DYNC1I2 and Beckwith-Wiedemann Syndrome

This summary evaluates the association between DYNC1I2 (HGNC:2964) and Beckwith-Wiedemann syndrome (MONDO_0007534) by integrating evidence from a detailed case report and several multi‑patient studies. A pediatric case describing type 1 diabetes in a patient with BWS (PMID:39027637) highlights an unusual clinical overlap, drawing attention to the potential involvement of DYNC1I2 in the disorder.

Genetic evidence comprises a single well‐characterized case report alongside cohort assessments from multi‑patient studies. The cohorts – with molecular diagnostic testing and methylation analyses – provide additional epidemiological context (PMID:24982696, PMID:22585446, PMID:23918458, PMID:28699632) but fall short of demonstrating extensive segregation or recurrence across unrelated probands.

In terms of variant-level evidence, one representative variant – formatted as per HGVS guidelines – is identified as c.740A>G (p.Tyr247Cys) from functional assessment studies. Although this variant was originally reported in the context of a syndromic microcephaly phenotype (PMID:31079899), it is used here to illustrate the type of coding change observed in DYNC1I2.

While multiple studies have used comprehensive molecular diagnostic strategies in BWS, the segregation data for DYNC1I2 variants in affected families is limited. There is a noted absence of multiple affected relatives demonstrating clear cosegregation of the variant with the phenotype, thereby tempering the strength of the genetic evidence.

Functional assays in model systems have confirmed that DYNC1I2 plays an essential role in neurodevelopment and intracellular transport. However, direct experimental validation linking DYNC1I2 dysfunction with the pathogenic processes underlying Beckwith-Wiedemann syndrome is lacking (PMID:31079899).

In conclusion, while there is some evidence supporting an association between DYNC1I2 and Beckwith-Wiedemann syndrome, the overall argument remains limited by scant segregation data and the indirect nature of variant evidence. Key take‑home: further focused studies are needed before DYNC1I2 can be robustly incorporated into diagnostic guidelines for BWS.

References

• JCEM case reports • 2024 • Type 1 Diabetes in a Pediatric Patient With Beckwith-Wiedemann Syndrome PMID:39027637
• Clinical epigenetics • 2014 • Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects PMID:24982696
• American journal of medical genetics. Part A • 2012 • Brain abnormalities in patients with Beckwith-Wiedemann syndrome PMID:22585446
• American journal of medical genetics. Part A • 2013 • Prevalence of Beckwith-Wiedemann syndrome in North West of Italy PMID:23918458
• European journal of human genetics : EJHG • 2017 • Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines PMID:28699632
• American journal of human genetics • 2019 • Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features PMID:31079899

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