SUPPLEMENTARY MATERIAL

Supplementary Table 1: rare coding sequence variant in RET and NRG1

Gene / Position (hg19) / Variant# / Function / Presence
RET / 43597793 / R114H / missense / case/control*
43597794 / R114R / synonymous / control only
43597812 / T120T / synonymous / case only
43597886 / V145G / missense / case only
43597916 / P155L / missense / case only
43597990 / R180X / missense / case only
43600606 / T278A / missense / case only
43600607 / T278N / missense / control only
43601830 / V292M / missense / case only
43601841 / T295T / synonymous / case only
43601861 / Asp302GlufsX53 / frameshift / case only
43601972 / S339L / missense / case only
43604649 / V412M / missense / case only
43606744 / T451T / synonymous / control only
43606776 / S462X / missense / case only
43606829 / E480K / missense / case only
43609968 / A640A / synonymous / case only
43610085 / P679P / synonymous / case/control
43610086 / A680T / missense / control only
43610129 / R694Q / missense / case only
43613884 / N783S / missense / case only
43615094 / S863S / synonymous / case/control
43615109 / P841P / synonymous / case only
43615133 / G849G / synonymous / case only
43619179 / G954G / synonymous / case only
43619198 / F961L / missense / case only
43622074 / D1031N / missense / control only
43622131 / R1050X / missense / case only
43623563 / M1064T / missense / case only
NRG1 / 31497552 / Q18E / missense / case only
31497623 / T41T / synonymous / case only
31497642 / A48T / missense / case only
31497658 / E53G / missense / case/control
31497672 / G58R / missense / case/control
31497817-31497819 / c.317_319insCGG / frameshift / case/control
31497975 / P159S / missense / control only
32453317 / P24P / synonymous / case only
32453325 / A28G / missense / case only
32463201 / E134K / missense / case only
32607102 / E239fsX10 / frameshift / case only
32616917 / H347Y / missense / case only
32616945 / P356L / missense / case only
32621429 / L483L / synonymous / case/control
32621437 / V486M / missense / case/control
32621804 / P608A / missense / case only
#, RET transcript NM_020975.4 and NRG1NM_031962.2 were used (CDS included in the study are reported in So et al. and Tang et al.); *, identified in Hapmap controls (coding sequence data provided by 1000 genome database).

Supplementary Figure 1: Haplotype blocks for common variants in RET and NRG1

Figure 1-A: RET common SNPs; 19 common SNPs (rs2506011, rs2506020, rs2435357, rs2435356, rs2435342, rs2506022, rs2435343, rs752977, rs752978, rs2506024, rs12767776, rs2505540, rs2435347, rs2505538, rs2505536, rs2505535, rs2505533, rs3123655, rs1800858) were shown together in a haplotype block (number in the cells means LD R-square value). All SNPs (starting at chr10: 43,574,936 and ending at chr10: 43595968 in human reference genome build 19)located in RET intron1 region, except rs1800858 from exon-1.

Figure 1-B: NRG1 common SNPs;10 common SNPs (rs7000590, rs4733130, rs4236709, rs7835688, rs7835688, rs2439312, rs9642727, rs13260545, rs10104033 and rs10503920) were shown together in a haplotype block (number in the cells means LD R-square value). All SNPs(starting at chr8: 32,400,628 and ending at chr8: 32,428,689 in human reference genome build 19) locate in NRG1 intron1 region.

Figure 1-A

Figure 1-B

Reference

So MT, Leon TY, Cheng G, Tang CS, Miao XP, Cornes BK, Diem NN, Cui L, Ngan ES, Lui VC, Wu XZ, Wang B, Wang H, Yuan ZW, Huang LM, Li L, Xia H, Zhu D, Liu J, Nguyen TL, Chan IH, Chung PH, Liu XL, Zhang R, Wong KK, Sham PC, Cherny SS, Tam PK, Garcia-Barcelo MM (2011) RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. PLoS One 6: e28986

Tang CS, Ngan ES, Tang WK, So MT, Cheng G, Miao XP, Leon TY, Leung BM, Hui KJ, Lui VH, Chen Y, Chan IH, Chung PH, Liu XL, Wong KK, Sham PC, Cherny SS, Tam PK, Garcia-Barcelo MM (2012) Mutations in the NRG1 gene are associated with Hirschsprung disease. Human Genetics 131: 67-76