Poster Presentation ESA-SRB-APEG-NZSE 2022

Dominant Osteogenesis Imperfecta Caused by a Heterozygous SP7 Variant (#466)

Karissa Ludwig 1 2 3 , Leanne Ward 4 , Nasrin Khan 4 , Marie-Eve Robinson 4 , Valancy Miranda 3 , Ghalib Bardai 3 , Pierre Moffatt 3 , Frank Rauch 3
  1. Queensland Children's Hospital, Brisbane, QLD, Australia
  2. West Moreton Health, Ipswich, QLD, Australia
  3. Shriners Hospitals for Children, Canada, Montreal, QC, Canada
  4. Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

Mutations in SP7 (osterix) have been identified as a rare cause of recessive osteogenesis imperfecta (‘OI type XII’) (1-3) and in two cases of dominant disease with bone fragility, high bone density and high bone turnover (4, 5). We present the first description of siblings with OI due to a heterozygous mutation in SP7.

The phenotype was characterized by fragility fractures (primarily of the long bone diaphyses), poor healing, scoliosis, and dental malocclusion. Both siblings had very low cortical volumetric bone mineral density on peripheral quantitative computed tomography of the radius (z-scores -6.6 and -6.7 at the diaphysis), porous cortices, and thin cortices at the radial metaphysis. Histomorphometry demonstrated thin cortices and low bone turnover with reduced osteoblast function. Both siblings were heterozygous for a missense variant in a highly conserved zinc finger domain of SP7 (c.1019A>C; p.Glu340Ala) on DNA sequencing. Co-transfection of plasmids carrying the SP7 mutation with DLX5 and a luciferase reporter demonstrated that this variant impacted gene function (reduced transcription co-activation compared to wild-type SP7).

The low cortical density and cortical porosity seen in our patients are consistent with previous reports of recessive OI due to SP7 mutations (1). However, the low bone turnover in our patients contrasts the high turnover state seen in patients with OI due to recessive SP7 mutations and in the cases with dominant SP7 mutations with high bone density (1, 4, 5).

This report indicates that dominant variants in SP7 can give rise to OI. The predominant feature, low cortical density, is common in patients with recessive SP7 mutations, however other features appear to depend on the specific variant.

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  2. 2. Lapunzina P, Aglan M, Temtamy S, Caparrós-Martín JA, Valencia M, Letón R, et al. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. American journal of human genetics. 2010;87(1):110-4.
  3. 3. Hayat A, Hussain S, Bilal M, Kausar M, Almuzzaini B, Abbas S, et al. Biallelic variants in four genes underlying recessive osteogenesis imperfecta. Eur J Med Genet. 2020;63(8):103954.
  4. 4. Whyte MP, Campeau PM, McAlister WH, Roodman GD, Kurihara N, Nenninger A, et al. Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7). Bone. 2020;137:115364.
  5. 5. Lui JC, Raimann A, Hojo H, Dong L, Roschger P, Kikani B, et al. A neomorphic variant in SP7 alters sequence specificity and causes a high-turnover bone disorder. Nat Commun. 2022;13(1):700.