Table 2.

Genes/loci with postulated pathogenesis for non-syndromic syndactyly

Type of non syndromic syndactyly		Locus/gene	OMIM	Common variant/s	Inheritance	Clinical presentation	Postulated contribution to pathogenesis	Key references
I-a	ZD1; Zygodactyly; Weidenreich type	3p21.31	609815	n.r	AD	Bilateral, symmetrical, Fingers: Normal Toes: 2/3 only	n.r	[64]
I-b	SD1; Lueken type	2q34-q36	185900	n.r	AD	Usually, bilateral Fingers: 3/4 Fingers, cutaneous/bony Toes: 2/3 Toes, cutaneous	n.r	[68, 69]
I-c	Montagu type	2q31-q32 HOXD13	n.r	c.917G > A; p.R306Q, c.916C > G; p.R306G	AD	Typically, bilateral Fingers: 3/4 Fingers only, cutaneous/bony Toes: Normal	Suppression of Retinoic Acid	[70]
I-d	Castilla type	n.r	n.r	n.r	AD	Bilateral Fingers: Normal Toes: 4/5 Toes only, cutaneous	n.r	[71]
II-a	SPD1; Vordingborg type	2q31; HOXD13	186000	Polyalanine repeat expansions, frameshift deletions, 2q31.1 microdeletion and G11A missense	AD	Fingers: SPD, mesoaxial (3/4 fingers) Toes: SPD, postaxial (4/5 toes)	Suppression of Retinoic Acid	[72]
II-b	SPD2; Debeer type	22q13.3; FBLN1	608180	t(12;22) (p11.2;q13.3)	AD	Fingers: SPD is central and postaxial Toes: Postaxial syndactyly	Increased expression of FGFR8	[73]
II-c	SPD3; Malik type	14q11.2-q13	610,234	n.r	AD	Fingers: SPD is central Toes: SPD postaxial	n.r	[65]
III	SDTY3; Johnston-Kirby type	6q21-q23; GJA1	186100	nt427G > A and c.T274C; p.Y92H	AD	Fingers: Complete, bilateral syndactyly of 4/5 Fingers; fifth finger short, middle digit missing or underdeveloped Toes: Normal	Reduces downstream BMP2 expression, contributing to overexpression of the FGF4 and FGF8	[74–76]
IV-a	SDTY4; Haas type	7q36; ZRS (LMBR1)	186200	Heterozygous variants in the SHH regulatory element (ZRS), and duplications	AD	Complete and Bilateral, often polydactyly associated Fingers: All fingers webbed; pre-/post-axial polydactyly, cup-shaped hand Toes: Normal	Alter the ZRS control/limb-specific SHH expression	[77, 78]
IV-b	Andersen-Hansen type	n.r	n.r	n.r	n.r	Fingers: All fingers webbed; pre-/post-axial polydactyly, cup-shaped hand Toes: Variable webbing of toes with polydactyly	n.r	[79]
V	SDTY5; Dowd type	2q31; HOXD13	186300	c.950A > G; p.Q317R, and polyalanine expansions	AD	Complete Fingers: 4/5 Fingers with metacarpals fusion; hypoplastic metacarpals 4/5 Toes: Mesoaxial webbing	Suppression of Retinoic Acid	[37, 80]
VI	Mitten type	n.r	n.r	n.r	AD	Unilateral Fingers: 2/5 Fingers Toes: 2/5 Toes	n.r	[81]
VII-a	Cenani-Lenz type; spoon-hand type	11p12–p11.2; LRP4	212780	Missense variations are most common, c.1117C > T; p.R373W	AR	Fingers: Total synostotic syndactyly with metacarpals fusion, spoon-head shape Toes: Total synostotic syndactyly with metatarsals fusion	WNT overexpression /Postulated to cause repression of Notch signaling	[82]
VII-b	Oligodactyly type	15q13.3; GREM1-FMN1	n.r	1.7 Mb duplication spanning both the GREM1 and FMN1 1 genes	AD	Fingers: Few deformed digits Toes: Variable syndactyly of toes	BMP antagonist GREM1(usually repressed by FGF); is active in mutant forms, suppressing BMP activity	[83]
VIII-a	Orel-Holmes type	Xq21.1; FGF16	309630	Nonsense variants p.R179X and p.S157X in exon 3	X-R	Fingers: 4/5 Metacarpal fusion Toes: Normal	Impair FGF16-FGFR1 interactions	[84, 85]
VIII-b	Lerch type	n.r	n.r	n.r	AD	Fingers: 4/5 Metacarpal fusion Toes: Normal	n.r	[1]
IX	MSSD; Malik-Percin type	17p13.3/ BHLHA9	609432	c.311T > C; p.Ile104Thr	AR	Fingers: Mesoaxial synostotic syndactyly with phalangeal reduction Toes: Preaxial webbing; distal phalangeal hypoplasia	Ectopic FGF8 expression restrict BMP suppression	[63, 86, 87]

AR autosomal recessive, AD autosomal dominant, XLR X-Linked recessive, n.r not reported due to insufficient evidence, SPD synpolydactyly