Skip to main content

Conference Program

Subpage Hero

Loading

Analysis of the Clinical and Genetic Characteristics of Twelve Skeletal Disorders in Mexican Patients

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
To date, 771 skeletal disorders (SD) caused by pathogenic variants in 552 genes have been described. These diseases affect bone homeostasis and development, leading to alterations in bone length, density, and/or shape.

In Mexico, molecular diagnosis of SD is not routinely performed; however, it is essential to provide appropriate genetic counselling and to offer access to new, specific therapies. For this reason, our main objective was to analyze the clinical and genetic characteristics of twelve skeletal disorders in Mexican patients.

Methods:
A total of 113 Mexican patients with clinical characteristics suggestive of twelve SD were referred from hospitals nationwide: achondroplasia, hypochondroplasia, Crouzon with acanthosis nigricans, Muenke, Apert, Crouzon, Saethre Chotzen, tibial hemimelia-polysyndactyly- triphalangeal thumb, multiple cartilaginous exostoses, cleidocranial dysplasia, cartilage-hair hypoplasia, and metatropic dysplasia.

Molecular analysis was conducted in two stages. In stage one, the genes most frequently associated with each SD (according to the literature) were screened (57 fragments of 9 genes: FGFR3, FGFR2, TWIST1, LMBR1, EXT1, EXT2, RUNX2, RMRP, and TRPV4), using polymerase chain reaction followed by Sanger sequencing. In the second stage, patients without a causal variant underwent whole exome sequencing (WES).

If pathogenic/likely pathogenic variants were detected, molecular analysis was conducted on affected or carrier family members. For newly detected variants, in silico and family segregation analysis were performed to assess their pathogenicity.

 

Results:
The two most common diseases were achondroplasia (n=29, 25.7%) and multiple cartilaginous exostoses (n=20; 17.7%).  In the first molecular stage, a probable causal variant was found in 75 patients (66%), so the remaining 38 patients underwent WES. This analysis has been completed in 22 patients, finding pathogenic/likely pathogenic variants in four of them, and in two, the initial diagnosis changed. In eight patients, variants of uncertain significance (VUS) were identified, which could potentially explain their phenotypes; segregation analysis will be conducted for these variants to gather more information. Ten patients remain without a molecular diagnosis, and their clinical characteristics will be re-evaluated to determine further actions. So far, we have achieved a diagnostic yield of 81% (79/97), ranging from 100% (achondroplasia, Apert, Crouzon with acanthosis nigricans) to 0% (Saethre Chotzen).

Other diseases with a high diagnostic yield were multiple cartilaginous exostoses (85%) and cartilage-hair hypoplasia (75%).

We detected 38 different variants, nine of which were novel. Six in EXT1 (p.Y22IFs+114, p.R227DFs*25, p.D315QFs*5, c.1164+2T>A p.E540*, and p.L570Pfs*15) and one in EXT2 (c.627-1G>A). Based on in silico and segregation analysis, these were classified as pathogenic. For the RUNX2 novel variant p.T135Dfs*26,  segregation analysis has yet to be completed . Additionally, we lack sufficient tools to classify the novel RMRP variant n.-39_-19del, as it codifies a lncRNA.

Analysis of 41 relatives has been useful to detect affected individuals, carriers and to obtain more information of VUS or novel variants.

 

Conclusion:
The diagnostic yield of this study in Mexico (81%) is higher than those reported in other populations: Lv et al. achieved 49%, and Scocchia et al. 42%. A clinical assessment that includes a detailed physical examination along with all relevant radiographic and laboratory evaluations increases the likelihood of reaching a molecular diagnosis. Our high diagnostic yield primarily reflects the clinical expertise of the medical geneticists involved in the study.

However, this work also highlights the need for standardized assessments and measurements for Mexican patients, particularly in cases of hypochondroplasia. The knowledge gained from evaluating these SDs will be valuable in establishing a clinical-molecular diagnostic strategy for our patients, reducing the diagnostic odyssey, providing appropriate genetic counseling, and offering access to new or emerging specific therapies.

 

Agenda

Sponsors