Table 3.

Rare Hemizygous Variants Identified in Hedgehog Signaling–related Genes

Gene	Role in Hedgehog Signaling Pathway	Diseases Associated with Gene Mutation	Trio ID	Mutation
SHH	Critical in embryonic patterning and tracheal cartilage formation; deletion causes tracheomalacia	Vertebral defects, anal atresia, tracheoesophageal fistula/esophageal atresia, renal dysplasia, and cardiac and limb abnormalities	5	NS, SNV
GLI2	Mediates Shh signaling, localized in cytoplasm, and activates PTCH expression; deletion causes tracheal stenosis	Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B	5	NS, SNV
BOC	Mediates muscle precursor cell interactions and promotes myogenic differentiation		5	NS, SNV
ADAM17	Implicated in cell–cell and cell–matrix interactions, including muscle development, and neurogenesis	Likely involved in autoimmune diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, and Crohn’s disease	5	NS, SNV
SMO	Transduces signals to other proteins after activation by a Hedgehog protein–patched protein complex	No known associated disease	4	NS, SNV
GLI3	Localized to cytoplasm and activates PTCH expression; deletion of Gli2 and Gli3 leads to stenotic trachea	Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, preaxial polydactyly type IV, and postaxial polydactyly types A1 and B	4	NS SNV
GLI1	Activated by Shh pathway and regulates stem cell proliferation	No known associated disease	3	NS, SNV
PTCH1	Receptor for Shh ligands; Hedgehog binding relieves inhibition of G protein–coupled receptor “smoothened” and initiates signaling	Basal cell nevus syndrome and holoprosencephaly	1	NS, SNV
ADCY9	Membrane-bound enzyme catalyzing cAMP formation; regulated by G protein–coupled receptors, protein kinases, and calcium	No known associated disease	1	NS, SNV
DISP2	May be required for normal Hedgehog signaling during embryonic pattern formation	No known associated disease	5	NS, SNV
EFCAB7	Encodes a calcium ion binding protein that mediates signaling by Hedgehog and by G protein–coupled receptors	Ellis-Van Creveld syndrome	2	NS, SNV
LRP2	Multiligand endocytic receptor with role in cell signaling; extracellular ligands include Shh	Donnai-Barrow syndrome and facio-oculo-acoustico-renal syndrome	2, 5	NS, SNV
TTC21B	Localized to cilium axoneme; may participate in retrograde intraflagellar transport in cilia	Various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4	3	NS, SNV
PSMB6	Member of the proteasome B-type family; is a 20S core β-subunit in the proteasome	No known associated disease	1	NS, SNV
DYNC2H1	Cytoplasmic dynein protein; involved in retrograde transport and intraflagellar transport, which is required for ciliary/flagellar assembly	Various primary ciliary dysfunction disorders that often involve polydactyly, abnormal skeletogenesis, and polycystic kidney disease	1	Stop-gain SNV

Definition of abbreviations: ID = identifier; NS = nonsynonymous; SNV = single-nucleotide variant.