Dyggve-Melchior-Clausen Syndrome in Ecuador: Expanding Knowledge on a Rare Genetic Disorder

Abstract

Background: Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal recessive skeletal dysplasia characterized by dwarfism, coarse facial features, and intellectual disability. Caused by loss-of-function variants in the DYM gene, which encodes dymeclin, DMC is predominantly reported in consanguineous populations but remains poorly studied in South America. Methods: We report a 21-year-old Ecuadorian male with clinical features suggestive of DMC. Comprehensive clinical, radiological, and genetic evaluations were conducted, including clinical exome sequencing and Sanger sequencing, followed by an in silico analysis to assess the structural and functional consequences of the identified variant. Results: Exome sequencing identified a homozygous c.1878delA (p.Lys626fs) frameshift variant in the DYM gene, which was confirmed by Sanger sequencing as inherited from heterozygous parents. Variants of uncertain significance were detected in other skeletal dysplasia-related genes but did not correlate with the phenotype. A comprehensive review of reported DYM variants was also conducted. Conclusions: This report documents the first case of DMC in Ecuador and the second in South America, expanding the global understanding of DMC's genetic diversity. It underscores the value of next-generation sequencing in rare disease diagnostics and highlights the critical need for inclusive genomic research in underrepresented populations to improve the understanding of genetic heterogeneity and rare disease epidemiology.

Keywords: DYM gene; Dyggve–Melchior–Clausen syndrome (DMC); Ecuador; Mestizo population; c.1878delA; dymeclin; rare genetic disorders.

Figure 1

Clinical and radiographic findings of the patient diagnosed with Dyggve–Melchior–Clausen syndrome. (A) Frontal, posterior, and lateral views illustrating short stature (-3 SD); coarse facial features; short trunk; kyphosis; pectus carinatum; and hip deformities. (B) Pelvic X-ray showing acetabular dysplasia. (C) Lateral radiograph of the dorsal spine revealing platyspondyly.

Figure 2

Family pedigree, genetic, and protein analysis of the reported case. (A) Pedigree illustrating the autosomal recessive inheritance pattern and the family members studied during the initial genetic evaluation. (B) Electropherogram showing the c.1878delA variants in DYM: the proband is homozygous for the deletion, whereas the father, mother, and sibling are heterozygous carriers. (C) Schematic representation of the DYM gene (green boxes denote exons). The transparent box highlights the coding region, showing the distribution of frameshift variants (orange boxes) and nonsense variants (purple boxes) previously reported worldwide in individuals with DMC syndrome. (D) Predicted functional domains of the DYM reference sequence. The in silico analysis identifies non-cytoplasmic (blue), transmembrane (purple), and cytoplasmic (yellow) domains. (E) DYM protein sequence harboring the c.1878delA variants. In the mutated sequence, only the non-cytoplasmic domain (blue) is predicted by InterPro. The remaining regions, which are not annotated as functional domains, are shown in gray. The segment highlighted in red represents the portion of the reference sequence that is lost as a result of the frameshift variants and subsequent premature termination. This model was generated using the mutant sequence to illustrate the predicted structural consequences of the c.1878delA variant.