Pyle disease is a rare autosomal recessive bone dysplasia characterized by the broadening of metaphyses with generalized cortical thinning. Homozygous truncating mutations in secreted frizzled-related protein 4 (SFRP4) were, to date, the only known variants causative for this type of skeletal disorder. It is the first SFRP4 missense mutations that occurred in compound heterozygosity in two siblings affected by Pyle disease, and have been identified using a whole-genome sequencing approach followed by a comprehensive in silico pathogenicity assessment. Pyle disease may be related not only to SFRP4 truncating mutations but also to other loss-of-function alterations that possibly impair the protein capacity to bind WNT ligands.

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