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This summary outlines the association between USB1 (HGNC:25792) and poikiloderma with neutropenia (MONDO:0011405). Poikiloderma with neutropenia is a rare autosomal recessive genodermatosis characterized by early‐onset skin changes, neutropenia, and recurrent infections. Multiple independent case reports have established that biallelic mutations in USB1 are causative for this phenotype (PMID:23823120). The disorder exhibits a consistent clinical picture across diverse populations, underscoring the gene–disease specificity.
Genetic evidence is robust with several reports describing novel and recurrent mutations in USB1. Among these, the variant c.267T>G (p.Tyr89Ter) has been identified in unrelated probands and underscores a founder effect in certain populations (PMID:22269211). Case series across different ethnic groups, including studies that identified up to 77 probands worldwide, reinforce the pathogenicity of USB1 variants. Segregation data from multi‐family studies further strengthens the role of this gene in the disease etiology (PMID:26987923).
Clinical reports detail that patients often present with hallmark features such as poikiloderma, neutropenia, and respiratory tract infections (e.g., pneumonia), along with other variable findings including growth delay and hyperpigmentation. Extended pedigree analyses have documented additional affected relatives, with a total tally of at least 19 affected members segregating the USB1 mutation within families. This convergence of clinical features and familial segregation patterns supports an unequivocal gene–disease correlation (PMID:35522049).
Beyond the clinical observations, the variant spectrum identified in USB1 spans several types of mutations including missense, frameshift, and splice site changes. The recurring observation of similar variant classes in independent case series indicates that loss-of-function is the predominant mechanism underlying poikiloderma with neutropenia. The consistent molecular findings, including the detection of the c.267T>G (p.Tyr89Ter) change, provide clear genetic evidence of pathogenicity across different cohorts.
Functional studies have been pivotal in delineating the molecular mechanism of USB1-associated pathogenesis. Experimental models demonstrate that USB1 encodes a phosphodiesterase responsible for the 3' end modification of U6 snRNA, a critical component for mRNA splicing. In human cell and yeast models, perturbation of USB1 function results in impaired snRNA maturation and aberrant miRNA deadenylation, which recapitulates the hematopoietic defects observed in patients (PMID:22899009; PMID:36862787). These findings provide a biologically plausible mechanism that links the molecular defect to the clinical phenotype.
In summary, the comprehensive genetic and experimental evidence firmly supports a strong gene–disease association between USB1 and poikiloderma with neutropenia. The convergence of multiple independent case reports, robust segregation analyses, and concordant functional data provides high confidence for this association. Key take‑home: incorporating USB1 genetic testing into diagnostic workflows is essential for accurate diagnosis and effective management of patients with poikiloderma with neutropenia.
Gene–Disease AssociationStrongMultiple independent case reports (>77 probands PMID:26987923) and robust segregation analyses across families establish a strong link between USB1 and poikiloderma with neutropenia. Genetic EvidenceStrongRecurrent and diverse loss-of-function mutations, including c.267T>G (p.Tyr89Ter), observed in unrelated probands and founder populations, support the pathogenic role of USB1 (PMID:22269211). Functional EvidenceStrongFunctional assays demonstrating impaired U6 snRNA processing and defective miRNA deadenylation in USB1-mutant cells align with the observed clinical phenotype (PMID:22899009; PMID:36862787). |