A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

Table 1

Syndactyly in humans classified according to the steps shown in Figure 1.

Step affected	Gene mutation	Name of syndrome or type of syndactyly as per Malik’s classification (OMIM if available)
IA: activation of the WNT canonical signaling or the accumulation of beta catenin	(i) LRP4	(i) Cenani–Lenz syndrome or type 7a syndactyly (212780)
	(ii) APC	(ii) Cenani–Lenz phenotype
IB: suppression of the BMP canonical signaling	(i) FMN1 deletions or duplication encompassing GREM1-FMN1	(i) Cenani–Lenz phenotype or type 7b syndactyly
	(ii) ZRS	(ii) Haas (type 4) syndactyly (186200); triphalangeal thumb polysyndactyly syndrome (174500)
	(iii) RAB23	(iii) Carpenter syndrome (201000)
	(iv) TWIST1	(iv) Saethre–Chotzen syndrome (101400)
	(v) GLI3	(v) Greig syndrome (175700) and other GLI3-related syndactyly
	(vi) GJA1	(vi) Johnston–Kirby type 3 syndactyly (186100)
II: increased activity of FGF8	(i) Gain-of-function mutations of FGFR1 or FGFR2	(i) Pfeiffer (101600), Apert (101200), and Saethre-Chotzen (101400) syndromes.
	(ii) FBLN1	(ii) Debeer type 2b syndactyly (608180)
III: suppression of retinoic acid or suppression of apoptosis/matrix degradation	(i) HOXD13	(i) Vordingborg type 2a syndactyly (186000) and syndactyly type 5 (186300)