Table 3.
Mutations known to date in different genes responsible for nonsyndromic SHFM
| Gene mutation | Edna position | Protein position | Effect | Phenotype | ||||
|---|---|---|---|---|---|---|---|---|
| DLX5 | ||||||||
| Nonsense | c.115G>T | p.Glu39* | Stop codon | SHFM | ||||
| Missense | c.505G>A | p. Glu169Lys | Substitution | Hypogonadotropic hypogonadism | ||||
| Missense | c.533A>C | p.Gln178Pro | Substitution | SHFM | ||||
| Missense | c.558G>T | p. Gln186His | Substitution | SHFM | ||||
| Missense | c.576C>G | p.Ile192Met | Substitution | Pierre Robin sequence | ||||
| Missense | c.593A>C | p. Asn198Thr | Substitution | Hypogonadotropic hypogonadism | ||||
| Frame shift | c.482_485dupACCT | − | AS and PTC | SHFM | ||||
| Gross deletions | ~1 Mb incl. entire gene and DLX6 | − | AS and PTC | SHFM | ||||
| Gross deletions | ~8.478 Mb incl. entire gene, DLX6 and >50 others | − | AS and PTC | SHFM | ||||
| Gross deletions | 0.9 − 1.8 Mb incl. entire gene, DLX6 and DSS1 | − | AS and PTC | SHFM | ||||
| Gross insertion | 719 kb incl. entire gene and DLX6 | − | AS and PTC | SHFM | ||||
| WNT10B | ||||||||
| Missense | c.265G>A | p.Asp89Asn | Substitution | Dental anomalies | ||||
| Missense | c.475G>C | p.Ala159Pro | Substitution | Dental anomalies | ||||
| Missense | c.569C>G | p.Pro190Arg | Substitution | Oligodontia | ||||
| Missense | c.632G>A | p.Arg211Gln | Substitution | Oligodontia | ||||
| Missense | c.661C>T | p.Arg221Trp | Substitution | SHFM | ||||
| Missense | c.767G>A | p.Cys256Tyr | Substitution | Obesity | ||||
| Nonsense | c.786G>A | p.Trp262T* | Substitution | Oligodontia | ||||
| Missense | c.849C>A | p.Ile283Ile | Substitution | Oligodontia | ||||
| Missense | c.851T>G | p.Phe284Cys | Substitution | Oligodontia | ||||
| Missense | c.986C>G | p. Thr329Arg | Substitution | SHFM | ||||
| Missense | c.986C>A | p. Thr329Lys | Substitution | SHFM | ||||
| Missense | c.994C>T | p. Arg332Trp | Substitution | SHFM | ||||
| Missense | c.1052G>A | p. Arg351His | Substitution | Dental anomalies | ||||
| Missense | c.1087C>T | p. Arg363Cys | Substitution | Dental anomalies | ||||
| Splice site | c.338 − 1G>C | − | Substitution | SHFM | ||||
| Frame shift | c.695_697delACA | p. Asn232del | Small deletions | SHFM | ||||
| Frame shift | c.293_299dupAGGGCGG | − | Small deletions | SHFM | ||||
| Frame shift | c.458_461dupAGCA | − | Small deletions | SHFM | ||||
| TP63 | ||||||||
| Missense | c.191A>G | p. Gln25Arg | Substitution | Heterotaxy | ||||
| Missense | c.289C>T | p. Arg58Cys | Substitution | SHFM | ||||
| Missense | c.343G>T | p. Gly76Trp | Substitution | Limb-mammary syndrome | ||||
| Missense | c.386C>T | p. Ser90Leu | Substitution | Cleft lip | ||||
| Missense | c.386C>G | p. Ser90Trp | Substitution | Limb-mammary syndrome | ||||
| Missense | c.448G>A | p. Ala111Thr | Substitution | Cleft palate | ||||
| Missense | c.497C>T | p. c.497C>T | Substitution | ADULT syndrome | ||||
| Missense | c.518G>A | p. Gly134Asp | Substitution | Limb-mammary syndrome | ||||
| Missense | c.518G>T | p. Gly134Val | Substitution | ADULT syndrome | ||||
| Missense | c.598A>G | p. Lys161Glu | Substitution | SHFM | ||||
| Missense | c.602T>C | p. Leu162Pro | Substitution | EEC syndrome | ||||
| Missense | c.605A>G | p. Tyr163Cys | Substitution | EEC syndrome | ||||
| Missense | c.691T>G | p. Tyr192Asp | Substitution | EEC syndrome | ||||
| Missense | c.692A>G | p. Tyr192Cys | Substitution | EEC syndrome | ||||
| Missense | c.697A>G | p.Lys194Glu | Substitution | SHFM | ||||
| Missense | c.721G>A | p. Val202Met | Substitution | EEC syndrome | ||||
| Missense | c.728G>A | p. Arg204Gln | Substitution | EEC syndrome | ||||
| Missense | c.728G>T | p. Arg204Leu | Substitution | EEC syndrome | ||||
| Missense | c.727C>T | p. Arg204Trp | Substitution | EEC syndrome | ||||
| Missense | c.740A>G | p. His208Arg | Substitution | EEC syndrome | ||||
| Missense | c.739C>G | p. His208Asp | Substitution | EEC syndrome | ||||
| Missense | c.739C>T | p. His208Tyr | Substitution | EEC syndrome | ||||
| Missense | c.797G>A | p. Arg227Gln | Substitution | EEC syndrome | ||||
| Missense | c.797G>C | p. Arg227Pro | Substitution | EEC syndrome | ||||
| Missense | c.799G>A | p. Val228Ile | Substitution | Congenital anomalies of the kidney and urinary track | ||||
| Missense | c.923G>A | p. Cys269Tyr | Substitution | EEC syndrome | ||||
| Missense | c.929G>C | p. Ser271Thr | Substitution | EEC syndrome | ||||
| Missense | c.932G>A | p. Ser272Asn | Substitution | EEC syndrome | ||||
| Missense | c.932G>C | p. Ser272Thr | Substitution | EEC syndrome | ||||
| Missense | c.935G>A | p. Cys273Tyr | Substitution | EEC syndrome | ||||
| Missense | c.946A>T | p. Met277Leu | Substitution | Skeletal abnormality | ||||
| Missense | c.952C>T | p. Arg279Cys | Substitution | EEC syndrome | ||||
| Missense | c.953G>A | p. Arg279His | Substitution | EEC syndrome | ||||
| Missense | c.952C>A | p. Arg279Ser | Substitution | EEC syndrome | ||||
| Missense | c.955C>T | p. Arg280Cys | Substitution | SHFM | ||||
| Missense | c.956G>A | p.Arg280His | Substitution | SHFM | ||||
| Missense | c.956G>T | p. Arg280Leu | Substitution | SHFM | ||||
| Missense | c.955C>A | p.Arg280Ser | Substitution | EEC syndrome | ||||
| Missense | c.1010G>A | p. Arg298Gln | Substitution | ADULT syndrome | ||||
| Missense | c.1009C>G | p. Arg298Gly | Substitution | ADULT syndrome | ||||
| Missense | c.1028G>A | p.Arg304Gln | Substitution | EEC syndrome | ||||
| Missense | c.1028G>C | p. Arg304Pro | Substitution | EEC syndrome | ||||
| Missense | c.1027C>T | p. Arg304Trp | Substitution | EEC syndrome | ||||
| Missense | c.1033T>C | p. Cys306Arg | Substitution | EEC syndrome | ||||
| Missense | c.1034G>A | p. Cys306Tyr | Substitution | EEC syndrome | ||||
| Missense | c.1037C>A | p. Ala307Asp | Substitution | EEC syndrome | ||||
| Missense | c.1037C>G | p. Ala307Gly | Substitution | EEC syndrome | ||||
| Missense | c.1039T>A | p. Cys308Ser | Substitution | EEC syndrome | ||||
| Missense | c.1040G>A | p. Cys308Tyr | Substitution | AEC syndrome | ||||
| Missense | c.1042C>T | p. Pro309Ser | Substitution | EEC syndrome | ||||
| Missense | c.1046G>A | p. Gly310Glu | Substitution | SHFM | ||||
| Missense | c.1048A>G | p. Arg311Gly | Substitution | EEC syndrome | ||||
| Missense | c.1051G>A | p. Asp312Asn | Substitution | EEC syndrome | ||||
| Missense | c.1053C>A | p. Asp312Glu | Substitution | EEC syndrome | ||||
| Missense | c.1052A>G | p. Asp312Gly | Substitution | EEC syndrome | ||||
| Missense | c.1051G>C | p. Asp312His | Substitution | EEC syndrome | ||||
| Missense | c.1054A>G | p. Arg313Gly | Substitution | Cleft lip | ||||
| Missense | c.1061C>A | p. Ala315Glu | Substitution | EEC syndrome | ||||
| Missense | c.1063G>C | p. Asp316His | Substitution | AEC syndrome | ||||
| Missense | c.1646T>C | p. Ile510Thr | Substitution | Rapp-Hodgkin syndrome | ||||
| Missense | c.1655T>C | p. Phe513Ser | Substitution | AEC syndrome | ||||
| Missense | c.1654T>G | p. Phe513Val | Substitution | Rapp-Hodgkin syndrome | ||||
| Missense | c.1659A>T | p. Leu514Phe | Substitution | AEC syndrome | ||||
| Missense | c.1658T>C | p. Leu514Ser | Substitution | AEC syndrome | ||||
| Missense | c.1657T>G | p. Leu514Val | Substitution | AEC syndrome | ||||
| Missense | c.1670G>T | p. Gly518Val | Substitution | AEC syndrome | ||||
| Missense | c.1672T>C | p. Cys519Arg | Substitution | AEC syndrome | ||||
| Missense | c.1681T>C | p. Cys522Arg | Substitution | AEC syndrome | ||||
| Missense | c.1681T>G | p. Cys522Gly | Substitution | AEC syndrome | ||||
| Missense | c.1683T>G | p. Cys522Trp | Substitution | AEC syndrome | ||||
| Missense | c.1685T>C | p. Leu523Pro | Substitution | AEC syndrome | ||||
| Missense | c.1695C>A | p. Phe526Leu | Substitution | AEC syndrome | ||||
| Missense | c.1706G>T | p. Gly530Val | Substitution | AEC syndrome | ||||
| Missense | c.1709T>C | p. Leu531Pro | Substitution | Ankyloblepharon filiforme adnatum associated with Hay-Wells syndrome | ||||
| Missense | c.1714A>C | p. Thr533Pro | Substitution | AEC syndrome | ||||
| Missense | c.1724A>T | p. Gln536Leu | Substitution | AEC syndrome | ||||
| Missense | c.1727T>C | p. Ile537Thr | Substitution | AEC syndrome | ||||
| Missense | c.1739C>T | p. Ser541Phe | Substitution | AEC syndrome | ||||
| Missense | c.1739C>A | p. Ser541Tyr | Substitution | Rapp-Hodgkin syndrome | ||||
| Missense | c.1747G>T | p. Asp544Tyr | Substitution | AEC syndrome | ||||
| Missense | c.1751T>C | p. Leu545Pro | Substitution | AEC syndrome | ||||
| Missense | c.1766T>A | p. Ile550Asn | Substitution | EEC syndrome | ||||
| Missense | c.1769C>A | p.Pro551His | Substitution | AEC syndrome | ||||
| Missense | c.1769C>T | p. Pro551Leu | Substitution | AEC syndrome | ||||
| Missense | c.1781G>C | p. Arg555Pro | Substitution | AEC syndrome | ||||
| Missense | c.1790T>C | p. Ile558Thr | Substitution | AEC syndrome | ||||
| Missense | c.1799G>A | p. Gly561Asp | Substitution | Rapp-Hodgkin syndrome | ||||
| Missense | c.1799G>T | p. Gly561Val | Substitution | AEC syndrome | ||||
| Missense | c.1805T>C | p. Leu563Pro | Substitution | EEC syndrome | ||||
| Missense | c.1807G>C | p. Asp564His | Substitution | Cleft lip | ||||
| Missense | c.1904G>T | p. Gly596Val | Substitution | Ectodermal dysplasia | ||||
| Missense | c.1910G>T | p. Arg598Leu | Substitution | AEC syndrome | ||||
| Missense | c.1919A>T | p. Asp601Val | Substitution | AEC syndrome | ||||
| Nonsense | c.1974G>A | p. Trp619* | PTC | SHFM | ||||
| Nonsense | c.2011A>T | p. Lys632* | PTC | Limb-mammary syndrome | ||||
| Nonsense | c.2017C>T | Gln634* | PTC | SHFM | ||||
| Nonsense | c.2032G>T | p. Glu639* | PTC | SHFM | ||||
| Splice site | c.63 − 1G>C | − | Intronic | Prostate carcinoma | ||||
| Splice site | c.580 − 2A>C | − | Intronic | SHFM | ||||
| Splice site | c.580 − 2A>G | − | Intronic | EEC syndrome | ||||
| Splice site | c.1350 − 2A>G | − | Intronic | EEC syndrome | ||||
| Splice site | c.1747G>T | − | Intronic | AEC syndrome | ||||
| Regulatory sequence | c.*374G>A | − | Stop loss | Bladder cancer | ||||
| Regulatory sequence | c.*2345C>T | − | Stop loss | Bladder cancer | ||||
| Regulatory sequence | c.62 + 6895C>T | − | Stop loss | Lung adenocarcinoma | ||||
| Regulatory sequence | c.*20609A>G | − | Stop loss | Bladder cancer | ||||
| Regulatory sequence | c.62 + 33817C>T | − | Stop loss | Lung adenocarcinoma | ||||
| Small deletion | c.970_972delATT | p.Ile324del | FS | EECUT plus syndrome | ||||
| Small deletion | c.1338_1341delACTT | p.Leu446Phefs*20 | FS and PTC | Orofacial clefting | ||||
| Small deletion | c.1693_1694delTT | p.Phe565Hisfs*12 | FS and PTC | EEC syndrome | ||||
| Small deletion | c.1815delG | p.Gln606Serfs*98 | FS and PTC | Rapp-Hodgkin syndrome | ||||
| Small deletion | c.1827delA | p.Glu609Aspfs*95 | FS and PTC | Rapp-Hodgkin syndrome | ||||
| Small deletion | c.1838delC | p.Pro613Leufs*91 | FS and PTC | Rapp-Hodgkin syndrome | ||||
| Small deletion | c.1859delC | p.Pro620Glnfs*84 | FS and PTC | AEC syndrome | ||||
| Small deletion | c.1860_1861delAA | p.Ser621Glnfs*11 | FS and PTC | EEC syndrome | ||||
| Small deletion | c.1900delC | p.Arg634Glyfs*70 | FS and PTC | Rapp-Hodgkin syndrome | ||||
| Small deletion | c.1904delG | p.Gly635Valfs*69 | FS and PTC | Rapp-Hodgkin syndrome | ||||
| Small deletion | c.1963delC | p.Arg655Glufs*49 | FS and PTC | AEC syndrome | ||||
| Small deletion | c.1976delA | p.Asn659Metfs*45 | FS and PTC | Rapp-Hodgkin syndrome | ||||
| Small insertions | c.819_820dupCC | − | FS and PTC | Cleft lip and palate | ||||
| Small insertions | c.1572dupA | − | FS and PTC | Rapp-Hodgkin syndrome | ||||
| Small insertions | c.1689_1690insA | − | FS and PTC | EEC syndrome | ||||
| Small insertions | c.1718_1720dupTCT | − | FS and PTC | AEC syndrome | ||||
| Small insertions | c.1833_1843dup11 | − | FS and PTC | AEC/Rapp-Hodgkin syndrome | ||||
| Small indel | c.953_954delGCinsAA | − | FS and PTC | EEC syndrome | ||||
| Gross deletion | >19,1059 bp incl. exons 1 − 4 | − | FS and PTC | EEC syndrome | ||||
| DLX6 | ||||||||
| Missense | c.632T>A | p.Val211Glu | Substitution | SHFM | ||||
| ZAK | ||||||||
| Missense | c.1103T>G | p.Phe368Cys | Substitution | SHFM | ||||
| Gross deletion | exons 12 − 16del | − | Small protein | SHFM | ||||
| EPS15L1 | ||||||||
| Small deletion | c.409delA | p.Ser137Alafs*19 | FS and PTC | SHFM | ||||
FS, frame shift; PTC, premature termination codon; SHFM, split-hand/foot malformation.