The 3M syndrome is causally linked with the mutations on the genes CUL7, OBSL1 , and CCDC8 . (21). The Mostof the Mutation types reported for 3M syndrome appearing on the 8 exons that encoding Ig domains of OBSL1 proteins (22). (23). In our case, on theother hand, we detected that a novel nonsense mutation on OBSL1 gene isthe cause of 3M syndrome.
New studies about of OBSL1 gene and protein suggestedthat the OBSL1 protein functions in cytoskeletaladaptor. This protein linking the nuclear proteins to the cytoplasmic supportnetwork. Additionally, other studies showed function as a scaffold protein.(24)Postulatedthat this would be to stabilize the cytoskeletal network or act as a scaffoldfor signaling complexes with a proposal that disruption of OBSL1 would causeeither skeletal or cardiac myopathy (27).Additionaly, IGFBP-2 and IGFB5 messenger ribonucleicacid levels collaborated with OBSL1 mutations in 3M syndrome (25).(26).In our current investigation, c.
842G>A mutation likely induce the growth-regulatory pathway.There is no specific treatment for 3M syndrome (28). However, some researcherssuggestedusing of human growth hormone (GH) for treatment. This mutation was identifiedusing the targeted NGS method and were confirmed by Sanger sequencing, on OBSL1gene, where reported as MSBN-causingmutation, that were not previously reported in the Iranian population.Theclinical assessment for short stature is most important symptom to 3M diagnosis.However, the 3M syndrome can identify via differential diagnosis like with mildsymptomatology and wide variety of causal factors.Therefore, the molecular diagnosis hasuseful and important implications for the family.
Once a mutation was found inthe proband, carrier determination should be performed for other relatedasymptomatic family members. Unfortunately, family members of the proband werenot available for segregation analysis.Due to the fact that 3M syndrome isinherited via an autosomal recessive pattern, early genetic assessment leading to an early diagnosis can also aid in the genetic counselling for the rest of family members. In conclusion, 3M syndrome needs to be considered in the differential diagnosis of patients with growth failure, especially those with prenatal onset and characteristic symptoms.It is therefore concluded that NGS is anexcellent method to determine all types of disease causing and novel mutationson 3M gene.
With NGS we are able to determine deletions, duplications and smallmutations which can cause 3M syndrome in single experiment assay. Thedevelopment of genetics and the availability of high throughput screening technologyprovide a great opportunity to identify gene variants that may explain diseasephenotypes. This report is the first study to screen for mutations in 3-Msyndrome genes in clinically diagnosed patients from Iran. It confirms thegenetic heterogeneity of 3-M syndrome in Iran, and shows the importance ofusing NGS genetic testing to confirm the diagnosis.