Fig. 4

Combination of preferential X inactivation and rearrangement-mediated disruption of NHS causes Nance–Horan syndrome in X-autosome balanced translocation carrier females. a X-inactivation studies were performed on the maternal half-sister using the incorporation of 5-ethynyl-2′-deoxyuridine (EdU) assay [15]. A skewed X-inactivation pattern with preferential inactivation of the normal X chromosome containing a normal NHS gene was revealed. Blue, DAPI counter-staining; Green, EdU; Orange, FISH signals from NHS and 19q subtel. Normal X has an NHS orange signal located interstitially, while derivative chromosome X has a 19q subtel orange signal located at the tip of the chromosome. Late-replicated chromosomes X were labeled strongly and extensively with EdU green signals across the chromosome relative to the other chromosome X and autosomes. Late replication is associated with X chromosome inactivation. b Screwdriver-shaped incisors are seen in the proband’s maternal half-sister (III-2). c Phenotypic comparison of allelic disorders caused by different dosages of NHS. d Quantitative model of dose effects of NHS on disease presentation and phenotype expressivity. hypo: NHS hypomorphic allele; mut: NHS truncating mutation allele; wt: NHS wild-type allele. NHS: Nance–Horan synfrome. CXN: X-linked congenital cataract. XLD: X-linked dominant. XL: X-linked. NA: not applicable. + : phenotype present. −: phenotype absent.?: phenotype unknown. XX, female; XY, male