Table 2.
Functional annotation for notable genes (subset)
| Genes | ➀ Syndrome and Phenotype Description When Mutated, in Human (OMIM Number) or ➁ Mouse ➂ Expression Site in Embryonic Limb (Mouse, Unless Stated) |
|---|---|
| 1p34.1-RNF220 | ➂ anterior limb bud (Ma et al., 2019) |
| 1p31.3-NFIA | ➀ brain malformations with or without urinary tract defects (613735); ➂ distal limb bud (Chaudhry et al., 1997) |
| 2p24.3-MYCNa | ➀ Feingold syndrome; syndactyly and reduced middle phalanges (164280); ➂ proliferating cells of distal limb bud mesenchyme (Ota et al., 2007) |
| 2p16.1-BCL11A | ➀ Dias-Logan syndrome; Intellectual development disorder with persistent fetal hemoglobin (61711); ➂ mesenchyme of early limb bud then autopod, anterior and posterior margin of proximal limb, subsequently interdigital (Yamamoto et al., 2019) |
| 2q13-EDARb | ➀ hypohidrotic ectodermal dysplasia; skin appendages absent, aberrant dermatoglyphs (224900) |
| 2q31.1-SP9 | ➂ apical ectodermal ridge, regulated by FGF10 (Kawakami et al., 2004) |
| 2q31.1-MAP3K20/ZAKa | ➀ split-foot malformation; mesoaxial polydactyly, nail duplications (616890); ➂ entire early limb bud (Spielmann et al., 2016) |
| 2q33.1-SATB2a | ➀ Glass syndrome; digit anomalies, sparse hair (612313); ➂ apical ectodermal ridge (Sheehan-Rooney et al., 2010) |
| 2q37.3-GPC1 | ➂ limb bud mesenchyme (chicken) (Saad et al., 2017) |
| 3p22.3-TRIM71 (LIN41) | ➂ distal limb and digit mesenchyme (mouse and chicken) (Lancman et al., 2005) |
| 3p14.3-WNT5Aa | ➀ Robinow syndrome; limb shortening, brachydactyly (180700); ➂ apical ectodermal ridge and progress zone (Yamaguchi et al., 1999) |
| 3p14.1-ADAMTS9 | ➁ limb-specific deletion causes syndactyl; ➂ broadly in early limb mesenchyme, subsequently digit perichondrium (McCulloch et al., 2009) |
| 3q26.2-EVI1a | ➀ RUSAT2; radioulnar synostosis, digit defects (616738); ➂ limb bud and digit pad mesenchyme (human, Figures 3G–3I) |
| 3q27.1-EPHB3 | ➂ limb bud epithelium and nonchondrogenic mesenchyme (Compagni et al., 2003) |
| 4p15.31-SLIT2 | ➂ interdigital mesenchyme and digit lateral margins (Holmes et al., 1998) |
| 4p15.2-RBPJa | ➀ Adams-Oliver syndrome; scalp and distal limb defects (short distal phalanges) (614814) |
| 4q28.1-INTUa | ➀ short-rib thoracic dysplasia 20 with polydactyly (617925) |
| 5q23.3-ADAMTS19 | ➂ posterior-proximal limb bud, regulated by SHH signaling (Lewandowski et al., 2015) |
| 6p24.3-TFAP2Aa | ➀ branchiooculofacial syndrome, incompletely penetrant polydactyly (113620); ➂ limb bud ectoderm and distal mesenchyme (Feng et al., 2008) |
| 6q21-PRDM1 | ➁ mutants lack posterior digits, whisker development; ➂ limb bud posterior mesenchyme, including zone of polarizing activity (Robertson et al., 2007) |
| 7p21.2-MEOX2 | ➁ mutants have selectively reduced limb musculature; ➂ limb bud myoblasts (Mankoo et al., 1999) |
| 7p14.3-CREB5 | ➂ interdigital condensing mesenchyme (Lehoczky et al., 2004) |
| 7p12.3-IGFBP3 | ➂ interdigital region (van Kleffens et al., 1998) |
| 8q21.13-ZFHX4 | ➂ conserved human enhancer drives reporter expression in mouse limb buds (Ali et al., 2016) |
| 8q23.1-RSPO2a | ➀ tetraamelia syndrome 2; absence of limbs (618021); ➂ apical ectodermal ridge (Szenker-Ravi et al., 2018) |
| 8q24.12-HAS2 | ➁ short limbs with phalanx duplication and misplaced interphalangeal joints; ➂ distal limb bud mesenchyme, regulated by SHH (Liu et al., 2013) |
| 9q22.31-ROR2a | ➀ Robinow syndrome; limb shortening, including brachydactyly (268310); ➂ distal limb mesenchyme (Matsuda et al., 2001) |
| 12q12-DBX2a | ➀ deletion at this locus alters hand size, digit morphology, and causes retention of fetal digital pads (Carlsen et al., 2015); ➂ genes at this locus are coordinately expressed in distal limb mesenchyme and embryonic digits (Beccari et al., 2021) |
| 12q12-NELL2a | ➂ distal limb and digit mesenchyme (mouse and chicken) (Lancman et al., 2005) |
| 12q24.21-TBX3a | ➀ ulnar-mammary syndrome; posterior digits reduced or absent (181450); ➂ anterior and posterior mesenchyme of embryonic limb bud and apical ectodermal ridge (Gibson-Brown et al., 1996) |
| 13q12.11-FGF9a | ➀ multiple synostoses syndrome 3; impaired interphalanx joint formation, broadened thumbs (612961); ➂ apical ectodermal ridge (Mariani et al., 2008) |
| 16q12.2-RPGRIP1La | ➀ Meckel syndrome; polydactyly (611561); ➂ protein located at primary cilium of embryonic limb mesenchymal cells; regulates SHH signaling (Gerhardt et al., 2015) |
| 16q12.2-FTOc | ➀ growth retardation, developmental delay, and facial dysmorphism; brachydactyly and cutis marmorata (612938) |
| 16q12.2-IRX3 | ➁ smaller limb when mutation combined with Irx5 mutation; ➂ proximal-anterior limb bud, interacts with SHH (Li et al., 2014) |
| 18q12.1-MAPRE2b | ➀ congenital symmetric circumferential skin creases; excess skin leading to ringed creases, principally on limbs (616734) |
| 18q21.2-TCF4a | ➀ Pitt-Hopkins syndrome; persistent fetal digital pads (610954); ➂ peridigital mesenchyme at distal digit tips (Cho and Dressler, 1998) |
| 18q23-SALL3 | ➁ lack of digit development when mutated with SALL1; ➂ distal posterior mesenchyme, regulated by SHH (Kawakami et al., 2009) |
| 22q13.31-CELSR1 | ➂ early limb bud with distal bias (Shima et al., 2002) |
a
Abnormalities on limb phenotype when gene mutated in human.
b
Abnormalities on skin or skin appendage phenotypes when gene mutated in human.
c
Abnormalities on both skin and limb phenotypes when gene mutated in human.