DVL1 – Robinow Syndrome

Robinow syndrome is a rare skeletal dysplasia characterized by facial dysmorphism, limb shortening, and digital anomalies. Multiple independent case reports and multi‐patient studies have implicated truncating variants in DVL1 as causative of this autosomal dominant disorder (PMID:25817016, PMID:25817014). These studies highlight that frameshift mutations in key domains of DVL1 lead to a protein product that disrupts downstream Wnt/planar cell polarity (PCP) signaling, central to normal skeletal development.

Genetic evidence shows that heterozygous pathogenic variants, such as c.1575_1582dup (p.Pro528ArgfsTer149), have been detected in multiple unrelated probands as well as in segregating family members (PMID:38982229). In several families, additional affected relatives carrying the mutant allele further substantiate the autosomal dominant inheritance pattern (PMID:35137569). The variant spectrum largely comprises frameshift mutations that lead to premature termination and loss of critical C-terminal domains of the protein.

Segregation analyses from these reports demonstrate that the mutant allele is present in affected members across generations, further consolidating the clinical correlation between DVL1 disruption and Robinow syndrome. Functional studies using cellular models have confirmed that these frameshift mutations result in a truncated protein that escapes nonsense-mediated decay, thereby perturbing the canonical and non-canonical Wnt signaling pathways (PMID:25817016). This experimental concordance directly connects the molecular defect with the observed phenotypic abnormalities.

Furthermore, comprehensive genotype–phenotype studies have revealed that the majority of DVL1 mutations cluster in the penultimate exon, an area critical for DEP domain function. These findings are supported by sophisticated in vitro assays where altered DVL1 activity was shown to disrupt normal signal transmission, consistent with the skeletal and craniofacial features seen in Robinow syndrome (PMID:25817014). The collective genetic and functional data not only benchmark the pathogenicity of these variants but also provide mechanistic insights into disease etiology.

Additional multi-family and cohort studies have reinforced the association between DVL1 mutations and the Robinow syndrome spectrum. Quantitative assessments from several reports indicate that a significant number of unrelated probands harboring de novo and familial truncating mutations add robust support for a strong gene–disease relationship (PMID:33048444). The convergence of mutation types, inheritance patterns, and functional aberrations places this association above ClinGen scoring thresholds.

In summary, robust genetic evidence, including segregation, variant spectrum, and functional validation, substantiates the role of DVL1 in autosomal dominant Robinow syndrome. The integration of clinical, molecular, and experimental data underscores the diagnostic utility of DVL1 testing. Key Take‑home sentence: Clinicians should incorporate DVL1 genetic analysis into the diagnostic workup for patients with features of Robinow syndrome to enable timely and precise management.

References

• Molecular genetics & genomic medicine • 2022 • A novel frameshift mutation of DVL1-induced Robinow syndrome: A case report and literature review PMID:35137569
• Prenatal Diagnosis • 2024 • Fetal phenotype and diagnosis of autosomal dominant Robinow syndrome due to novel DVL1 variant PMID:38982229
• American journal of human genetics • 2015 • Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome PMID:25817014
• American journal of human genetics • 2015 • DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome PMID:25817016
• American journal of medical genetics. Part A • 2021 • Novel pathogenic genomic variants leading to autosomal dominant and recessive Robinow syndrome PMID:33048444

Evidence Based Scoring (AI generated)