the parathyroid glands.

SUBMITTER: Bowl MR

PROVIDER: S-EPMC1201662 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGenomic disorders present a wide spectrum of unrelated clinical entities that result from genomic rearrangements. Interstitial insertions requiring three points of breakage are rare genomic rearrangement events. The pseudoautosomal region PAR1, homologous between the Xp22 and Yp11 loci, has a high crossover and recombination rate. A 180 bp human-specific palindrome at Xq27.1 appears to be a hotspot for genomic rearrangement, and several genetic diseases/phenotypes associated with Xq27.1 palindrome-driven genomic rearrangement have been reported. Here we investigate a Chinese family with an extremely rare X-linked compound phenotype that remains undiagnosed. We attempt to identify underlying genetic causes by an integrated genome analysis.MethodsA five-generation Chinese family with a distinct X-linked compound phenotype was recruited. Peripheral blood samples were collected and genomic DNA was extracted. Systemic physical and lab examinations were performed to evaluate the phenotype. An integrated genomic analysis was performed. Genotyping and linkage analysis were conducted to map the disease locus. Whole exome sequencing was performed to detect mutations in coding region. Whole genome sequencing was used to detect single nucleotide variations, small insertions, small deletions, or large structural variations. Copy number variation scanning was also performed on the genome scale. Interstitial insertion was confirmed by gap-PCR and quantitative-PCR, and breakpoint junctions were identified by genome walking and direct sequencing. Expression of products of genes nearby to the Xq27.1 palindrome was measured in peripheral blood from patients and unrelated controls via quantitative-PCR.ResultsThe identified compound phenotype of genu varum, cubitus valgus, and everted lipsdoes not match any reported clinical entities. Fine mapping and linkage analysis identified a candidate interval of 4 Mb on the X chromosome. No potential coding region mutations were detected. A 105 kb genomic fragment of PAR1 containing no coding genes was duplicated and inserted into the center of a human-specific palindrome at Xq27.1. The interstitial insertion fully cosegregated with the family phenotype. No expression of FGF13 or SOX3 was detected in peripheral blood from the proband or unrelated controls.ConclusionWe report an extremely rare phenotype associated with an infrequently-seen genomic rearrangement. The novel compound phenotype is X-linked and characterized by genu varum, cubitus valgus, and everted lips. A 105 kb interstitial insertion of a PAR1 fragment into the Xq27.1 palindrome is associated with the phenotype in the family. The present study identified the underlying genetic cause of the phenotype, expanding the spectrum of known human-specific Xq27.1 palindrome insertion events and associated phenotypes.

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An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3, causes X-linked recessive hypoparathyroidism.

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