Molecular characterization of a recurrent 10.9 kb CYP24A1 deletion in Idiopathic Infantile Hypercalcemia

International audienceLoss-of-function mutations in CYP24A1 (MIM 126065 20q13.2), the gene encoding the 24-hydroxylase responsible for 25-OH-D and 1,25-(OH)2D degradation, are identified in about 20% of patients presenting Idiopathic Infantile Hypercalcemia (IIH) (MIM 143880). Common features of this autosomal recessive condition included hypercalcemia with hypercalciuria, suppressed PTH and a high 25-OH-D3:24,25-(OH)2D3 ratio. Medical care mainly relies on sun protection and life-long contraindication of vitamin D to avoid complications such as early nephrocalcinosis and renal failure.Molecular diagnosis therefore keeps a crucial place in the diagnosis of IIH, and genetic counseling should be systematically recommended to prevent vitamin D administration in affected siblings.In this report is described the molecular characterization of a CYP24A1 deletion identified in two unrelated families. This highlights the potential role of CYP24A1 copy number variations (CNV) in IIH. Considering the presence of CNV affecting CYP24A1 in public databases, CNV analysis should be systematically added to the sequencing studies in IIH. Targeted Massively Parallel Sequencing (MPS) study coupled with a CNV detection tool called CovCop is a powerful method to detect genic rearrangement and improve genetic analysis

Progressive osseous heteroplasia: a model for the imprinting effects of GNAS inactivating mutations in humans.

International audienceCONTEXT: Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, and studies in different families have shown that POH is also caused by paternally inherited GNAS mutations. OBJECTIVE: Our purpose was to characterize parental origin of the mutated allele in de novo cases of POH and to draw phenotype/genotype correlations according to maternal or paternal transmission of a same GNAS mutation. DESIGN AND SETTING: We conducted a retrospective study on patients addressed to our referral center for the rare diseases of calcium and phosphorus metabolism. PATIENTS AND METHODS: We matched 10 cases of POH with cases of pseudohypoparathyroidism type 1a carrying the same GNAS mutations. MAIN OUTCOME MEASURES: The parental origin of the mutated allele was studied using informative intragenic polymorphisms and subcloning of PCR products. RESULTS: Paternal origin of GNAS mutations was clearly demonstrated in eight POH cases including one patient with mutation in exon 1. Genotype/phenotype analyses suggest that there is no direct correlation between the ossifying process and the position of the inactivating GNAS mutation. It is, however, more severe in patients in whom origin of the mutation is paternal. Severe intrauterine growth retardation was clearly evidenced in paternally inherited mutations. CONCLUSIONS: Clinical heterogeneity makes genetic counseling a delicate matter, especially in which paternal inheritance is concerned because it can lead to either a mild expression of pseudopseudohypoparathyroidism or a severe expression of POH

Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties

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