On the association between Chiari malformation type 1, bone mineral density and bone related genes

Núria Martínez-Gil; Leonardo Mellibovsky; Demián Manzano-López González; Juan David Patiño; Monica Cozar; Raquel Rabionet; Daniel Grinberg; Susanna Balcells

doi:10.1016/j.bonr.2022.101181

On the association between Chiari malformation type 1, bone mineral density and bone related genes

Bone Rep. 2022 Mar 15:16:101181. doi: 10.1016/j.bonr.2022.101181. eCollection 2022 Jun.

Authors

Núria Martínez-Gil¹, Leonardo Mellibovsky², Demián Manzano-López González³, Juan David Patiño¹, Monica Cozar¹, Raquel Rabionet¹, Daniel Grinberg¹, Susanna Balcells¹

Affiliations

¹ Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, CIBERER, IBUB, IRSJD, Barcelona, Spain.
² Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Spain.
³ Servicio de Neurocirugía, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain.

Abstract

Background: Chiari malformation type 1 (C1M) is a neurological disease characterized by herniation of the cerebellar tonsils below the foramen magnum. Cranial bone constriction is suspected to be its main cause. To date, genes related to bone development (e.g. DKK1 or COL1A2) have been associated with C1M, while some bone diseases (e.g. Paget) have been found to cosegregate with C1M. Nevertheless, the association between bone mineral density (BMD) and C1M has not been investigated, yet. Here, we systematically investigate the association between C1M and BMD, and between bone related genes and C1M.

Methods: We have recruited a small cohort of C1M patients (12 unrelated patients) in whom we have performed targeted sequencing of an in-house bone-related gene panel and BMD determination through non-invasive DXA.

Results: In the search for association between the bone related genes and C1M we have found variants in more than one C1M patient in WNT16, CRTAP, MYO7A and NOTCH2. These genes have been either associated with craniofacial development in different ways, or previously associated with C1M (MYO7A). Regarding the potential link between BMD and C1M, we have found three osteoporotic patients and one patient who had high BMD, very close to the HBM phenotype values, although most patients had normal BMD.

Conclusions: Variants in bone related genes have been repeatedly found in some C1M cases. The relationship of bone genes with C1M deserves further study, to get a clearer estimate of their contribution to its etiology. No direct correlation between BMD and C1M was observed.

Keywords: BMD, Bone Mineral Density; Bone mineral density; C1M, Chiari Malformation type 1; CRTAP; Chiari malformation type 1; HBM, High Bone Mass; MYO7A; NOTCH2; WNT16.