Figure 3

Models for a modifier(s) and effects of the duplication size. In models A-C, the yellow bars show chromosome 17, and the light green bars indicate other chromosomes. The two red dots represent the duplication at 17p13.3, and the blue dots indicate a putative modifier(s). Black painted diamonds represent limb malformation positive patients, dot-associated and gray painted diamonds indicate clinically normal carriers with the duplications and the modifier(s) respectively, and white painted diamonds denote clinically normal subjects without both the duplications and the modifier(s). A. This model assumes that co-existence of the duplication and a cis-acting modifier(s) causes limb malformation. If co-existence of the duplication and the cis-acting modifier(s) is associated with incomplete penetrance, this can explain all the transmission patterns observed to date, including the patient-to-carrier transmission and the presence of ≥ 2 affected children. B. This model postulates that the presence of a cis-acting modifier(s) on the normal chromosome 17 leads to limb malformation by enhancing the expression of the single BHLHA9, together with duplicated BHLHA9 on the homologous chromosome. C. This model postulates that co-existence of the duplication at 17p13.3 and a modifier(s) on other chromosome causes limb malformation. In models D-E, the red bars represent BHLHA9, the blue circles indicate a physiological cis-regulatory element for BHLHA9, and the green circles indicate a non-physiological modifier(s) for BHLHA9. D. The physiological cis-regulatory element may be duplicated or non-duplicated, depending on its position relative to the size of the duplications. BHLHA9 expression can be higher in small duplications than large duplications. E. The non-physiological modifier(s) can be transferred to various positions of the duplication positive chromosome 17, depending on the recombination places (see Model A). BHLHA9 expression can be higher in small duplications than large duplications irrespective of the position of the modifier(s).