Background Congenital pulmonary airway malformation type IV (CPAM IV) and pleuropulmonary blastoma (PPB) exhibit significant radiographic and histopathological overlap, making their differentiation challenging. While DICER1 mutations are known to predispose individuals to the PPB spectrum, the molecular association between CPAM IV and early-stage PPB remains controversial. Case presentation We report a girl pathologically diagnosed with CPAM IV. Whole-exome sequencing (WES) of the lesion tissue identified a heterozygous splicing variant in the DICER1 gene (c.4206 + 1G > T). Sanger sequencing subsequently confirmed this variant to be germline, inherited from her asymptomatic father. Bioinformatic analysis predicted that this variant disrupts the highly conserved donor splice site of intron 22. Functional validation by RT-PCR demonstrated that the c.4206 + 1G > T variant results in exon fragment deletion. According to the ACMG/AMP guidelines, this variant was classified as likely pathogenic. Additionally, a somatic DICER1 hotspot mutation (c.5438A > G p.E1813G) was detected in the tissue, consistent with the two-hit tumorigenesis model. At the 22-month postoperative follow-up, although chest CT revealed a small cystic lucency with surrounding calcification, the patient remained clinically stable, without evidence of malignant progression or extrapulmonary involvement. Conclusion This article reports a case of CPAM IV carrying a pathogenic germline variant and a somatic hotspot mutation in the DICER1 gene. Our findings support the view that DICER1-associated CPAM IV may represent an early stage within the PPB disease spectrum. Given the incomplete penetrance of DICER1 syndrome and an approximately 50% risk of transmission to offspring, we propose that DICER1 genetic testing could be considered for selected pediatric patients diagnosed with CPAM IV, regardless of family history. This approach may aid in early and accurate differentiation, inform surgical management, and guide the development of appropriate long-term surveillance strategies.
Ya Dao, Shan Pei, Xichen Zhang et al.· Frontiers in Pediatrics· 0 citations
BACKGROUND
Primary ciliary dyskinesia (PCD) is a rare genetic disorder that is predominantly inherited in an autosomal recessive pattern and is caused by structural or functional ciliary abnormalities. Previous studies on the genetic susceptibility prevalence of PCD have been largely based on limited populations, and there is a lack of global estimates derived from large-scale population genetic databases. This study estimates the carrier frequency and genetic susceptibility prevalence of PCD via the latest data from the gnomAD v4.1.0 database and compares the results with those of previous studies.
METHODS
We selected genes related to PCD with "Definitive" or "Strong" associations as determined by the ClinGen Motile Ciliopathy Gene Curation Expert Panel. According to ACMG/AMP guidelines, variables were classified for pathogenicity, including loss-of-function variants (pLOFs) and pathogenic/likely pathogenic missense variants. Using the allele frequency (AF) of these variants from the Genome Aggregation Database (gnomAD) v4.1.0 (containing data from 807,162 individuals) and applying the Hardy‒Weinberg equilibrium principle, we calculated the global and population-specific genetic susceptibility prevalence and carrier frequency of PCD.
RESULTS
Among the 31 PCD-associated genes, 5252 eligible variants were included, comprising 5156 pLOF and 96 P/LP variants. The estimated global genetic susceptibility prevalence of PCD is approximately 1 in 20,103, with a corresponding overall carrier frequency of approximately 1 in 25. The Middle East region has the highest prevalence rate of 1 in 4,744, as well as the highest carrier frequency.
CONCLUSION
The estimated global genetic susceptibility prevalence of primary ciliary dyskinesia is approximately 1 in 20,103, with an overall carrier frequency of 1 in 25, indicating significant heterogeneity among ethnic populations. The global genetic susceptibility prevalence estimate is lower than the previous estimate of 1/7,554.
Rutao Dai, Ya Dao, Xichen Zhang et al.· Orphanet Journal of Rare Dis...· 0 citations
