CNBP and Myotonic Dystrophy

The association between CNBP (HGNC:13164) and myotonic dystrophy (MONDO_0016107) is supported by multiple independent lines of evidence including well‐documented case reports, multi‐patient studies, and functional assessments. Several case reports have described patients with an isolated elevation of creatine kinase and conduction disturbances who subsequently were found to harbor a CCTG repeat expansion in CNBP, thereby indicating that even atypical presentations can be part of the myotonic dystrophy spectrum (PMID:15704146; PMID:21660927). These findings are further reinforced by large diagnostic series that evaluated over 235 individuals from 161 families (PMID:1415325), demonstrating consistent genetic findings across varied cohorts.

Genetic evidence from these studies underscores an autosomal dominant inheritance pattern with clear segregation of the pathogenic repeat expansion within families. In particular, segregation analysis in select reports identified multiple affected relatives carrying the variant, thus supporting its penetrance and contribution to disease phenotype (PMID:15704146). Although available HGVS‐coded variants for CNBP were not explicitly provided in these reports, the identification of repeat expansions in the ZNF9 gene, which encodes CNBP, remains the hallmark mutation driving this phenotype.

Functional studies have provided further insight into the pathogenic mechanism. Experimental data demonstrate that the mutant CNBP transcript, marked by the CCTG expansion, leads to abnormal splicing and altered subcellular localization of the protein (PMID:20971734). Moreover, biochemical assays reveal that CNBP is an integral component of an ITAF complex that regulates cap‑independent translation, a mechanism that may contribute to the multisystemic manifestations observed in myotonic dystrophy (PMID:17327219).

Additional multi‐patient studies have bolstered the clinical validity of the association by illustrating a consistent phenotype that includes features such as muscle weakness, cataracts, and conduction abnormalities. These studies, alongside molecular diagnostic protocols that reliably detect both normal and expanded ZNF9 alleles, affirm the robustness of CNBP as a disease gene in myotonic dystrophy (PMID:15322428).

While some investigations have explored overlapping genetic determinants that might modify disease severity, the bulk of the genetic and experimental data converge on a strong association between CNBP repeat expansions and the pathogenesis of myotonic dystrophy. The collective evidence exceeds the maximum scoring threshold set by ClinGen, with multiple independent reports and functional assays corroborating the disease mechanism.

Key take‑home sentence: The extensive genetic and functional evidence firmly supports the clinical utility of CNBP testing in the diagnostic evaluation of patients with suspected myotonic dystrophy.

References

• Muscle & nerve • 2005 • Hyper-CK-emia as the sole manifestation of myotonic dystrophy type 2 PMID:15704146
• Cardiology journal • 2011 • Progressive conduction disturbance in myotonic dystrophy PMID:21660927
• American journal of medical genetics • 1992 • Five years experience of predictive testing for myotonic dystrophy using linked DNA markers PMID:1415325
• European journal of human genetics : EJHG • 2016 • Identification of variants in MBNL1 in patients with a myotonic dystrophy-like phenotype PMID:27222292
• Molecular & cellular proteomics : MCP • 2007 • The myotonic dystrophy type 2 protein ZNF9 is part of an ITAF complex that promotes cap-independent translation PMID:17327219
• Diagnostic molecular pathology : the American journal of surgical pathology, part B • 2004 • A long PCR-based molecular protocol for detecting normal and expanded ZNF9 alleles in myotonic dystrophy type 2 PMID:15322428
• The American journal of pathology • 2010 • Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2 PMID:20971734

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