Rare copy number variants in array-based comparative genomic hybridization in early-onset skeletal fragility

Alice Costantini; Sini Skarp; Anders Kampe; Maria Pettersson; Riikka Makitie; Minna Mannikko; Hong Jiao; Fulya Taylan; Anna Lindstrand; Outi Makitie

doi:10.1530/boneabs.6.P114

Objectives: Early-onset osteoporosis is characterized by low bone mineral density (BMD) and reduced bone strength since childhood or young adulthood. Although several monogenic forms have already been identified, the spectrum of mutations and genes behind this condition remain inadequately characterized. Furthermore, it is not clear whether genetic factors determine susceptibility to bone fractures in children with normal BMD. In order to further explore the genetic background we screened a cohort of 69 young Finnish patients with mild to severe skeletal fragility for novel pathogenic copy-number variants (CNVs).

Methods: We used a custom-made high-resolution 400K comparative genomic hybridization array (array-CGH) with enriched probe density in over 300 genes important for bone metabolism and over 800 genes involved in ciliary function. Findings were validated with breakpoint PCR or whole genome sequencing.

Results: The study cohort included 15 subjects with primary osteoporosis before age 30 years and 54 subjects with a pathological fracture history before age 16 years but mostly normal BMD. Overall, we identified three novel likely pathogenic CNVs: a 4.6-kb deletion involving exons 1-4 of COL1A2 (NM_000089.3), a 11-kb duplication of exon 3 in PLS3 (NM_005032.6) and a 1.6-Mb deletion affecting the entire ETV1 gene and in part DGKB. Mutations in COL1A2, encoding the α2 chain of type I collagen, and PLS3, encoding plastin 3, have already been linked to monogenic forms of osteoporosis but deletions in COL1A2 are rare and duplications have not been described in PLS3. Both CNVs were identified in subjects with significant osteoporosis and were present also in other affected members in the two families. Mutations in the transcription factor ETV1, which plays a role e.g. in Ewing sarcoma, and in the diacylglycerol kinase beta (DGKB), have not yet been associated with skeletal fragility. This third CNV therefore needs to be further investigated.

Conclusion: Our study expands the number of CNVs currently known to cause bone fragility and underscores the validity of this method in finding novel candidate genes for early-onset osteoporosis. This study has been supported by the Swedish Research Council. The authors declare no conflict of interest.

Disclosure: The authors declared no competing interests.

Bone Abstracts

P114