Overlapping Xq13.3 duplications define an X-linked hypotrichosis simplex and implicate TAB3 dosage sensitivity.

Xq13.3 duplication increasing TAB3 dosage and dysregulating TAK1-NF-κB signaling

Three unrelated families present with X-linked hypotrichosis simplex (XLHS): normal hair at birth followed by progressive scalp thinning, more severe in males. Partially overlapping Xq13.3 duplications define a critical interval spanning TAB3, FTHL17 and part of DMD. Only TAB3 protein accumulates in affected scalp, pointing to TAB3 as the most likely dosage-sensitive driver. Mouse and keratinocyte TAB3-overexpression models recapitulate the phenotype via impaired TAK1-NF-κB signaling, and anti-inflammatory treatment improved hair density.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A convincing dosage-causality demonstration, backed by tissue proteomics and functional models, defining a previously unrecognized X-linked entity. The anti-inflammatory therapeutic lead is preliminary but mechanistically coherent. Interpreting such regulatory duplications remains a challenge for WGS pipelines.

Analysis by Dr Thibaut Benquey