Nanopore-based haplotype-resolved X-chromosome inactivation analysis for clinical severity assessment in X-linked disorders: an AIFM1 family study with proof-of-concept application to a mosaic PDHA1 carrier

Haplotype-resolved Nanopore (long-read) workflow for clinical analysis of X-chromosome inactivation (XCI) and severity assessment of X-linked diseases in carrier females

A haplotype-resolved Nanopore workflow is developed for clinical analysis of X-chromosome inactivation (XCI) in female carriers of X-linked pathogenic variants. Applied to a family with an AIFM1 variant showing marked intrafamilial phenotypic variability, the workflow demonstrates that XCI bias correlates with clinical severity in carriers. A proof-of-concept is also performed in a mosaic PDHA1 carrier, showing the transferability of the approach.

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Clinical quantification of XCI bias is a recurring challenge in X-linked disease genetics — often insufficiently precise with standard methods (HUMARA methylation). This haplotype-resolved Nanopore workflow opens a path toward a clinically applicable tool for genetic counseling of carrier females, particularly when unexplained phenotypic variability is present.