ABSTRACT
Osteogenesis Imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and fracture. Mutations in 20 distinct genes can cause OI, and therefore, the genetic diagnosis of OI is frequently difficult to obtain because of the great number of genes that can be related with this disease. Studies that report the most frequently mutated genes in OI patients can help to improve molecular strategies for diagnosis of the disease. In order to characterize the mutation profile of OI in Brazilian patients, we analyzed 30 unrelated patients through SSCP screening, NGS gene panel, and/or Sanger sequencing for the 11 most frequently mutated genes in the database of mutations, including COL1A1, COL1A2, P3H1, CRTAP, PPIB, SERPINH1, SERPINF1, FKBP10, SP7, WNT1 and IFITM5. Disease-causing variants were identified in COL1A1, COL1A2, FKBP10, P3H1, and IFITM5. A total of 28 distinct mutations were identified, including seven novel changes. Our data show that the analysis of these five genes is able to detect at least 95% of causative mutations in OI disorder from Brazilian population. However, it has to be taken into considerations that distinct populations can have different frequencies of disease-causing variants. Hence, it is important to replicate this study in other groups.
ABSTRACT
Approximately a hundred patients with terminal 10q deletions have been described. They present with a wide range of clinical features always accompanied by delayed development, intellectual disability and craniofacial dysmorphisms. Here, we report a girl and a boy with craniosynostosis, developmental delay and other congenital anomalies. Karyotyping and molecular analysis including Multiplex Ligation dependent probe amplification (MLPA) and Array Comparative Genomic Hybridization (aCGH) were performed in both patients. We detected a 13.1 Mb pure deletion at 10q26.12-q26.3 in the girl and a 10.9 Mb pure deletion at 10q26.13-q26.3 in the boy, both encompassing about 100 genes. The clinical and molecular findings in these patients reinforce the importance of the DOCK1 smallest region of overlap I (SRO I), previously suggested to explain the clinical signs, and together with a review of the literature suggest a second 3.5 Mb region important for the phenotype (SRO II). Genotype-phenotype correlations and literature data suggest that the craniosynostosis is not directly related to dysregulated signaling in suture development, but may be secondary to alterations in brain development instead. Further, genes at 10q26 may be involved in the molecular crosstalk between brain and cranial vault.
