Advancing Standardization in Fragile X Syndrome Molecular Diagnosis: A Dual-Structured and Scoping Review

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Abstract
Background: Fragile X syndrome (FXS) requires molecular confirmation, yet diagnostic workflows vary in their capacity to characterize expansions and connect diagnosis with subsequent care. This review evaluated alignment between current recommendations and published diagnostic practice. Methods: We combined a structured review of recommendations for FMR1 molecular diagnosis, complementary testing, genetic counseling, and family testing with a scoping review of peer-reviewed primary studies reporting FMR1 diagnostic or screening workflows relevant to pediatric FXS. PubMed/MEDLINE, Embase, and Scopus were searched without date restrictions. Thirty-four studies were included, with design-specific risk-of-bias assessment and exploratory exact analyses of factors associated with post-initial FMR1 testing. Results: Molecular or genomic testing was reported in all 34 studies, but workflows ranged from conventional PCR and Southern blot to TP-PCR, methylation-sensitive assays, and sequencing-based approaches. Post-initial FMR1 testing was reported in 22/34 studies (64.7%), with positive-result follow-up documented in 19/34 (55.9%) and follow-up of inconclusive or initially negative results in 14/34 (41.2%). FMR1 sequencing was uncommon (3/34, 8.8%). Genetic counseling was addressed in 32/34 studies (94.1%), but documented as delivered in only 9/34 (26.5%); family evaluation and multidisciplinary management were also inconsistently reported. Conclusions: Published evidence broadly supports molecular FMR1 testing but shows variability in molecular characterization and downstream care. Standardization should prioritize analytically appropriate workflows, additional testing when required by the initial result or assay limitations, and stronger integration of molecular diagnosis with genetic counseling, family evaluation, and multidisciplinary management.
Funding Information
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (001)

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