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The First Report of Biallelic Missense Mutations in the SFRP4 Gene Causing Pyle Disease in Two Siblings
Anna Sowińska-Seidler1, Paweł Sztromwasser2,3, Katarzyna Zawadzka3
1Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Background:
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. SFRP4 controls cortical and trabecular bone remodeling by differential regulation of the canonical and non-canonical WNT signaling in both bone compartments. Loss-of-function mutations in the SFRP4 gene lead to the protein deficiency causing skeletal phenotype typical for Pyle disease.
Results:
Herein, we report on the first SFRP4 missense mutations that occurred in compound heterozygosity in two siblings affected by Pyle disease, and which we have identified using a whole-genome sequencing approach followed by a comprehensive in silico pathogenicity assessment. The variants we have found were extremely rare and evaluated to be disease-causing by several online available tools and software.
Conclusion:
With this paper, we have shown that 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. As we have expanded here, the range of deleterious variants underlying Pyle disease, we contribute to the knowledge on the pathogenesis of this rare skeletal disorder.
Insights
Pyle disease, a rare bone disorder, can be caused by new types of SFRP4 gene mutations beyond truncating variants. This expands our understanding of the skeletal disorder
Area of Science:
- Genetics
- Bone Biology
- Rare Diseases
Background:
- Pyle disease is a rare autosomal recessive bone dysplasia.
- It is characterized by broadened metaphyses and generalized cortical thinning.
- Previously, only homozygous truncating mutations in secreted frizzled-related protein 4 (SFRP4) were known to cause Pyle disease.
Purpose of the Study:
- To identify novel genetic variants associated with Pyle disease.
- To investigate the role of SFRP4 gene mutations beyond truncating variants.
Main Methods:
- Whole-genome sequencing was employed to identify genetic variants in affected siblings.
- In silico pathogenicity assessment was performed to evaluate the identified variants.
Main Results:
- The first SFRP4 missense mutations in compound heterozygosity were identified in two siblings with Pyle disease.
- These identified variants were extremely rare and predicted to be disease-causing.
Conclusions:
- Pyle disease can result from SFRP4 loss-of-function alterations beyond truncating mutations.
- These new findings expand the spectrum of deleterious variants underlying Pyle disease and contribute to understanding its pathogenesis.
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