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

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.

Fig. 1

Pedigree of the three C1M families. In black the C1M members, the arrow indicates the proband, the alterantive allele of the variant is highlighted in red color.

Fig. 2

Linear representation of the WNT16 (A), CRTAP (B), MYO7A (C) and NOTCH2 (D) with its domains and regions. For WNT16 in orange N-terminal domain, in yellow the CRD domain, in light brown thumb domain, in dark brown finger and in orange circles the O-palmitoleoyl serine modification (reviewed in Martínez-Gil et al., 2022). For CRTAP in green the tetratico repeat motif, triangles show the four CXXXC domains from (Ishikawa and Bächinger, 2013). For MYO7A in dark blue the Myosin motor and in red the actin binding site, in dark yellow the isoleucine-glutamine (IQ) motif, in pink the Single alpha-helix (SAH) domain, in green the Myosin Tail Homology 4 (MyTH4) domains, in light blue the FERM domains and in purple the SRC Homology 3 (SH3) domain from uniprot. For NOTCH2 in yellow the EGF-like domain, in orange the EGF-like with calcium binding, in green the cysteine-rich Lin-12/Notch (LNR) Repeats and in dark blue the Ankyrin (ANK) domains from uniprot.The black arrow signals the position of the variants found and ID patient where is found.