“…The variation in phenotypes is attributed to the complex genetic interactions between discovered and unrevealed susceptibility loci or modifier loci in different genetic backgrounds, which regulate the development of ENS [3,5]. A series of genetic studies have already implicated several genes, including the RET proto-oncogene [7], the endothelin receptor type B gene ( EDNRB ) [8–10], the endothelin-3 gene ( EDN3 ) [11], the glial-cell-line-derived neurotrophic factor gene ( GDNF ) [12,13], the SRY-related HMG-box 10 gene ( SOX10 ) [14], the neurturin gene ( NRTN ) [15], the endothelin converting enzyme 1 gene ( ECE1 ) [16], the zinc finger homeobox 1B gene ( ZFHX1B ) [17], the paired-like homeobox 2B gene ( PHOX2B ) [18], the KIF1 binding protein gene ( KIF1BP ) [19], and the transcription factor 4 gene ( TCF4 ) [16]. Of these, the EDNRB gene, which is involved in the EDN3/EDNRB signaling, is known to play a key role in the development of HSCR, as either the heterozygous or homozygous mutation of this gene is found in HSCR patients [10,20,21].…”