Table 1.
Genetic determinants for selected syndromic syndactyly phenotypes
| Gene | Type of syndrome | OMIM | Common variant/s | Inheritance | Clinical presentation | Postulated contribution to pathogenesis | Key references |
|---|---|---|---|---|---|---|---|
| 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, 47–49] | |
| 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, 50–52] |
| 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] |
| Other loci/variants | Clinical presentation | Postulated contribution to pathogenesis | Key references |
|---|---|---|---|
| 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] |
AR autosomal recessive, AD autosomal dominant, XLR X-Linked recessive, n.r not reported due to insufficient evidence, EMID2 EMI domain containing 2, LMBR1 Limb development membrane protein 1, IRF6 Interferon regulatory factor 6, YY1AP1 YY1 associated protein 1, KATNB1 Katanin,p80 subunit B1, FGFR2 Fibroblast growth factor receptor 2, TPS Thumb polysyndactyly syndrome