Combined approach for finding susceptibility genes in DISH/chondrocalcinosis families: whole-genome-wide linkage and IBS/IBD studies

Twelve families with exuberant and early-onset calcium pyrophosphate dehydrate chondrocalcinosis (CC) and diffuse idiopathic skeletal hyperostosis (DISH), hereafter designated DISH/CC, were identified in Terceira Island, the Azores, Portugal. Ninety-two (92) individuals from these families were selected for whole-genome-wide linkage analysis. An identity-by-descent (IBD) analysis was performed in 10 individuals from 5 of the investigated pedigrees. The chromosome area with the maximal logarithm of the odds score (1.32; P =0.007) was not identified using the IBD/identity-by-state (IBS) analysis; therefore, it was not investigated further. From the IBD/IBS analysis, two candidate genes, LEMD3 and RSPO4 , were identified and sequenced. Nine genetic variants were identified in the RSPO4 gene; one regulatory variant (rs146447064) was significantly more frequent in control individuals than in DISH/CC patients ( P =0.03). Four variants were identified in LEMD3 , and the rs201930700 variant was further investigated using segregation analysis. None of the genetic variants in RSPO4 or LEMD3 segregated within the studied families. Therefore, although a major genetic effect was shown to determine DISH/CC occurrence within these families, the specific genetic variants involved were not identified. Connective tissue disease: Genes associated with pathological calcium deposition Two genes have been identified in association with diseases involving excessive calcium deposition in connective tissues. A group headed by Dr. Jácome Armas at the Hospital de Santo Espírito da Ilha Terceira, Azores, Portugal investigated 12 families with early-onset idiopathic skeletal hyperostosis (DISH) and chondrocalcinosis (CC). DISH involves bony hardening (calcification) of the ligaments where they attach to the spine, and CC is the deposition of calcium-containing crystals in connective tissues. The group performed whole-genome sequencing and statistical analysis on 92 family members with the aim of identifying the genetic cause of the diseases, co-occurrence of which is very common on Terceira Island. Two genes appear to be involved in the co-occurrence of DISH and CC; however, the authors were unable to confirm the particular variants involved among the several genetic variants identified.