Table 2 Characterization of gene variants associated with vertebral malformations. Bial–biallelic, Comp het–compound heterozygous, Hemi–hemizygous, Het–heterozygous, Hom–homozygous, MF–multifactorial, ND–not determined; ^agenes associated with several syndromes

KFS

 (a) Mendelian genes

  GDF3

Het

Mendelian

Regulator of BMP and TGFβ signaling pathways

[182, 183]

  GDF6

Het

Mendelian

Regulator of BMP and TGFβ signaling pathways

[182, 184]

  MEOX1

Hom, Comp het

Mendelian

Induced by TGFβ

[54, 185]

  MYO18B

Hom, Comp het

Mendelian

Involved in PI3K/AKT/mTOR and ERK/MAPK signaling pathways

[57, 186]

 (b) Candidate genes

  BAZ1B

Het

ND

Regulator of Wnt/β catenin signaling pathway

[61, 187]

  CDAN1

ND

ND

Target of mTOR signaling pathway

[62, 188]

  CHRNG

ND

ND

None

[62]

  COL6A1

ND

ND

Involved in PI3K-Akt and ERK/MAPK signaling pathways

[62, 182]

  COL6A2

ND

ND

Involved in PI3K-Akt and ERK/MAPK signaling pathways

[62, 182]

  FLNB

ND

ND

Involved in MAPK and SMAD signaling pathways

[62, 182]

  FREM2

Het

ND

Involved in BMP and ERK/MAPK signaling pathways

[61, 189]

  GLI3

ND

ND

Involved in Hedgehog and TGFβ signaling pathways

[62, 182]

  KMT2D

Het

ND

Regulator of Wnt/β catenin signaling pathway

[61, 182]

  MYH3

ND

ND

A possible inhibitor of TGFβ signaling pathway

[62, 190]

  PAX1

ND

ND

Regulator of Hedgehog signaling pathway

[62, 182]

  POR

ND

ND

Regulator of Hedgehog signaling pathway

[62, 191]

  RIPPLY2^a

Hom, Comp het

ND

Regulator of Notch signaling pathway

[58, 182]

  SUFU

Het

ND

Regulator of Hedgehog, Wnt/β catenin and Notch signaling pathways

[61, 182]

  TNXB

ND

ND

Involved in PI3K-Akt signaling pathway

[62, 182]

  VANGL1^a

Het

ND

Involved in Wnt/PCP signaling pathway

[61, 182]

CS

 (a) Risk genes

  TBX6^a

Bial, Het

MF

Regulator of Notch signaling pathway

[68, 182]

 (b) Candidate genes

  Human studies

   FBN1

Het

ND

Involved in TGFβ and ERK/MAPK signaling pathways

[78, 182]

   PTK7

Het

ND

Involved in Wnt/PCP and ERK/MAPK signaling pathways

[79, 182]

   SOX9

Het

ND

Regulator of Wnt/β catenin signaling pathway, involved in BMP and FGFR3 signaling pathways

[80, 182]

   TBXT^a

Het

ND

Target of Wnt/β catenin signaling pathway

[76, 182]

  Genes within CNVs

   DHX40

ND

ND

None

[75]

   DSCAM

ND

ND

A possible regulator of ERK/MAPK signaling pathway

[75, 192]

   MYSM1

ND

ND

Regulator of PI3K/AKT signaling pathway

[75, 193]

   NBPF20

ND

ND

None

[75]

   NOTCH2

ND

ND

Receptor of Notch signaling pathway, involved in NF-κB signaling pathway

[75, 182]

   RASA2

ND

ND

Involved in G-protein, and Ras/MAPK signaling pathways

[75, 182]

   SNTG1

ND

ND

None

[75]

  Genes within DMRs

   COL5A1

ND

ND

Involved in PI3K/AKT/mTOR and ERK/MAPK signaling pathways

[145, 182]

   GRID1

ND

ND

None

[145]

   GSE1

ND

ND

None

[145]

   IGHG1

ND

ND

Regulator of TGFβ/SMAD3 signaling pathway

[145, 194]

   IGHG3

ND

ND

None

[145]

   IGHM

ND

ND

None

[145]

   KAT6B

ND

ND

A possibly regulator of Wnt/β catenin signaling pathway

[144]

   RGS3

ND

ND

Regulator of G-protein signaling pathway, and have a function in Wnt signaling pathway

[145, 182]

   RNF213

ND

ND

Involved in non-canonical Wnt signaling pathway

[145, 182]

   ROBO2

ND

ND

Regulator of ERK/MAPK signaling pathway

[145, 195]

   SORCS2

ND

ND

Regulator of Wnt/PCP signaling pathway

[145, 196]

   TNS3

ND

ND

Regulator of membrane receptor signaling pathways

[143]

  Animal studies

   Dstyk

Het

ND

Regulator of mTORC1/TFEB signaling pathway

[81]

SCD

 (a) Mendelian genes

  DLL3

Hom, Comp het

Mendelian

Ligand of Notch signaling pathway, involved in Wnt and Hedgehog signaling pathways

[89, 182]

  HES7

Het

Mendelian

Target of Notch signaling pathway

[182, 197]

  LFNG

Hom, Comp het

Mendelian

Target of Notch signaling pathway, involved in Wnt and Hedgehog signaling pathways

[91, 182]

  MESP2

Hom, Comp het

Mendelian

Involved in Notch and FGF signaling pathways

[182, 198]

  RIPPLY2^a

Het

Mendelian

Regulator of Notch signaling pathway

[90, 182]

  TBX6^a

Het

Mendelian

Regulator of Notch signaling pathway

[69, 182]

 (b) Candidate genes

  DMRT2

Hom

ND

Regulator of SOX9

[93, 199]

DSS

 Candidate genes

  COX2

ND

ND

Regulator of TGFβ signaling pathway

[99, 200]

  DCC

ND

ND

None

[99]

  LRP5

ND

ND

Receptor of Wnt/β catenin signaling pathway

[99, 182]

  VDR

ND

ND

Involved in BMP and retinoic acid signaling pathways

[99, 182]

  ZNF704

ND

ND

None

[99]

Currarino syndrome

 (a) Mendelian genes

  MNX1

Het

Mendelian

Regulator of PI3K/AKT/mTOR and Wnt/β catenin signaling pathways

[107, 201, 202]

 (b) Candidate genes

  ARID5A

ND

ND

NF-κB signaling pathway activates ARID5A expression

[106, 203]

  CDH2

ND

ND

Involved in Wnt/β catenin signaling pathway

[106, 182]

  ETV3L

ND

ND

Regulator of FGF signaling pathway

[106, 204]

  HOXB4

ND

ND

Regulator of Wnt/β catenin signaling pathway

[106, 205]

  ITIH2

ND

ND

None

[106]

  NCAPD3

ND

ND

Involved in NF-κB signaling pathway

[106, 206]

  TLE4

ND

ND

Regulator of canonical Wnt, Notch and TGFβ signaling pathways

[106, 182]

NTDs

 Risk genes

  CCL2

Het, Hom

MF

Regulator of PI3K-AKT and ERK/MAPK signaling pathways

[110, 207]

  FUZ

Het

MF

Involved in Hedgehog signaling pathway

[113, 182]

  VANGL1^a

Het

MF

Involved in Wnt/PCP signaling pathway

[112, 182]

  VANGL2

Het

MF

Involved in Wnt/β catenin signaling pathway

[109, 182]

  TBXT^a

Het

MF

Target of Wnt/β catenin signaling pathway

[111, 182]

  AMOT

ND

MF

Involved in Hippo-Merlin signaling pathway

[122, 182]

  ARHGAP36

ND

MF

Regulator of Hedgehog signaling pathway

[122, 208]

  CELSR1

ND

MF

Involved in Wnt/PCK signaling pathway

[124, 209]

  COL15A1

ND

MF

Involved in ERK signaling pathway

[122, 182]

  DACT1

ND

MF

Involved in Wnt signaling pathway

[126, 182]

  DISP2

ND

MF

Involved in Hedgehog signaling pathway

[125, 182]

  DLC1

ND

MF

Involved in MAPK signaling pathway

[120, 210]

  DTX1

ND

MF

Regulator of Notch signaling pathway

[122, 182]

  FREM2^a

ND

MF

Involved in BMP and ERK/MAPK signaling pathways

[125, 188]

  FZD6

ND

MF

Receptor of Wnt/β catenin signaling pathway

[125, 182]

  GPR50

ND

MF

Regulator of Notch signaling pathway

[122, 211]

  GRHL3

Het, Hom

MF

None

[119]

  ITGB1

ND

MF

Involved in PI3K/Akt signaling pathway

[120, 212]

  MTHFR

ND

MF

None

[120]

  MYO1E

ND

MF

Involved in ERK signaling pathway

[120, 182]

  NKRF

ND

MF

Regulator of NF-κB signaling pathway

[122, 182]

  PAX3

Het

MF

Involved in Wnt, Hedgehog and Notch signaling pathways

[123, 182]

  PRICKLE1

ND

MF

Regulator of Wnt/β catenin signaling pathway

[125, 182]

  PTK7^a

Het

MF

Involved in Wnt/PCP and ERK/MAPK signaling pathways

[118, 182]

  RXRγ

ND

MF

Involved in retinoic acid signaling pathway

[122, 182]

  SCRIB

Het

MF

Involved in MAPK signaling pathway

[121, 124, 182]

  SHROOM3

ND

MF

None

[123]

  TKTL1

ND

MF

None

[122]

CDS

 Risk genes

  CELSR1^a

Het

MF

Involved in Wnt/PCK signaling pathway

[141, 209]

  VANGL1^a

Het

MF

Involved in Wnt/PCP signaling pathway

[112, 182]

IDs

 Genes within DMRs

  CDKN1C

Het

Mendelian

None

[150, 151]

  H19

ND

ND

Involved in canonical Wnt signaling pathway

[150, 151, 182]

  IGF2

Het

Mendelian

Involved in IGF2 signaling pathway

[150, 151, 182]

  KCNQ1OT1

ND

ND

Regulator of BMP signaling pathway

[151, 182]

Other genes (Table 1)

 Mendelian genes

  ACVR1

Het

Mendelian

Regulator of BMP, TGF-β, Akt and NF-κB signaling pathways

[155, 182]

  AFF4

Het

Mendelian

A possible regulator of BMP signaling pathway

[156, 213]

  ARSL

Hom

Mendelian

None

[157]

  COL11A1

Het

Mendelian

Involved in ERK/MAPK and PI3K/AKT/mTOR signaling pathways

[158, 182]

  COL2A1

Het

Mendelian

Involved in PI3K/AKT/mTOR and ERK/MAPK signaling pathways

[159, 182]

  DDRGK1

Hom, Comp het

Mendelian

Regulator of NF-κB signaling pathway

[160, 214]

  EBP

Het

Mendelian

None

[161]

  FN1

Het

Mendelian

Involved in ERK/MAPK and PI3K/AKT/mTOR signaling pathways

[162, 182]

  GDF11

Het

Mendelian

Involved in TGF-β signaling pathway

[163, 182]

  GPC3

Hemi

Mendelian

Regulator of Wnt, Hedgehog, FGF and BMP signaling pathways

[164, 215]

  GPC4

Hemi

Mendelian

Involved in Wnt/PCP signaling

[165, 182]

  HSPG2

Hom, Comp het

Mendelian

Involved in ERK signaling pathway

[166, 182]

  INPPL1

Hom, Comp het

Mendelian

Regulator of PI3K-Akt and NF-κB signaling pathways

[167, 182]

  JAG1

Het

Mendelian

Regulator of Notch signaling pathway

[168, 182]

  KIAA0586

Hom, Comp het

Mendelian

Involved in Hedgehog signaling pathway

[169, 182]

  LBR

Hom, Het, Comp het

Mendelian

None

[170]

  NADSYN1

Het

Mendelian

None

[171]

  NOTCH2^a

Het

Mendelian

Receptor of Notch signaling pathway, involved in NF-κB signaling pathway

[172, 182]

  NSDHL

Het

Mendelian

Regulator of TGF-β and Hedgehog signaling pathways

[173, 216]

  PDE4D

Het

Mendelian

Involved in cAMP signaling pathway

[174, 182]

  POGZ

Het

Mendelian

A possible regulator of Wnt signaling pathway

[175, 217]

  SLC26A2

Hom, Comp het

Mendelian

Regulator of FGFR3 signaling pathway in mouse models

[176, 218]

  SLC29A3

Hom, Comp het

Mendelian

Regulator of insulin signaling pathway

[177, 219]

  SLC35D1

Hom, Comp het

Mendelian

Candidate gene for Notch signaling pathway

[178, 220]

  SOX9^a

Het, Hom

Mendelian

Regulator of Wnt/β catenin signaling pathway, involved in BMP and FGFR3 signaling pathways

[182, 224]

  SUMF1

Hom, Comp het

Mendelian

Regulator of FGF signaling pathway

[179, 221]

  TNFRSF11A

Het

Mendelian

Involved in PI3K-Akt and NF-kappaB signaling pathways

[180, 182]

  TRPV4

Het

Mendelian

Regulator of TGF-β signaling pathway

[181, 222]

 (b) Candidate genes

  KIAA1217

Het

Mendelian

Regulator of Notch and Wnt/β-catenin signaling pathways

[40, 223]