Table 1 Genetic determinants for selected syndromic syndactyly phenotypes

1 (a) Genetic determinants in coding regions

 ROR2

Brachydactyly type B (BDB1)

113000

c.1324C.T; p.R441X

AD

Brachydactyly characterized by hypoplasia/aplasia of distal phalanges in combination with distal symphalangism, fusion of carpal/tarsal bones, and partial cutaneous syndactyly

Facilitate WNT Overexpression

[20, 40]

 SOST

Sclerosteosis

269500

Nonsense mutations

AR

Presence of asymmetric cutaneous syndactyly of the index and middle fingers in many cases. The jaw has an unusually square appearance

[29, 41]

 LRP4

Sclerosteosis, 2

614305

c.3508C > T; p.R1170W and c.3557G > C; p.W1186S

AD, AR

Progressive skeletal overgrowth. Syndactyly is a variable manifestation

[26, 28, 42]

 GLI3

Pallister–Hall syndrome

146510

Haploinsufficiency, c.1468_1469insG and c.1007_1008dupAC

AD

Hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and variable degree of syndactyly

BMP suppression

[30, 43, 44]

Greig cephalopolysyndactyly syndrome

175700

c.2374C > T; p.Arg792*

AD

Frontal bossing, scaphocephaly, and hypertelorism associated with pre- and postaxial polydactyly and variable syndactyly

 LMBR1

Triphalangeal thumb-polysyndactyly syndrome

174500

Position 287 on ZRS enhancer

AD

Thumb in this malformation is usually opposable and possesses a normal metacarpal. Variable degree of syndactyly

[31, 32, 45]

 DHCR7

Smith–Lemli–Opitz syndrome

270400

c.453G > A; p.W151X

AR

Affects multiple body systems with Syndactyly of toes 2 and 3 being a common finding

[33, 46]

 RAB23

Carpenter syndrome

201000

Homozygous nonsense/frameshift pathogenic variants c.434 T > A; p.L145X

AR

Craniosynostosis, polysyndactyly, obesity, and cardiac defects

[39, 47,48,49]

 FGFR2

Apert syndrome

101200

c.755C > G; p.S252W or c.758C > G; p.P253W

AD

Craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet with a tendency to fusion of bony structures

FGF Overexpression

[7, 34, 50,51,52]

 FGFR1/FGFR2

Pfeiffer syndrome

101600

FGFR1 – p.P252R

AD

Type 1, the classic syndrome, is compatible with life and consists of craniosynostosis, midface deficiency, broad thumbs, broad great toes, brachydactyly, and variable syndactyly

 TWIST1;FGFR3

Saethre–Chotzen syndrome

101400

FGFR3 p.P250R, deletion of TWIST1

AD

Craniosynostosis, facial dysmorphism, and hand and foot abnormalities. The degree of syndactyly is also variable

[35, 36, 53]

 HOXD13

Brachydactyly-syndactyly syndrome

610713

Polyalanine constriction, c.950A > G; p.Q317K

n.r

Brachydactyly and syndactyly (partial cutaneous webbing) in association with oligodactyly

Retinoic acid suppression

[10, 37]

 LRP4

Sclerosteosis, 2

614305

c.1151A > G; p.Tyr384Cys

AD, AR

Progressive skeletal overgrowth. Syndactyly is a variable manifestation

Repression of Notch signaling

[54]

1 (b) Genetic determinants in non-coding regions

 Intron EMID2

Holoprosencephaly spectrum disorder and severe upper limb syndactyly

Ectopic SHH expression

[55]

 Intron 5 LMBR1

Cutaneous syndactyly without polydactyly

Decreased ICD

[45]

 Intron IRF6

Van der Woude syndrome (MIM: 119,300)

Unclassified

[56]

 Exonization of 22 intronic YY1AP1

Grange syndrome (MIM: 602,531) with complete cutaneous syndactyly. Fingers: third, fourth, and fifth finger and third/fourth finger of the right hand. Toes: bilateral cutaneous syndactyly of her second/third toes

Unclassified

[57]

 Intron 6 KATNB1

Congenital microcephaly, lissencephaly, short stature, polysyndactyly, and dental abnormalities

Unclassified

[58]

 Intron 8 FGFR2

Apert syndrome (MIM 101,200)

Unclassified

[59]

 IVS8-1G > C variant DHCR7

Smith-Lemli-Opitz syndrome (MIM 270,400)

BMP suppression

[60]

 Pre-ZRS region

TPS (MIM: 174,500)

Ectopic expression

[61]