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

WESa

aff/unaff

Sb Pat# Sex Agec Ethnicity StatusPIDD sub-

groupeGene Inh. Zyg.

SNV or

CNVVariant Type of

mutationVariant 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 IBTK 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 ICD40LG f* XL Hemi SNV CD40LG:NM_000074:exon2:c.233_234delinsAA:p.S78* Frameshift

indel 5 308230 1993E4

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) Frameshift deletion 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 5614602 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 Frameshift insertion 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)

Frameshift indel 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) Frameshift deletion 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 IIFOXP3 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/ Living V Potential AR Hom SNV Potential novel gene3:exon15:c.1315A>G:p.M439V Missense 3 Novel

latino ancestry novel gene3

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 Frameshift deletion 5

6154012013,

similar phenotype

E20CORO1A AR Het SNV CORO1A:NM_001193333:exon4:c.248_249delCT: p.P83Rfs*1 Frameshift

deletion 5

1/0 5 27.1 Female 28y USA-Hispanic/ latino ancestry 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 3269840 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 VBTK 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

Potential novel gene6 AR Het SNV Potential novel gene6:exon8:c.914C>T:p.P305L (paternal) Missense 3

NovelPotential

novel gene6 AR Het SNV Potential novel gene6:exon4:c.364G>C:p.E122Q (maternal) Missense 3

2/0 3 33.1 Female 30y Norway Living V Potential novel gene1 AR Hom SNV Potential novel gene1:exon20:c.1916T>A:p.L639H Missense 4 607594 Novel

1/0 3 34.1 Male 6y USA-Hispanic/ latino ancestry Living V

LYST AR Het SNV LYST:NM_000081:exon23:c.6782G>A:p.R2261H (paternal) Missense 3214500 1997 E27,

E28LYST 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 VSTAT1 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 VLIG4 AR Het SNV LIG4:NM_002312.3:exon2:c.1341G>T:p.W447C (maternal) Missense 4

606593 2001 E33LIG4 AR Het SNV LIG4:NM_002312.3:exon2:c.482delC:p.A161Vfs*6 (paternal) Frameshift

deletion 5

1/2 4 39.1 Male 18y Norway Living V Potential novel gene1 AR Hom SNV Potential novel 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 3147890 2015 E34,

E35MX2 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 5243150 2013 E36

TTC7A AR Het SNV TTC7A:NM_020458:intron8:c.1001+3_1001+6delAAGT (HGMD) (paternal) Frameshift deletion 4

4/0 4 45.1 Male adult Norway Living VI Potential novel gene5 AD Het SNV Potential novel gene5:exon10:c.1082C>T: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 both affected) Missense 3 131300Not

reported with 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 3600802 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*5In only 55 out of 159 reads (revertant mosaicism) (HGMD)

Frameshift insertion 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 (somatic mosaicism) (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 SNVPIK3CD:NM_005026:exon13:c.1573G>A:p.E525K (paternal) (HGMD) in 20/53, 37/68, and 87/204 reads in all 3 affected siblings. Only in 6/38 reads in the father, who likely was mosaic for the variant, and mildly affected.

Missense 5 615513 2013 E19

1/1 4 68.1 Male 12m UK Deceased VIII

Potential novel gene2 AR Het SNV Potential novel gene2:exon10:c.1276C>T:p.R426C Missense 3

NovelPotential

novel gene2 AR Het SNV Potential novel gene2:exon13:c.1744C>T:p.R582* Nonsense 5

1/0 3 69.1 Female 5m NA NA VIIIPRF1 AR Het SNV PRF1:NM_005041:exon2:c.445G>A:p.G149S (HGMD) Missense 5

603553 1999 E54PRF1 AR Het SNV PRF1:NM_005041:exon3:c.1081A>T:p.R361W (HGMD) Missense 5

1/0 4 70.1 Male 8y USA-Asian ancestry 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, butnot 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 Deceased VIII IRF8 AR Het SNV IRF8: exon7:c.602C>T:p.A201V (maternal) Missense 3 614894 2012 E60

ancestry 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 VIIIEPG5 AR Het SNV EPG5:NM_020964:exon36:c.6112T>G:p.C2038G (~HGMD) Missense 3

242840 2013 E62EPG5 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

2/2 581.1 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 5613101 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, monozygotic twins) 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 Potential novel gene1 AR Hom SNV Potential novel 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) Frameshift deletion 5

612541 2009 E71G6PC3 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 IXG6PC3 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 IXFANCB 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 IX FANCC AR Het SNV FANCC:NM_000136:exon2:c.67delG:p.D23Ifs*23 (HGMD) Frameshift 5 227645 1992 E77

proband deletion

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 IXFANCA 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.T1131AIn only 75% of the reads (revertant mosaicism) (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) Frameshift insertion 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 Frameshift deletion 5 245480 1999 E83

1/0 3 106.1 Male 23y Norway Living IXRTEL1 AR/AD Het SNV RTEL1:NM_016434:exon24:c.2083A>T:p.I695F (maternal) Missense 3

615190 2013 E84RTEL1 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 Potential novel gene4 AR Hom SNV Potential novel gene4:exon1:c.155G>A:p.G52D Missense 3 611291 Novel

1/0 3 109.1 Male 6y USA-Hispanic/ latino ancestry Living IV

PGM3 AR Het CNV del6q14.1-q14.2, g.(Chr6:83145962-84389166)x1 (hg19) Deletion 5615816 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 out

of 208 reads post-HSCT, his mother was 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 5608971 1998 E87

IL7R AR Hemi SNV IL7R: NM_002185.3:exon3:c.361dupA:p.I121Nfs*8In only 74% of the reads (revertant mosaicism)

Frameshift insertion 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-frame deletion 5

219700 1986IV 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, butnot 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 IVJAK3 AR Het SNV JAK3:NM_000215.3:exon12:c.1695C>A:p.C565* (HGMD) (paternal) Nonsense 5

600802 1995 E40JAK3 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 XCBL 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 6066552011 (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 XPLXNA1 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 XRECQL4 AR Het SNV RECQL4:NM_004260.3:exon14:c.2269C>T:p.Q757* (HGMD) (paternal) Nonsense 5

268400 2000 E101RECQL4 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) lymphoproliferative disease, hemophagocytic lymphohistiocytosis (HLH) and NK cell deficiency, ix) neutrophil defect or congenital condition with bone marrow failure such as dyskeratosis congenita 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 E102 to

produce variant call format files (.vcf) using the Atlas2 variant calling method.E103- E106 Variants

were annotated using the in-house developed Cassandra E107 annotation pipeline based on

ANNOVAR. E108 Analyses methods are available through cloud computing.E102 For the Oslo

samples, reads that passed Illumina’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; http://broadinstitute.github.io/picard/).

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, FILTUS E112 was 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 http://www2.cscc.unc.edu/aric/), E113 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

present in homozygous state and allele 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 patterns belonging 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 evaluate pathological

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) E117 were 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 performed on 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

(http://nucleobytes.com/index.php/4peaks).

Copy number variants (CNVs)

For all probands CNV predictions were initially performed from WES data using

ExCopyDepth.E119 CNV predictions from the Oslo samples were annotated using cnvScan.E120

Annotated CNVs were then filtered using PIDD(475), and rare CNVs were selected based on

an in-house database, CNV score, a high-quality stringent map of Database of Genomic

Variants (DGV),E121 1000 Genomes CNVs E122 and ClinVar variants.E123 Remaining rare CNVs

were evaluated in light of clinical phenotype and assessed using IGV. Predictions for

homozygous and hemizygous CNVs for the BCM-HGSC generated WES data were annotated

using HMZDelFinder.124 Subsequently, microarray CNV detection was applied in selected cases

where no disease-causing variants were detected after exome sequencing or when CNV

prediction data indicated the presence of a relevant CNV. A BCM chromosomal microarray

using a custom-designed genome-wide diagnostic chromosomal Agilent oligoarray (BCM CMA

version 10) with exon coverage of 4,200 genes, including 400 PIDD genes,E125, E126 was used to

analyze the BHCMG samples. In Oslo samples were tested with a custom 1M Agilent high

resolution exonic focused oligoarray with four or more probes for over 80% of the GENCODE

v.15 exonic and CDS regions (+ 1600 bp flanking regions).E119

Repository Figure legends

Figure E1

(A) CNV prediction (HMZDel Finder) identified a hemizygous deletion of a region within

MAGT1 in proband 28.1 and his uncle (patient 28.4, Table E1), shown by a red line (patient

exome data) deviating from a pool of reference exomes marked with black lines. Visualisation

of the exome sequencing results of the two affecteds and a male control in IGV, indicated lack

of reads covering MAGT1 exon 4 to 8 in the two affecteds. Array CGH confirmed the

heterozygous deletion of MAGT1 exon 4 to 8 in the obligate carrier (individual 28.2), the

mother of proband 28.1 (Table E1) and sister of patient 28.4. (B) An unaffected, obligate

carrier female (90.2) had two brothers and a son with Hoyeraal-Hreidarsson syndrome who

died. The brothers were the original Hoyeraal-Hreidarsson patients reported in 1970,E127 but

no DKC1 mutation had been identified by Sanger sequencing. Exon-wise chromosomal

microarray (CMA) detected a duplication of exon 2 to 15 of the X-linked DKC1 in the obligate

carrier (90.2, Table E1), and in her daughter (90.4). Both females had skewed X-chromosome

inactivation patterns in blood. Sanger sequencing across the region of the duplication in the

two carriers and the proband (90.1) resulted in a PCR product of ~2 kb and revealed the

tandem location of the duplication. Duplication breakpoints were compatible with mediation

by homologous sequence elements in introns 1 and 3’ of DKC1. (C) CNV prediction

(ExCopyDepth)E119 indicated a heterozygous deletion of exons 4 and 5 in IKZF1 in proband 1.1.

Exome data visualized in IGV showed a halved number of reads in the region of the predicted

deletion compared to two controls. Exon-wise aCGH confirmed a heterozygous deletion of

exons 4 and 5. Sanger sequencing identified breakpoints in introns 3 and 5. The unaffected

mother (1.2) and brother (1.4) did not harbour the deletion.

Figure E2

In proband 63.1, CNV prediction (ExCopyDepth)119 indicated a homozygous deletion of

affecting TERC (data not shown). Visualization of the exome sequencing results for him and

for two normal controls in IGV, indicated halved read coverage of 3’ part of TERC. Exon tiling

aCGH confirmed a heterozygous deletion affecting 3’ part of TERC.

Figure E3

(A) CNV prediction (ExCopyDepth)E119 indicated a heterozygous deletion of exons 2 to 11 in

NCF1 in proband 104.1 (data not shown). Visualization of the exome sequencing results for

her and for two normal controls in IGV, indicated absence of reads covering NCF1 exons 6 and

7 in 104.1, and decreased coverage of additional NCF1 exons. MLPA confirmed the proband’s

homozygous deletion of the entire NCF1 gene. No parental samples were available. On closer

examination of the reads covering NCF1 virtually all reads in both 104.1 and controls had low

mapping quality due to the presence of two pseudo-NCF1 ( -Ψ NCF1) genes with >99%

homology to NCF1 in humans.E128 Poor mapping quality likely explains the presence of some

NCF1 reads in 104.1 notwithstanding her confirmed homozygous whole-gene deletion. The

deletion was confirmed with MLPA (performed by Dr Dirk Roos and Mr. Martin de Boer in

their clinical CGD lab at the Department of Blood Cell Research, Sanquin Blood Supply

Organization, Amsterdam, the Netherlands), but undetectable on exon-wise aCGH due to the

NCF1 pseudogene. (B) CNV prediction (HMZDel finder)E104 indicated a deletion affecting the

5’end of SMARCAL1 in proband 122.1. Her parents were related and exon-wise aCGH

confirmed her homozygous deletion of SMARCAL1, which included exons 3 and 4.

Figure E4

In proband 30.1 (Table E1) and his affected sibling (30.4), cSNP data detected a region of

homozygosity within which CNV prediction (Conifer, Convex, and the in-house developed

HMZDel Finder)E129, E130 indicated a deletion at the 5’ end of DOCK8. The various bioinfomatic

CNV prediction programs detects segmental deletions and duplications by comparing average

read depths over the region of interest from several exomes with read depths from the

individual exome data. The predicted deletion is shown by the red line (patient exome data)

deviating from a pool of reference exomes marked with black lines. Exon-wise CMA confirmed

homozygosity in both affected individuals and heterozygosity in both parents for a deletion of

DOCK8 exons 1 to 19.

Figure E5

(A) Exome sequencing identified a homozygous missense variant in G6PC3 (c.482G>A) in the

deceased proband (91.4) with neutropenia and a congenital heart defect. His deceased cousin

(91.1) who succumbed to a similar disease was heterozygous for the missense variant. The

cousin (91.1) also had a heterozygous frameshift variant in G6PC3 (c.210delC). G6PC3

deficiency causes Dursun syndrome, atrial septal defect, and severe congenital neutropenia

type 4 (MIM: 612541), compatible with the boys’ shared phenotype. Exome data analysis

confirmed absence of heterozygosity (AOH) in the region of G6PC3 in the proband (91.4), but

not in his cousin (91.1). Compared to other severe congenital neutropenias (SCNs), G6PC3-

SCN4 may confer reduced risk of myeloid malignancy.E131, E132 On the other hand, both boys

had a heterozygous RUNX1 variant (MIM: 601626), previously reported to be associated with

acute myeloid leukemia.E72 (B) Exome sequencing identified two likely disease-causing

variants in JAK3 in an adult with combined immunodeficiency. Reduction of JAK3 expression

was shown experimentally. In addition, the proband has a known CVID-related variant in

TNFRSF13B (c.310T>C, p.C104R, NM_012452). (C) Exome sequencing identified one disease

causing variant in SH2D1A, and one likely disease modifying variant in FANCB in proband

93.1. FANCB maps 2.5 Mb from SH2D1A on the X chromosome and the variants were likely

inherited en bloc. His mother was a carrier of both variants. (D) Exome sequencing identified

two missense variants in ZAP70 (c.733G>A and c.1505C>T) in proband 27.1. The ZAP70

variants were regarded to be disease-causing, even if she had milder symptoms than others

with ZAP70 mutations. Sanger sequencing confirmed that the variants co-segregated with

disease in the family. In addition, exome sequencing detected a homozygous variant in

RNF168 (c.307G>A) in 27.1, and Sanger sequencing confirmed heterozygosity in her parents.

Fibroblasts cultured from skin biopsy from proband 27.1 exhibited increased radiosensitivity,

a hallmark of RNF168-related disease (RIDDLE syndrome OMIM#611943), but to our

knowledge, not described in ZAP70 deficiency. Impaired function of both proteins may explain

the proband’s blended phenotype.

Figure E6

(A) In proband 119.1, with atypical Schimke immunoosseous dysplasia (MIM: 242900),

exome sequencing identified a potential splicing variant in SMARCAL1 (c.2070+2dup)

predicted to inactivate the donor site of SMARCAL1 exon 11, potentially leading to skipping of

exon 12 (I: from Alamut®). PCR amplification over SMARCAL1 exon 12 on cDNA showed that

most transcripts spliced exon 12 normally in the proband, with a main product of ~850-900

bps as seen in the normal control (II: electropherogram from Bioanalyzer 2100 (Agilent)). In

addition, a small amount of a shorter PCR product was observed in 119.1, but not in the

control. Sanger sequencing revealed that this product lacked exon 12 (III). Sanger sequencing

confirmed heterozygosity for the splicing variant in the mother (119.2) and the affected,

deceased sister (119.4). Sanger sequencing also confirmed heterozygosity the SMARCAL1

missense variant (c.2114C>T) in the sisters and their father (119.3). The incomplete splicing

defect, with normal product as well as presence of a smaller amount of an aberrant shorter

transcript, may explain the uncharacteristically mild phenotype in the affected siblings, with

an adult height close to the 2.5 percentile, onset of focal segmental glomerulosclerosis in the

third decade, and a mild immunodeficiency. (B) Exome sequencing identified a potential

splicing variant in GATA2 (c.1143+5G>A) in proband 84.1. The variant was predicted to

inactivate the donor site of GATA2 exon 6 (I: from Alamut®). PCR amplification of GATA2 exon

4 to 7 on cDNA showed that most transcripts were normally splice resulting in a main product

of ~400 bps, as seen in the normal control (II: electropherogram from Bioanalyzer 2100

(Agilent)). A slightly longer PCR product including 64 bps of intron 6 sequence via a cryptic

donor site in intron 6 (III), was observed in 84.1 (Table E1), but not in the control. Sanger

sequencing identified the GATA2 splicing variant in the proband’s deceased monozygotic twin

(84.4). Both had classical GATA2-related phenotype with disseminated warts and malignant

transformation. Parental testing confirmed that the variant had arisen de novo.

Figure E7

(A) In proband 97.1 with autosomal recessive Fanconi anemia, exome sequencing detected a

missense variant in FANCA (c.3391A>G) and normal sequence in ¼ of reads. Exon-wise aCGH

confirmed the presence of a heterozygous deletion of FANCA exons 27 to 36 as predicted by

CNV analysis (ExCopyDepth). Sanger sequencing of the affected brother (97.4) identified the

same missense variant in the homozygous state. Sanger sequencing for the proband and her

brother revealed a peak with wild type sequence in her only, likely due to revertant

mosaicism, in keeping with her milder disease. Proband 97.1 had a milder clinical course than

her affected brother, who had classic Fanconi anemia, required HSCT, and did not have the

wild-type revertant. Revertant mosaicism and an associated milder phenotype has been

reported for FANCA,E133 with somatic mosaicism occurring in up to 25% of cases.E52, E53

(B) Exome sequencing identified a missense variant in KRAS (c.37G>T) in proband 65.1 in

13.6% of reads. Sanger sequencing confirmed that the variant was present in mosaic state and

parental testing showed that it was de novo.

Figure E8

Exome sequencing identified a missense variant in MBTPS2 (c.758G>C) in proband 115.1.

Parental Sanger sequencing confirmed that the X-linked variant was inherited from the

unaffected mother (115.2) and not present in the unaffected brother (115.4). The proband

was initially suspected of having a SCID-like, however, his phenotype is consistent with the

severe MBTPS2-related disease (IFAP).E134

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