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Human hereditary malformation syndromes are caused by mutations in the genes of the signal transduction molecules involved in fetal development. Among them, the Sonic hedgehog (SHH) signaling pathway is the most important, and many syndromes result from its disruption. The output of the SHH pathway is shown as GLI activity, which is generated by SHH in a concentration-dependent manner, i.e., the sum of activating form of GLI (GLIA) and repressive form of GLI (GLIR). Which gene is mutated and whether the mutation is loss-of-function or gain-of-function determine in which concentration range of SHH the imbalance occurs. In human malformation syndromes, too much or too little GLI activity produces symmetric phenotypes affecting brain size, craniofacial (midface) dysmorphism, and orientation of polydactyly with respect to the axis of the limb.
Gene OMIM# | *165230 | *165240 | *600725 | *601309 | *601500 | *607035 | *611254 | ||||||||
Gene | GLI2 | GLI3 | SHH | PTCH1 | SMO | SUFU | KIF7 | ||||||||
Location | 2q14.2 | 7p14.1 | 7q36.3 | 9q22.32 | 7q32.1 | 10q24.32 | 15q26.1 | ||||||||
Phenotype OMIM# | #615849 | #610829 | #175700 | #174200 | #146510 | #142945 | #109400 | #610828 | #241800 | #601707 | #109400 | #617757 | #200990 | #607131 | #614120 |
Disease | CJS | HPE9 | GCPS | PAPA1 | PHS | HPE3 | BCNS | HPE7 | PHLS | CRJS | BCNS | JBTS32 | ACLS | AGBK | HLS2 |
Inheritance | AD | AD | AD | AD | AD | AD | AD | AD | AR | Mos | AD | AR | AR | AR | AR |
Mutation type | LOF | LOF | LOF 1 | LOF | GOF | LOF 2 | LOF | GOF | LOF | GOF | LOF 3 | partial LOF | LOF | LOF | LOF |
Height | Short | Short | Short | Short | Tall | Short | Normal | ||||||||
hypopituitalism | Y | Y | Y | Y | Y | ||||||||||
Head size | Micro | Micro | Macro | Micro | Macro | Macro | Micro | Macro | Macro | Macro | Macro | ||||
Holoprosencephaly | less common | variable degree | less common | variable degree | variable degree | Anencephaly | |||||||||
Intellectual disability | some patients | Y | Normal, mild (rare) | Y | less common | Y | Speech delay | mild to moderate | less common | mild | Severe | Y | |||
Eyes (telorism) | Hypo | Hypo | Hyper | Normal | Hypo | Hypo | Hyper | Hypo | Hyper | Hyper | Hyper | Hyper | |||
Microphthalmia | Y | Y | Synophthalmia (in some) | Y | |||||||||||
Mid-Face | hypo | hypo | wide | hypo | wide | hypo | wide | wide | |||||||
Cleft lip/palate | both | both | both | both | both (5%) | both | Cleft palate | both (5%) | both | Cleft palate | |||||
SMMCI | Y | Y | Y | ||||||||||||
Hands Polydactyly | Post-Ax (some) | Post-Ax | Post/Pre-Ax | Post/Pre-Ax | Post-Ax | Post-Ax | Pre-Ax | Post-Ax | Post/Pre-Ax | Post-Ax | |||||
Hand Syndactyly | Y | Y | Y | ||||||||||||
Feet polydactyly | Post-Ax (in some) | Post-Ax | Post/Pre-Ax | Post/Pre-Ax | Post-Ax | Post-Ax | Pre-Ax (in some) | Post-Ax | Post/Pre-Ax | Post/Pre-Ax | |||||
Feet syndactyly | Y | Y | Y | ||||||||||||
Tumor | HTH | NBCC/DMB/OC | HTH | DMB | NBCC/DMB |