RepositoryTable E1 - Disease-associated, potentially causative and contributory variants in the PIDD cohort

WESa
aff/
unaff / Sb / Pat# / Sex / Agec / Ethnicity / Status / PIDD sub-groupe / Gene / Inh. / Zyg. / SNV or CNV / Variant / Type of mutation / Variant classg / OMIM# / Year first reported / Ref.
1/0 / 4 / 1.1 / Male / 30y / Norway / Living / I / IKZF1 / AD / Het / CNV / del7p12.2, g.(Chr7: 50435853-50451072)x1 (hg19) / Deletion / 5 / 603023 / Novel / E1
1/0 / 1 / 2.1 / Male / 20y / Norway / Living / I / BTK f* / XL / Hemi / SNV / BTK:NM_000061:exon15:c.1511A>T:p.D504V (HGMD) (maternal) / Missense / 4 / 300755 / 1993 / E2
ELF4 fp / XL / Hemi / SNV / ELF4:NM_001421:exon6:c.560C>A:p.T187N (maternal) / Missense / 3 / 300775 / 2005 / E3
1/2 / 3 / 3.1 / Male / 2,5y / Ecuador / Living / I / CD40LG f* / XL / Hemi / SNV / CD40LG:NM_000074:exon2:c.233_234delinsAA:p.S78* / Frameshiftindel / 5 / 308230 / 1993 / E4
PSTPIP1 fn / AD / Het / SNV / PSTPIP1:NM_003978:exon14:c.1115C>T:p.A372V (paternal) / Missense / 3 / 604416 / 2002 / E5
1/0 / 3 / 5.1 / Female / 7y / Turkey / Living / I / AICDA / AR / Hom / SNV / AICDA:NM_020661.2:exon2:c.71G>A:p.R24Q (~HGMD) / Missense / 4 / 605258 / 2000 / E6
1/0 / 3 / 6.1 / Male / 20y / Norway / Living / I / CD40LG / XL / Hemi / SNV / CD40LG:NM_000074:exon5:c.495delA:p.R165Sfs*26 (HGMD) / Frameshiftdeletion / 4 / 308230 / 1993 / E4
1/0 / 3 / 7.1 / Female / NA / USA-European ancestry / Living / I / SKIV2L / AR / Het / SNV / SKIV2L:NM_006929.4:exon11:c.1120C>T:p.R374* / Nonsense / 5 / 614602 / 2012 / E7
SKIV2L / AR / Het / SNV / SKIV2L:NM_006929.4:exon27:c.3416G>C:p.R1139P / Missense / 3
1/0 / 3 / 8.1 / Male / NA / USA / Deceased / I / SP110 / AR / Hom / SNV / SP110:NM_004509:exon6:c.586dupT:p.Q231fs / Frameshiftinsertion / 5 / 235550 / 2006 / E8
1/1 / 2 / 9.1 / Male / 6y / USA-European ancestry / Living / II / FOXP3 f* / XL / Hemi / SNV / FOXP3:NM_014009:exon8:c.737T>C:p.L246P (maternal) / Missense / 3 / 304790 / 2001 / E9
RUNX1 fp / AD / Het / SNV / RUNX1:NM_001754:exon9:c.1381A>G:p.N461D / Missense / 3 / 601626 / 1999 / E10
1/0 / 16 / 10.1 / Female / 20y / USA-European ancestry / Living / II / COPA / AD / Het / SNV / COPA:NM_001098398:exon9:c.728A>G:p.D243G (parental) / Missense / 5 / 601924 / 2015 / E11
2/0 / 9 / 11.1 / Female / 20y / USA-European ancestry / Living / II / COPA / AD / Het / SNV / COPA:NM_001098398:exon8:c.698G>A:p.R233H (parental) / Missense / 5 / 601924 / 2015 / E11
1/0 / 3 / 12.1 / Female / 14y / USA-European ancestry / Living / II / COPA / AD / Het / SNV / COPA:NM_001098398:exon9:c.718T>C:p.W240R (paternal) / Missense / 4 / 601924 / 2015 / E11
1/4 / 5 / 13.1 / Female / 8y / USA-European ancestry / Living / II / CBL / AD/ de novo / Het / SNV / CBL:NM_005188:exon8:c.1111T>C:p.Y371H (HGMD) (de novo) / Missense / 5 / 613563 / 2010 / E12
1/0 / 3 / 14.1 / Male / 6y / USA-European ancestry / Deceasedd / II / CTLA4 / AD / Het / SNV / CTLA4:NM_005214:exon2:c.410C>A:p.P137Q (paternal) / Missense / 3 / 616100 / 2014 / E13, E14
1/0 / 4 / 15.1 / Female / 20y / Norway / Living / II / CTLA4 / AD / Het / SNV / CTLA4:NM_005214:exon1: c.94_101delinsTTCTCTTCATCA: p.P32Ffs*29(maternal) / Frameshiftindel / 5 / 616100 / 2014 / E13, E14
1/2 / 3 / 16.1 / Female / 21y / Ecuador / Living / II / CASP10 / AD / Het / SNV / CASP10:NM_032977.3:exon 9:c.1202_1208del:p.C401Lfs*15 (paternal) / Frameshiftdeletion / 5 / 603909 / 1999 / E15
1/0 / 2 / 17.1 / Female / NA / USA-European ancestry / Living / II / PLCG2 / AD / Het / SNV / PLCG2:NM_002661:exon21:c.2300C>T:p.P767L / Missense / 3 / 614468 / 2012 / E16
1/1 / 3 / 19.1 / Male / 12y / Ecuador / Living / II / FOXP3 f* / XL / Hemi / SNV / FOXP3:NM_014009:exon12:c.1208G>A:p.G403E / Missense / 3 / 304790 / 2001 / E9
NRAS fn / AD/ de novo / Het / SNV / NRAS:NM_002524:exon4:c.379A>G:p.T127A, outside hot spot region / Missense / 3 / 614470 / 2007 / E17
1/0 / 3 / 20.1 / Female / 12y / Norway / Living / II / FASLG / AD / Het / SNV / FASLG:NM_000639.1:exon2:c.394G>C:p.G132R (paternal) / Missense / 3 / 601859 / 1996 / E18
1/2 / 4 / 22.1 / Female / 6y / USA-European ancestry / Living / III / COPA / AD / Het / SNV / COPA:NM_001098398:exon9:c.772C>T:p.H258Y (de novo) / Missense / 4 / 601924 / 2015 / E11
1/0 / 2 / 23.1 / Male / 9y / Norway / Living / III / PIK3CD / AD / Het / SNV / PIK3CD:NM_005026:exon15:c.1821G>T:p.E607D / Missense / 3 / 615513 / 2013 / E19
1/2 / 3 / 24.1 / Female / 13y / USA-Hispanic/ latinoancestry / Living / V / Potentialnovel gene3 / AR / Hom / SNV / Potentialnovel gene3:exon15:c.1315A>G:p.M439V / Missense / 3 / Novel
2/0 / 4 / 26.1 / Male / 9y / USA-European ancestry / Living / V / CORO1A / AR / Het / SNV / CORO1A:NM_001193333:exon11:c.1078delC: p.Q360Rfs*45 / Frameshiftdeletion / 5 / 615401 / 2013, similar phenotype / E20
CORO1A / AR / Het / SNV / CORO1A:NM_001193333:exon4:c.248_249delCT: p.P83Rfs*1 / Frameshiftdeletion / 5
1/0 / 5 / 27.1 / Female / 28y / USA-Hispanic/ latinoancestry / Living / V / RNF168 fp / AR / Hom / SNV / RNF168: NM_152617:exon2:c.307G>A:p.D103N / Missense / 3 / 611943 / 2009 / E21
ZAP70 f* / AR / Het / SNV / ZAP70: NM_001079:exon12:c.1505C>T:p.P502L / Missense / 3 / 269840 / 1994 / E22
ZAP70 f* / AR / Het / SNV / ZAP70: NM_001079:exon6:c.733G>A:p.G245R / Missense / 3
2/0 / 3 / 28.1 / Male / 16y / Norway / Living / V / BTK fn / XL / Hemi / SNV / BTK:NM_000061.2:intron2:c.141+11C>T (HGMD) / Splicing / 3 / 300755 / 2003 / E23
MAGT1 f* / XL / Hemi / CNV / delXq21.1, g.(chrX:77096742-77112995)x0 (hg19) (maternal) / Deletion / 5 / 300853 / 2011 / E24
2/0 / 4 / 30.1 / Male / NA / Turkey / Deceasedd / V / DOCK8 / AR / Hom / CNV / del9p24.3, g.(Chr9:24850-379936)x0 (hg19) / Deletion / 5 / 243700 / 2009 / E25
1/4 / 5 / 31.1 / Female / 13Y / Turkey / Living / V / DCLRE1C / AR / Hom / SNV / DCLRE1C:NM_001033855:exon3:c.194C>T:p.T65I / Missense / 3 / 602450 / 2001 / E26
1/2 / 3 / 32.1 / Male / 6m / USA-European ancestry / Living / V / Potentialnovel gene6 / AR / Het / SNV / Potentialnovel gene6:exon8:c.914C>T:p.P305L (paternal) / Missense / 3 / Novel
Potentialnovel gene6 / AR / Het / SNV / Potentialnovel gene6:exon4:c.364G>C:p.E122Q (maternal) / Missense / 3
2/0 / 3 / 33.1 / Female / 30y / Norway / Living / V / Potentialnovel gene1 / AR / Hom / SNV / Potentialnovel gene1:exon20:c.1916T>A:p.L639H / Missense / 4 / 607594 / Novel
1/0 / 3 / 34.1 / Male / 6y / USA-Hispanic/ latinoancestry / Living / V / LYST / AR / Het / SNV / LYST:NM_000081:exon23:c.6782G>A:p.R2261H (paternal) / Missense / 3 / 214500 / 1997 / E27, E28
LYST / AR / Het / SNV / LYST:NM_000081:exon4:c.281C>T:p.T94I (maternal) / Missense / 3
1/1 / 3 / 35.1 / Male / 3y / Ecuador / Living / V / WAS / XL / Hemi / SNV / WAS:NM_000377:exon2:c.208G>A:p.G70R (HGMD) (de novo) / Missense / 4 / 301000 / 1994 / E29
1/0 / 3 / 36.1 / Female / 3y / USA-European ancestry / Living / V / DOCK8 / AR / Hom / SNV / DOCK8:NM_203447:exon47:c.6137T>G:p.L2046R / Missense / 3 / 243700 / 2009 / E25
1/0 / 1 / 37.1 / Male / 4y / Norway / Deceased / V / STAT1 f* / AD/AR / Het / SNV / STAT1:NM_007315:exon19:c.1627T>C:p.C543R / Missense / 3 / 614162 / 2011 / E30
TNFRSF13B fp / AD / Het / SNV / TNFRSF13B:NM_012452:exon4:c.542C>A:p.A181E (HGMD) / Missense / 5 / 240500 / 2005 / E31, E32
1/0 / 3 / 38.1 / Male / 5y / Norway / Living / V / LIG4 / AR / Het / SNV / LIG4:NM_002312.3:exon2:c.1341G>T:p.W447C (maternal) / Missense / 4 / 606593 / 2001 / E33
LIG4 / AR / Het / SNV / LIG4:NM_002312.3:exon2:c.482delC:p.A161Vfs*6 (paternal) / Frameshiftdeletion / 5
1/2 / 4 / 39.1 / Male / 18y / Norway / Living / V / Potentialnovel gene1 / AR / Hom / SNV / Potentialnovel gene1:exon20:c.1916T>A:p.L639H / Missense / 4 / 607594 / Novel
1/0 / 3 / 40.1 / Male / 25y / Turkey / Deceasedd / V / DCLRE1C / AR / Hom / SNV / DCLRE1C:NM_001033855.1:exon10:c.632G>T:p.G211V (HGMD) / Missense / 4 / 602450 / 2001 / E26
1/2 / 3 / 41.1 / Male / 2y / USA-European ancestry / Living / VIII / MX2 / AR / Het / SNV / MX2:NM_002463:exon2:c.166G>A:p.A56T (maternal) / Missense / 3 / 147890 / 2015 / E34, E35
MX2 / AR / Het / SNV / MX2:NM_002463:exon5:c.643T>A:p.S215T (paternal) / Missense / 3
1/0 / 3 / 43.1 / Female / 12y / USA-European ancestry / Living / V / TTC7A / AR / Het / SNV / TTC7A:NM_020458:exon2:c.211G>A:p.E71K (HGMD) (maternal) / Missense / 5 / 243150 / 2013 / E36
TTC7A / AR / Het / SNV / TTC7A:NM_020458:intron8:c.1001+3_1001+6delAAGT (HGMD) (paternal) / Frameshiftdeletion / 4
4/0 / 4 / 45.1 / Male / adult / Norway / Living / VI / Potentialnovel gene5 / AD / Het / SNV / Potentialnovel gene5:exon10:c.1082CT:p.P361L / Missense / 3 / 607594 / Novel
2/0 / 2 / 46.1 / Female / 24y / Norway / Living / VI / CTLA4 / AD / Het / SNV / CTLA4:NM_005214:exon2:c.410C>T:p.P137L (paternal) / Missense / 3 / 616100 / 2014 / E13, E14
1/2 / 3 / 47.1 / Female / 1y / USA-European ancestry / Living / VI / NFKB2 / AD / Het / SNV / NFKB2:NM_001077494:exon22:c.2557C>T:p.R853* (HGMD) (de novo) / Nonsense / 5 / 615577 / 2013 / E37, E38, E39
2/0 / 6 / 48.1 / Male / 55y / Norway / Living / VI / TGFB1 / AD / Het / SNV / TGFB1:exon6:c.1010G>A:p.S337N (in bothaffected) / Missense / 3 / 131300 / Not reportedwith PIDD
1/1 / 5 / 49.1 / Male / 18y / USA-European ancestry / Living / VI / JAK3 f* / AR / Het / SNV / JAK3:NM_000215:exon15:c.1924G>C:p.G642R / Missense / 3 / 600802 / 1995 / E40
JAK3 f* / AR / Het / SNV / JAK3:NM_000215:exon5:c.452C>G:p.P151R (HGMD) / Missense / 3
TNFRSF13B fp / AD / Het / SNV / TNFRSF13B:NM_012452:exon3:c.310T>C:p.C104R (HGMD) (maternal) / Missense / 5 / 240500 / 2005 / E31, E32
1/0 / 1 / 50.1 / Male / 13y / USA-European ancestry / Living / VI / STAT1 / AD/AR / Het / SNV / STAT1:NM_007315:exon14:c.1154C>T:p.T385M (HGMD) / Missense / 5 / 614162 / 2011 / E30
1/0 / 3 / 53.1 / Male / 16y / Norway / Living / VI / IL10 / AR / Hom / SNV / IL10:NM_000572.2:exon5:c.482T>C:p.F161S / Missense / 3 / 124092 / 2012 / E41
1/0 / 3 / 54.1 / Male / 6y / Norway / Living / VI / SH2D1A / XL / Hemi / SNV / SH2D1A:NM_002351:intron1:c.137+1G>A (HGMD) (de novo) / Splicing / 5 / 308240 / 1998 / E42
1/0 / 3 / 56.1 / Female / 6y / Ecuador / Living / VII / IL12RB1 / AR / Hom / SNV / IL12RB1:NM_005535:exon16:c.1791+2T>G (HGMD) / Splicing / 5 / 614891 / 1998 / E43, E44
1/0 / 3 / 57.1 / Male / 5y / Norway / Living / VII / CFP / XL / Hemi / SNV / CFP:NM_002621.2:exon8:c.962G>A:p.W321* (HGMD) (maternal) / Nonsense / 5 / 312060 / 1995 / E45
1/0 / 2 / 58.1 / Female / 40y / Norway / Living / VII / IFNGR2 / AR / Hom / SNV / IFNGR2:NM_005534:exon4:c.421G>A:p.G141R (HGMD) / Missense / 5 / 614889 / 2005 / E46
1/2 / 3 / 59.1 / Male / 6m / Turkey / Living / VII / IKBKG / XL / Hemi / SNV / IKBKG:NM_001099857:exon10:c.1167dupC:p.E390Rfs*5
In only 55 outof 159 reads (revertantmosaicism) (HGMD) / Frameshiftinsertion / 5 / 300291 / 2000 / E47
1/0 / 1 / 60.1 / Female / 3y / Mexico / Living / VII / STAT3 / AD / Het / SNV / STAT3:NM_139276:exon15:c.1309C>T:p.H437Y (HGMD) / Missense / 5 / 147060 / 2007 / E48
1/0 / 2 / 61.1 / Male / 4y / Norway / Living / VII / STAT1 / AD/AR / Het / SNV / STAT1:NM_007315:exon14:c.1163A>G:p.K388R (~HGMD) / Missense / 4 / 614892 / 2001 / E49
1/0 / 3 / 62.1 / Female / 12y / Norway / Living / VII / STAT1 / AD/AR / Het / SNV / STAT1:NM_007315:exon23:c.2113G>C:p.G705Q (de novo) / Missense / 4 / 614892 / 2001 / E49
1/0 / 4 / 63.1 / Male / 49y / Norway / Living / IX / TERC / AD / Het / CNV / del3q26.2, g.(Chr3:169482168_169483029-169485768_169486206)x1 (hg19) / Deletion / 5 / 127550 / 2001 / E50
1/0 / 3 / 64.1 / Female / NA / Qatar / NA / VII / IFNGR2 / AR / Hom / SNV / IFNGR2:NM_005534:exon4:c.421G>A:p.G141R (HGMD) / Missense / 5 / 614889 / 2005 / E46
1/0 / 3 / 65.1 / Female / 4y / Norway / Deceased / VIII / KRAS / AD/ de novo / Het / SNV / KRAS:NM_004985:exon2:c.37G>T:p.G13C
In 15/110 reads (somaticmosaicism) (de novo) / Missense / 5 / 614470 / 2011 / E51
1/0 / 2 / 66.1 / Female / 3y / USA-European ancestry / Living / VIII / STAT3 (GOF) / AD / Het / SNV / STAT3:NM_139276:exon10:c.1032G>C:p.Q344H / Missense / 5 / 615952 / 2014 / E52, E53
3/4 / 7 / 67.1 / Male / 12y / Middle East / Living / VIII / PIK3CD / AD / Het / SNV / PIK3CD:NM_005026:exon13:c.1573G>A:p.E525K (paternal) (HGMD) in 20/53, 37/68, and 87/204 reads in all 3 affectedsiblings.Only in 6/38 reads in thefather,wholikelywasmosaic for the variant, and mildlyaffected. / Missense / 5 / 615513 / 2013 / E19
1/1 / 4 / 68.1 / Male / 12m / UK / Deceased / VIII / Potentialnovel gene2 / AR / Het / SNV / Potentialnovel gene2:exon10:c.1276C>T:p.R426C / Missense / 3 / Novel
Potentialnovel gene2 / AR / Het / SNV / Potentialnovel gene2:exon13:c.1744C>T:p.R582* / Nonsense / 5
1/0 / 3 / 69.1 / Female / 5m / NA / NA / VIII / PRF1 / AR / Het / SNV / PRF1:NM_005041:exon2:c.445G>A:p.G149S (HGMD) / Missense / 5 / 603553 / 1999 / E54
PRF1 / AR / Het / SNV / PRF1:NM_005041:exon3:c.1081A>T:p.R361W (HGMD) / Missense / 5
1/0 / 4 / 70.1 / Male / 8y / USA-Asianancestry / Living / II / CCDC40 / AR / Hom / SNV / CCDC40:NM_017950:exon20:c.3181-2A>G / Splicing / 4 / 613808 / 2011 / E55
1/0 / 1 / 71.1 / Female / 13y / Canada-Native American / Living / VIII / ATP6V0A2 f* / AR / Hom / SNV / ATP6V0A2:NM_012463:intron12:c.1514+1G>A (HGMD) / Splicing / 4 / 611716, 219200 / 2008, but
not PIDD / E56, E57
FBN1 fp / AD / Het / SNV / FBN1:NM_000138: exon27:c.3336G>A:p.M1112I / Missense / 3 / 154700 / 1991 / E58, E59
1/4 / 5 / 72.1 / Male / adult / USA-European ancestry / Deceased / VIII / IRF8 / AR / Het / SNV / IRF8: exon7:c.602C>T:p.A201V (maternal) / Missense / 3 / 614894 / 2012 / E60
IRF8 / AR / Het / SNV / IRF8:exon7:c.671C>T:p.P224L (paternal) / Missense / 3
1/0 / 1 / 73.1 / Female / NA / Germany / Living / VIII / DOCK8 / AR / Hom / SNV / DOCK8:NM_203447.3:intron36:c.4626+76A>G / Splicing / 3 / 243700 / 2009 / E25
1/4 / 6 / 74.1 / Male / 9y / USA-European ancestry / NA / VIII / WAS / XL / Hemi / SNV / WAS:NM_000377:exon10:c.1181C>T:p.P394L (maternal) / Missense / 3 / 301000 / 1994 / E29
1/1 / 2 / 75.1 / Male / 3y / USA-European ancestry / Living / VIII / IFIH1 / AD / Het / SNV / IFIH1:NM_022168:exon13:c.2549G>A:p.R850Q (not maternal) / Missense / 3 / 615846 / 2014 / E61
1/2 / 3 / 76.1 / Male / 12y / Chile / Living / VIII / EPG5 / AR / Het / SNV / EPG5:NM_020964:exon36:c.6112T>G:p.C2038G (~HGMD) / Missense / 3 / 242840 / 2013 / E62
EPG5 / AR / Het / SNV / EPG5:NM_020964:exon37:c.6410C>G:p.T2137R / Missense / 3
1/2 / 3 / 77.1 / Female / 5y / Chile / Deceased / VIII / NFKBIA / AD / Het / SNV / NFKBIA:NM_020529:exon5:c.847A>T:p.S283C (paternal) / Missense / 3 / 612132 / 2003 / E63
1/0 / 1 / 78.1 / Female / 2,5y / NA / NA / VIII / RAB27A / AR / Hom / SNV / RAB27A:NM_004580:exon3:c.220G>C:p.D74H (~HGMD) / Missense / 4 / 607624 / 2002 / E64, E65
1/0 / 2 / 79.1 / Male / 22y / UK / Living / VIII / PIK3CD / AD / Het / SNV / PIK3CD:NM_005026:exon10:c.1246T>C:p.C416R (HGMD) / Missense / 4 / 615513 / 2013 / E19
2/2 / 5 / 81.1 / Female / 5y / Middle East / Living / VIII / DOCK8 / AR / Hom / CNV / del9p24.3, g.(Chr9:368128-452113)x0 (hg19) / Deletion / 5 / 243700 / 2009 / E25
81.5 / Male / NA / Middle East / NA / VIII / RAG1 / AR / Hom / SNV / RAG1:NM_000448:exon2:c.1211G>A:p.R404Q (HGMD) / Missense / 5 / 601457 / 1996 / E66
1/0 / 1 / 83.1 / Female / 9y / USA-European ancestry / Living / VIII / STXBP2 / AR / Het / SNV / STXBP2:NM_006949:exon14:c.1213C>T:p.R405W (HGMD) / Missense / 5 / 613101 / 2009 / E67
STXBP2 / AR / Het / SNV / STXBP2:NM_006949:intron14:c.1247-1G>C / Splicing / 5
1/0 / 5 / 84.1 / Female / 45y / Norway / Deceased / VIII / GATA2 / AD / Het / SNV / GATA2:NM_001145661.1:intron7a:c.1143+5G>A (de novo, monozygotictwins) / Splicing / 4 / 614038 / 2011 / E68
1/0 / 6 / 85.1 / Male / 8y / Turkey / Deceasedd / VIII / ITK / AR / Hom / SNV / ITK:NM_005546.3:exon16:c.1727G>A:p.R576Q / Missense / 3 / 613011 / 2009 / E69
1/0 / 3 / 86.1 / Female / 18y / Norway / Living / VIII / GATA2 / AD / Het / SNV / GATA2:NM_001145661.1:exon6:c.1061C>T:p.T354M (de novo) (HGMD) / Missense / 5 / 614038 / 2011 / E68
1/0 / 2 / 87.1 / Male / 52y / Norway / Living / VIII / Potentialnovel gene1 / AR / Hom / SNV / Potentialnovel gene1:exon20:c.1916T>A:p.L639H / Missense / 4 / 607594 / Novel
1/0 / 1 / 88.1 / Male / 26y / Norway / Living / VIII / GATA2 / AD / Het / SNV / GATA2:NM_001145661.1:exon7a:c.1078T>A:p.W360R / Missense / 4 / 614038 / 2011 / E68
0/1 / 3 / 90.1 / Male / 13y / Norway / Deceased / IX / DKC1 / XL / Hemi / CNV / dupXq28, g.(ChrX:153992076-154006200)x2 (hg19) / Duplication / 4 / 305000 / 1998 / E70
2/0 / 2 / 91.1 / Male / NA / Mexico / Living / IX / G6PC3 f* / AR / Het / SNV / G6PC3:NM_138387:exon1:c.210delC:p.F71Sfs*46 (HGMD) / Frameshiftdeletion / 5 / 612541 / 2009 / E71
G6PC3 f* / AR / Het / SNV / G6PC3:NM_138387:exon4:c.482G>A:p.R161Q (HGMD) / Missense / 5
RUNX1 fp / AD / Het / SNV / RUNX1:NM_001754:exon8:c.952T>G:p.S318A (HGMD) / Missense / 3 / 601626; 601399 / 1999 / E72
91.4 / Male / NA / Mexico / Living / IX / G6PC3 f* / AR / Hom / SNV / G6PC3:NM_138387:exon4:c.482G>A:p.R161Q (HGMD) / Missense / 5 / 612541 / 2009 / E71
RUNX1 fp / AD / Het / SNV / RUNX1:NM_001754:exon8:c.952T>G:p.S318A (HGMD) / Missense / 3 / 601626; 601399 / 1999 / E72
1/0 / 3 / 93.1 / Male / 40y / Norway / Deceased / IX / FANCB fp / XL / Hemi / SNV / FANCB:NM_001018113:exon4:c.989T>C:p.I330T (maternal) / Missense / 3 / 300514 / 2004 / E73
SH2D1A f* / XL / Hemi / SNV / SH2D1A:NM_002351:exon1:c.80G>A:p.G27D (~HGMD) (maternal) / Missense / 3 / 308240 / 1998 / E42
1/0 / 1 / 94.1 / Female / 13y / Norway / Living / IX / LRRC8A f* / AD / Het / SNV / LRRC8A:NM_001127244:exon3:c.275C>T:p.T92M / Missense / 3 / 613506 / 2003, only translocation / E74
MYH9 fp / AD / Het / SNV / MYH9:NM_002473:exon31:c.4198C>T:p.R1400W (HGMD) / Missense / 3 / 600208 / 2002 / E75
ROR2 fp / AD/AR / Het / SNV / ROR2:NM_004560:exon9:c.1742G>A:p.R581H / Missense / 3 / 113000 / 2000 / E76
0/2 / 3 / 95.2 / Female / mom / Norway / Living 20y proband / IX / FANCC / AR / Het / SNV / FANCC:NM_000136:exon2:c.67delG:p.D23Ifs*23 (HGMD) / Frameshiftdeletion / 5 / 227645 / 1992 / E77
95.3 / Male / dad / Norway / Living 20y proband / IX / FANCC / AR / Het / SNV / FANCC:NM_000136:exon7:c.553C>T:p.R185* (HGMD) / Nonsense / 5
1/0 / 3 / 96.1 / Female / 10y / Norway / Living / IX / STAT3 (GOF) / AD / Het / SNV / STAT3:NM_139276:exon14:c.1243G>A:p.E415K (de novo) / Missense / 5 / 615952 / 2014 / E52
1/0 / 4 / 97.1 / Female / 34y / Norway / Living / IX / FANCA / AR / Het / CNV / 16q24.3, g.(Chr16:89811272-89833745)x1 (hg19) / Deletion / 5 / 227650 / 1996 / E78
FANCA / AR / Het / SNV / FANCA:NM_000135.2:exon34:c.3391A>G:p.T1131A
In only 75% ofthereads (revertantmosaicism) (HGMD) / Missense / 5 / 227650 / 1996 / E78
1/0 / 4 / 98.1 / Female / 16y / Pakistan / Living / IX / G6PC3 / AR / Hom / SNV / G6PC3:NM_138387:exon1:c.130C>T:p.P44S (HGMD) / Missense / 5 / 612541 / 2007 / E71
1/0 / 3 / 99.1 / Female / 25y / Norway / Living / IX / RPL5 / AD/ de novo / Het / SNV / RPL5:NM_000969:exon2:c.48C>A:p.Y16*​ (HGMD) / Missense / 5 / 612561 / 2008 / E79, E80
1/0 / 3 / 100.1 / Male / 14y / Norway / Living / IX / GIF / AR / Hom / SNV / GIF:NM_005142:intron1:c.79+1G>A (HGMD) / Splicing / 5 / 261000 / 2004 / E81
1/0 / 3 / 101.1 / Female / 9y / Middle East / Living / IX / FANCA / AR / Hom / SNV / FANCA:NM_000135.2:exon29:c.2851C>T:p.R951W (HGMD) / Missense / 4 / 227650 / 1996 / E78
1/0 / 5 / 102.1 / Male / 6y / Norway / Living / IX / RUNX1 / AD / Het / SNV / RUNX1:NM_001754:exon5:c.485_486insA:p.F163Vfs*50 (de novo) / Frameshiftinsertion / 5 / 601399 / 1999 / E10
1/0 / 1 / 104.1 / Female / 71y / Norway / Living / IX / NCF1 / AR / Hom / CNV / del7q11.23, g.(chr7:74188309-74203659)x0 (hg19) / Deletion / 5 / 233700 / 1989 / E82
1/0 / 1 / 105.1 / Male / 55y / Norway / Living / IX / CEBPE / AR / Hom / SNV / CEBPE:NM_001805:exon2:c.537delC:p.P179Pfs*5 / Frameshiftdeletion / 5 / 245480 / 1999 / E83
1/0 / 3 / 106.1 / Male / 23y / Norway / Living / IX / RTEL1 / AR/AD / Het / SNV / RTEL1:NM_016434:exon24:c.2083A>T:p.I695F (maternal) / Missense / 3 / 615190 / 2013 / E84
RTEL1 / AR/AD / Het / SNV / RTEL1:NM_016434:exon3:c.190C>T:p.R64* (paternal) / Nonsense / 5
2/0 / 9 / 108.1 / Male / 4m / Middle East / Deceased / IV / Potentialnovel gene4 / AR / Hom / SNV / Potentialnovelgene4:exon1:c.155G>A:p.G52D / Missense / 3 / 611291 / Novel
1/0 / 3 / 109.1 / Male / 6y / USA-Hispanic/ latinoancestry / Living / IV / PGM3 / AR / Het / CNV / del6q14.1-q14.2, g.(Chr6:83145962-84389166)x1 (hg19) / Deletion / 5 / 615816 / 2014 / E85
PGM3 / AR / Hemi / SNV / PGM3:NM_015599.2:exon6:c.715G>C:p.D239H (maternal) / Missense / 5
1/0 / 4 / 110.1 / Female / 6m / Afghanistan / Living / IV / PGM3 / AR / Hom / SNV / PGM3:NM_015599.2:exon6:c.737A>G:p.N246S / Missense / 5 / 615816 / 2014 / E85
1/0 / 3 / 111.1 / Male / 20y / USA-European ancestry / Living / IV / IL2RG / XL / Hemi / SNV / IL2RG:NM_000206:exon4:c.562C>T:p.Q188* (HGMD) (maternal) In 132 outof 208 reads post-HSCT, his motherwas donor / Nonsense / 5 / 300400 / 1993 / E86
1/0 / 4 / 112.1 / Female / 2y / USA-European ancestry / Living / IV / IL7R / AR / Het / CNV / del5p13.2, g.(Chr5:35867357−35867581)x1 (hg19) (maternal) / Deletion / 5 / 608971 / 1998 / E87
IL7R / AR / Hemi / SNV / IL7R: NM_002185.3:exon3:c.361dupA:p.I121Nfs*8
In only 74% ofthereads (revertantmosaicism) / Frameshiftinsertion / 5
1/2 / 3 / 113.1 / Male / 4m / Ecuador / Living / IV / CFTR f* / AR / Het / SNV / CFTR:NM_000492:exon10:c.1520_1522del:p.507_508del (HGMD) (paternal) / In-framedeletion / 5 / 219700 / 1986
IV / CFTR f* / AR / Het / SNV / CFTR:NM_000492:exon13:c.1826A>G:p.H609R (HGMD) (maternal) / Missense / 4
IV / RTEL1 fp / AD/AR / Het / SNV / RTEL1:NM_016134:exon27:c.2545G>A:p.G849S / Missense / 3 / 615190 / 2013 / E84
1/0 / 3 / 114.1 / Female / 5y / East-African / Living / IV / IL7R / AR / Hom / SNV / IL7R:NM_002185.3:intron5:c.707-2A>G / Splicing / 5 / 608971 / 1998 / E87
1/0 / 3 / 115.1 / Male / 5y / Norway / Living / IV / MBTPS2 / XL / Hemi / SNV / MBTPS2:NM_015884.3:exon6:c.758G>C:p.G253A (HGMD) (maternal) / Missense / 5 / 308205 / 2009, but
not SCID / E88
1/0 / 2 / 116.1 / Male / 3ya / Norway / Deceasedd / IV / IL2RG / XL / Hemi / SNV / IL2RG:NM_000206.2:intron7:c.924+5G>A (HGMD) (maternal) / Splicing / 3 / 300400 / 1993 / E86
1/0 / 3 / 117.1 / Male / 1y / Norway / Living / IV / JAK3 / AR / Het / SNV / JAK3:NM_000215.3:exon12:c.1695C>A:p.C565* (HGMD) (paternal) / Nonsense / 5 / 600802 / 1995 / E40
JAK3 / AR / Het / SNV / JAK3:NM_000215.3:exon14:c.1837C>T:p.R613* (maternal) / Nonsense / 5
1/0 / 5 / 119.1 / Female / 35y / Norway / Living / X / SMARCAL1 / AR / Het / SNV / SMARCAL1:NM_014140:exon12:c.2070+2dupT / Splicing / 5 / 242900 / 2002 / E89
SMARCAL1 / AR / Het / SNV / SMARCAL1:NM_014140:exon13:c.2114C>T:p.T705I (HGMD) / Missense / 4
1/1 / 3 / 120.1 / Female / 8y / USA-European ancestry / Living / X / MYB / AD/de novo / Het / CNV / del6q23.2q23.3, g.(Chr6:134850426-138250910)x1 (hg19) (de novo) / Deletion / 5 / 189990 / Novel PIDD gene / E90, E91, E92, E93
1/2 / 3 / 121.1 / Male / 15y / Norway / Living / X / CBL fp / AD/ de novo / Het / SNV / CBL:NM_005188:exon13:c.2108C>T:p.P703L (maternal) / Missense / 3 / 613563 / 2010 / E12
PIEZO1 f* / AD / Het / SNV / PIEZO1:NM_001142864:exon19:c.2610G>A:p.M870I (de novo) / Missense / 4 / 194380 / 2013 / E94, E95
1/2 / 3 / 122.1 / Female / 4y / Pakistan / Living / X / SMARCAL1 / AR / Hom / CNV / del2q35, g.(Chr2:217279427-217281031)x0 (hg19) / Deletion / 5 / 242900 / 2002 / E89
1/2 / 3 / 123.1 / Male / NA / Turkey / Living / X / DSP / AR / Hom / SNV / DSP:NM_004415:exon24:c.7912G>T:p.E2638* / Nonsense / 5 / 606655 / 2011 (this phenotype), 2006 / E96
1/0 / 3 / 124.1 / Male / 6m / Pakistan / Deceased / X / CLPB / AR / Hom / SNV / CLPB:NM_030813:exon3:c.512T>C:p.L171P / Missense / 3 / 616271 / 2015 / E97, E98
1/2 / 3 / 125.1 / Female / 6m / Ecuador / Living / X / PLXNA1 fp / AD / Het / SNV / PLXNA1:NM_032242:exon14:c.2980G>C:p.V994L (de novo) / Missense / 3 / 601055 / 2015 / E99
RET f* / AD / Het / SNV / RET:NM_020975:intron10:c.1879+1G>T (~HGMD) (de novo) / Splicing / 5 / 142623 / 1994 / E100
1/2 / 3 / 126.1 / Female / 2y / Ecuador / Living / X / PSTPIP1 / AD / Het / SNV / PSTPIP1:NM_003978:exon12:c.865G>C:p.D289H / Missense / 3 / 604416 / 2002 / E5
1/0 / 3 / 127.1 / Female / 3y / Norway / Living / X / RECQL4 / AR / Het / SNV / RECQL4:NM_004260.3:exon14:c.2269C>T:p.Q757* (HGMD) (paternal) / Nonsense / 5 / 268400 / 2000 / E101
RECQL4 / AR / Het / SNV / RECQL4:NM_004260.3:intron17:c.3056-3C>A (maternal) / Splicing / 3

a)Number of affected and unaffected individuals WES tested in each family.

b)Number of individuals Sanger sequenced or CNV tested in each family in order to verify segregation of the variant.

c)Age at inclusion.

d)Deceased during the WES study.

e)PIDD subgroups, based on clinical presentation pre-WES: i) antibody deficiency including hyper IgM syndrome, ii) autoimmune disease, iii)autoinflammatory disorder, iv) severe combined immunodeficiency (SCID), v) combined immunodeficiency (not SCID) and selective T cell deficiency, vi) common variable immunodeficiency, vii) defect in innate immunity including mucocutaneous candidiasis, hyper IgE syndrome, mendelian susceptibility to mycobacterial disease, and complement deficiency, viii) lymphoproliferativedisease, hemophagocyticlymphohistiocytosis (HLH) and NK cell deficiency, ix)neutrophil defect or congenitalcondition with bone marrow failure such as dyskeratosiscongenita and Fanconi-like phenotype, anemia and thrombocytopenia x) immuno-osseous dysplasia, chromosomal disorder and other syndromic PIDD.

f)More than one gene with disease-causing and/or disease-modifying variants; exemplifying phenotypes consistent with diagnostic criteria for each gene; * The main disease-related gene variants among them, pPotential disease-modifying gene variants, nRelevant, but not consistent with criteria (i.e., f*, fp or fn).

g)Guidelines for variant classification recommended by the American College of Medical Genetics and Genomics (ACMG).E117

Abbreviations: HGMD, variant registered in Human Gene Mutation Database; ~HGMD, variant located in identical nucleotide or amino acid position registered in HGMD; Inh, inheritance pattern for disease gene; NA, data not available; y, years; Zyg, zygozity of the detected variant.

Supplementary Methods

Clinical samples

Participation in the study was offered to families referred to Baylor-Hopkins Center for Mendelian Genomics (BHCMG) at Baylor College of Medicine (BCM), and the Center for Human Immunobiology, Division of Immunology Allergy and Rheumatology at Texas Children’s Hospital (TCH) in Houston USA, and Oslo University Hospital (OUS), Oslo, Norway. Families originated from the following countries: Afghanistan, Argentina, Canada, Chile, Colombia, Ecuador, Germany, Italy, Mexico, Norway, Pakistan, Palestine, Peru, Poland, Qatar, Russia, Saudi Arabia, Somalia, Sweden, Turkey, United Kingdom, and United States. The study was approved by the regional ethical committee for medical and health research ethics in Norway (REC South-East), and under protocols approved by Institutional Review Board for Human Subjects Research at Baylor College of Medicine, Houston TX USA (H-29697- Genome Sequencing to Elucidate the Causes and Mechanisms of Mendelian Genetic Disorders). Parents or guardians consented on behalf of children under age 16 years. The molecular analyses of Norwegian participants were performed in accordance with the Norwegian Biotechnology Act.

WES data processing

At BCM-HGSC, data were processed through the HGSC-developed Mercury pipeline E102to produce variant call format files (.vcf) using the Atlas2 variant calling method.E103-E106Variants were annotated using the in-house developed Cassandra E107 annotation pipeline based on ANNOVAR.E108 Analyses methods are available through cloud computing.E102For the Oslo samples, reads that passedIllumina’s standard filter aligned to the human reference genome (hg19), using Novoalign (v3.02)(Novocraft Technologies, Selangor, Malaysia).Initial alignment files were realigned using the Genome Analysis Toolkit (GATK, v3.1),E109, E110 and PCR duplicates were marked using Picard (v1.88; Next, base quality scores were recalibrated and variant calling was performed with GATK. ANNOVAR (v2013August23) E108 was used for variant annotation. Human genome mutation database (HGMD)E111 annotations, in-house database frequency and additional information on PIDD candidate genes were added to the ANNOVAR annotated files via an in-house annotation pipeline. In brief, minor differencies in bioinformatics pipelines between the two centers, both were based on the GATK best practices and ANNOVAR.

Variant evaluation

For samples tested in Oslo, FILTUSE112was utilized for variant filtering and prioritization. For the BCM-HGSC samples, Variant Analyzer was used for variant filtering and prioritization after all variants with minor allele frequency (MAF) above 0.05 in the NHLBI Exome Sequencing Project (ESP) Exome Variant Server were filtered out.As of December 2015, the two HGSC-BCM in-house databases contain exomes from >10,000 individuals (ARIC, Atherosclerosis Risk In Communities and exomes from >5000 individuals with various genetic diseases or their healthy relatives (BCM-CMG, Center for Mendelian Genomics). The in-house database in Oslo contains > 400 exomes from individuals with various disorders such as global developmental delay, intellectual disability and neurodegenerative diseases.The reported potential disease-causing variants were not presentin homozygous state andallele frequency was less than 0.0001 in heterozygous/hemizygous state (for dominant/X-linked inheritance respectively) in the ExAC database (as of November 2015), with the exception of modifying variants with known functional effect. Some candidate genes belonged to an established potential PIDD gene list.E114 Additional lines of evidence included biological validation consistent with guidance proposed for unique discoveries in single cases,E115 presence of PIDD gene protein homologues with relevant expression patternsbelonging to the PIDD gene interactome, and segregation with identical immunophenotype in several individuals within the same family and/or other families. Pending biological validation,E115,E114 these genes are referred to in this paper as “potentially novel” in order to allow for the consideration of overall diagnostic yield. The Integrative Genomic Viewer (IGV) E116 was used to visualize sequencing alignment data and Alamut (v2.4.6) (Interactive Biosoftware, Rouen, France) to evaluatepathological relevance.

ACMG Guidelines

The functional impact of the detected variants was evaluated based on criteria (Table E1) adapted from the Guidelines recommended by the American College of Medical Genetics and Genomics (ACMG)E117were adapted for evaluation of functional impact of the reported potential disease-causing variants, as stated below;

5 – Pathogenic variants

Frameshift/nonsense

Changes that alters the canonical ±1 or 2 splice sites

Variants that alters the inition codon

Single or multiexon deletions

These variants are considered clear pathogenic without further interpretation in genes where loss of function in a known mechanism of disease and unless occurring in last exon or within last 50 bases of the second to last exon.

Reported as disease-causing with functional protein studies supportive of damaging effect on the gene or gene product

4 - Likely pathogenic variants

De novo in a gene supporting the phenotype of the patient (but without confirmation of paternity and maternity)

Variant affecting a critical and well-established functional domain

Missense variant where a same variant has reported in patient with similar phenotype (but without functional evidence provided) or different missense change has previously been determined to be pathogenic (except when previously reported variant affected splicing).

Cosegregation with disease in multiple affected family members in a gene known to cause the relevant disease.

Variants predicted to affect splicing, with support from RNA studies

3 – Variants of unknown significance (VUS)

Missense variant without proven functional effect on the protein

Variants predicted to affect splicing, without support from RNA studies

2 – Unlikely pathogenic variants

Synonymous and intronic variants without predicted effect on splicing

UTR variants

Allele frequency is grater than expected for the disorder

1 – Clearly not pathogenic variants

“Common” polymorphisms with a high frequency in databases of control individuals

Sanger sequencing validation and variant segregation within families

Sanger sequencing was performed on genomic DNA extracted from peripheral blood. Primers were designed using Primer3 software,E118 sequencing was performedon an ABI 3730 sequencer (Applied Biosystems, Life Technologies, CA, USA), and sequence data were analyzed using SeqScape v2.7 (Life Technologies, CA, USA) and 4Peaks software (