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Recent multi‐patient studies have clearly established a robust association between heterozygous mutations in SNRPB and cerebrocostomandibular syndrome. The evidence stems from a combined analysis of 16 patients from one study (12 sporadic and 4 familial cases (PMID:26971886)) and additional cases from independent investigations (PMID:25504470). In these patients, recurrent intronic mutations affecting an alternatively spliced regulatory exon were consistently observed.
The genetic data demonstrate that the disease follows an autosomal dominant inheritance pattern. Multiple familial cases provided segregation evidence, with affected relatives being observed in each pedigree, thereby reinforcing the association between SNRPB variants and the disorder. Specifically, the familial transmission of altered SNRPB supports the role of a dominant negative or haploinsufficiency mechanism.
Detailed genetic evidence comes from reported variants such as c.155+302G>C. Although classified as an intronic change, this variant is predicted to alter the splicing machinery of SNRPB, thereby disrupting normal transcript regulation. Additional recurrent variants, including c.155+301G>C and c.155+406C>A, further underscore the specificity of SNRPB mutations in cerebrocostomandibular syndrome.
Functional assays have provided compelling experimental support for the pathogenicity of these variants. Quantitative RT-PCR analysis in patient leukocytes revealed a significant increase in the PTC-introducing transcript, in line with the expected splicing disruption (PMID:25504470). Moreover, knockdown models in Xenopus and other systems have recapitulated key craniofacial and thoracic malformations, linking the molecular defect directly to the clinical phenotype.
The aggregated evidence from both genetic and functional studies justifies a ClinGen categorization of the gene-disease association as Strong. Over 21 probands collectively have been described with these recurrent mutations, and the segregation data from familial cases coupled with direct experimental demonstration of mis-splicing provide a coherent mechanistic narrative.
Key take‑home: SNRPB mutation screening is clinically valuable for the accurate diagnosis of cerebrocostomandibular syndrome, with both genetic and functional evidence converging on a definitive pathogenic mechanism.
Gene–Disease AssociationStrongA total of 21 probands across independent studies, including clear familial segregation (PMID:26971886) and concordant functional findings (PMID:25504470). Genetic EvidenceStrongMultiple recurrent intronic variants (e.g. c.155+302G>C) have been identified in 21 probands with cerebrocostomandibular syndrome, with segregation observed in familial cases. Functional EvidenceStrongFunctional assays, including quantitative RT-PCR and animal model knockdowns, demonstrate that SNRPB mutations lead to mis‐splicing and recapitulate key craniofacial and thoracic phenotypes. |