Table 2 Genes/loci with postulated pathogenesis for non-syndromic syndactyly

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

[74,75,76]

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]