Introduction
Patients and Methods
Results
Gene & Inheritance | No./gender | c.DNA, AA change | No |
Type
| dbSNP | Classification | gnomAD Exomes ƒ = | Method | |||
---|---|---|---|---|---|---|---|---|---|---|---|
Varsome | Provean | SIFT | Polyphen | ||||||||
I. Immunodeficiency affecting cellular and humoral immunity (n = 128) | |||||||||||
a. Severe combined immunodeficiencies (n = 87) | |||||||||||
T-B- severe combined immunodeficiency (n = 60) | |||||||||||
RAG1 (AR) | 10♂/8♀ | c.424C > T, p.Arg142Ter | n = 1 |
Nonsense
| rs773929270 | Pathogenic | NA | NA | NA | 0.00000399 | Sanger (n = 16) NGS (n = 1) WES (n = 1) |
c.906C > G, p. Asp302Glu | n = 1 |
Missense
| - | VUS-LP | Neutral | Damaging | 0.982 | 0.00617 | |||
c.1003 T > C, p.Cys335Arg | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | |||
c. 2434C > T, p. Gln812Ter | n = 3 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.1221G > C, p.Gln407His | n = 1 |
Missense
| - | Likely pathogenic | Neutral | Damaging | 0.994 | - | |||
c.1228C > T, p.Arg410Trp | n = 1 |
Missense
| rs758288006 | Likely pathogenic | Deleterious | Damaging | 1.000 | 0.000012 | |||
c.1277_1279delAAG, p.Glu425del | n = 1 |
Deletion In frame
| - | VUS | Deleterious | NA | NA | - | |||
c.1669G > A, p.Ala557Thr | n = 1 |
Missense
| - | VUS | Neutral | Damaging | 0.999 | - | |||
c.1693G > C, p.Ala565Pro | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | |||
c.1677G > C, p.Arg559Ser | n = 1 |
Missense
| rs199474681 | VUS | Deleterious | Damaging | 0.995 | - | |||
c.1766_1769dupACCT, p. Asn591ProfsTer14 | n = 2 |
Insertion
| - | Pathogenic | NA | NA | NA | ||||
c.2487_2488delGAinsTT, p.Arg829_Lys830delinsSerTer | n = 2 |
Deletion Insertion
| - | VUS | NA | NA | NA | - | |||
c.1861A > G, p. Lys621Glu | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 0.994 | - | |||
c.2521C > T, p.Arg841Trp | n = 1 |
Missense
| rs104894287 | Likely pathogenic | Deleterious | Damaging | 1.000 | 0.0000359 | |||
c.2918G > A, p.Arg973His | n = 1 |
Missense
| rs1384545687 | VUS | Neutral | Damaging | 0.999 | 0.00000399 | |||
c.2924G > A, p.Arg975Gln | n = 1 |
Missense
| rs1507396647 | Pathogenic | Neutral | Damaging | 0.998 | 0.0000439 | |||
c.2965G > A, p.Asp989Asn | n = 1 |
Missense
| - | VUS | Neutral | Damaging | 0.998 | - | |||
RAG2(AR) | 11♂/14♀ | c.86 T > C, p.Phe29Ser | n = 1 |
Missense
| - | VUS | Neutral | Damaging | 0.994 | - | Sanger (n = 23) NGS (n = 1) WES (n = 1) |
c.104G > T, p.Gly35Val | n = 11 |
Missense
| rs148508754 | VUS | Neutral | Damaging | 1.000 | 0.00000398 | |||
c.283G > A, p.Gly95Arg | n = 1 |
Missense
| rs36001797 | Likely pathogenic | Deleterious | Damaging | 1.000 | 0.0000318 | |||
c.379A > T, p.Lys127Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.442C > T, p.Arg148Ter | n = 2 |
Nonsense
| rs1315729938 | Pathogenic | NA | NA | NA | - | |||
c.475C > T, p.Arg159Cys | n = 1 |
Missense
| rs764485070 | VUS | Deleterious | Damaging | 1.000 | 0.0000199 | |||
c.644C > T, p.Thr215Ile | n = 6 |
Missense
| rs35691292 | Benign | Deleterious | Damaging | 0.510 | 0.00329 | |||
c.686G > A, p.Arg229Gln | n = 6 |
Missense
| rs121917894 | Likely pathogenic | Deleterious | Damaging | 0.999 | 0.00000796 | |||
c.980 T > A, p.Val327Asp | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 0.842 | - | |||
c.1257C > G, p.Cys419Trp | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 0.999 | - | |||
DCLRE1C (AR) | 4♀ + 1♂ | c.1147C > T, p.Arg383Ter | n = 1 |
Nonsense
| rs752241422 | Likely pathogenic | NA | NA | NA | 0.00000796 | NGS (n = 5) |
Deletion exon 5 | n = 3 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | |||
Deletion exon 6 | n = 3 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | |||
c.500C > T, p.Thr167Met | n = 1 | Missense | rs149556109 | VUS-LP | Deleterious | Damaging | 1.000 | 0.000014 | |||
c.1450_1472dup, p.Phe492Glyfs*60 | n = 1 | Insertion | - | Pathogenic | NA | NA | NA | - | |||
ADA (AR) | 7♂/2♀ | c.50A > G, p.His17Arg | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | - | Sanger (n = 6) NGS (n = 2) WES (n = 1) |
c.58G > A, p. Gly20Arg | n = 1 |
Missense
| rs121908724 | Likely pathogenic | Deleterious | Damaging | 1.000 | 0 | |||
c.164_172delCGCTCACCC, p.Pro55_Thr57del | n = 1 |
Deletion In frame
| - | Likely pathogenic | NA | NA | NA | - | |||
c.956_960delAAGAG, p.Glu319GlyfsTer3 | n = 1 |
Deletion
| rs771266745 | Pathogenic | NA | NA | NA | 0.000119 | |||
c.218 + 1G > A | n = 3 |
Intronic
| rs528390681 | Pathogenic | NA | NA | NA | 0.0000119 | |||
c.773G > A, p.Arg258Gln | n = 2 |
Missense
| rs751635016 | Pathogenic | Neutral | Tolerated | 0.725 | 0.00000398 | |||
LIG4 (AR) | 1♀ | c.832C > T, p.Arg278Cys | n = 1 |
Missense
| rs574912936 | Likely pathogenic | Deleterious | Damaging | 1.000 | 0.000024 | NGS (n = 1) |
NHEJ1 (AR) | 1♂/1♀ | c.178-1G > A | n = 2 |
Intronic
| - | Pathogenic | NA | NA | NA | - | NGS (n = 2) |
T-B + severe combined immunodeficiency (n = 27) | |||||||||||
IL2RG (XL) | 8♂ | c.2 T > C, p.Met1Thr | n = 2 |
Missense
| rs886041334 | Pathogenic | Neutral | Damaging | 0.421 | - | WES (n = 8) |
c.115G > C, p.Asp39His | n = 1 |
Missense
| - | Pathogenic | Neutral | Damaging | 1.000 | - | |||
c.677G > A, p.Arg226His | n = 1 |
Missense
| rs869320660 | Pathogenic | Deleterious | Damaging | 1.000 | - | |||
c.865C > T, p.Arg289Ter | n = 1 |
Nonsense
| rs137852508 | Pathogenic | NA | NA | NA | - | |||
c.924 + 2 T > G | n = 1 |
Intronic
| - | Pathogenic | NA | NA | NA | - | |||
c.545G > A, p.Cys182Tyr | n = 1 |
Missense
| rs1064794027 | Likely pathogenic | Deleterious | Damaging | - | ||||
NA | n = 1 | ||||||||||
JAK3 (AR) | 6♂/6♀ | c.308G > A, p.Arg103His | n = 1 |
Missense
| rs774202259 | Pathogenic | Deleterious | Damaging | 1.000 | 0.00000398 | Sanger (n = 1) WES (n = 11) |
c.1027G > C, p.Ala343Pro | n = 1 |
Missense
| - | Likely pathogenic | Neutral | Damaging | 0.954 | - | |||
c.1207C > T, p.Arg403Cys | n = 1 |
Missense
| rs1257606008 | Likely pathogenic | Neutral | Tolerated | 0.108 | 0.00000797 | |||
c.2164G > A, p.Val722Ile | n = 1 |
Missense
| rs3213409 | Benign | Neutral | Damaging | 0.001 | 0.00862 | |||
c.1351C > T, p.Arg451Ter | n = 1 |
Nonsense
| rs267605358 | Pathogenic | NA | NA | NA | 0.000032 | |||
c.1374G > A, p.Trp458Ter | n = 1 |
Nonsense
| rs1467541371 | Likely pathogenic | NA | NA | NA | 0 | |||
c.1765G > A, p.Gly589Ser | n = 2 |
Missense
| rs886039394 | Likely pathogenic | Deleterious | Damaging | 1.000 | 0.00000577 | |||
c.1142 + 1G > A | n = 4 |
Intronic
| - | Pathogenic | NA | NA | NA | - | |||
c.3011_3013delTCT, p.Phe1004del | n = 2 |
Deletion
In frame
| - | Likely pathogenic | Deleterious | NA | NA | - | |||
CD3ε (AR) | 1♂ | c.269 T > A, p.Leu90Ter | n = 1 |
Nonsense
| - | Likely pathogenic | NA | NA | NA | - | WES (n = 1) |
CD247 (AR) | 1♂ | c.41C > T, p.Ala14Val | n = 1 |
Missense
| - | VUS | Neutral | Tolerated | 0.002 | - | WES (n = 1) |
IL7RA (AR) | 3♂/1♀ | c.482_483delAA, p.Lys161SerfsTer14 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | WES (n = 4) |
c.394C > T, p.Pro132Ser | n = 2 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | 0.00000398 | |||
c.315C > A, p.Ser105Arg | n = 1 |
Missense
| - | VUS | Neutral | Tolerated | 0.997 | - | |||
LAT (AR) | 1♀ | c.355C > T, p.Arg119Ter | n = 1 |
Nonsense
| rs746082940 | Likely pathogenic | NA | NA | NA | 0.000012 | WES (n = 1) |
c.66 + 176C > T | n = 1 |
Intronic
| rs34282488 | VUS | NA | NA | NA | 0.00767 | |||
b. Combined immunodeficiencies generally less profound than severe combined immunodeficiency (n = 41) | |||||||||||
DOCK8 (AR) | 14♂/9♀ | Deletion Exon 1 to 44 | n = 1 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | NGS (n = 22) WES (n = 1) |
Deletion Exon 6 and 7 | n = 1 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | |||
Deletion Exon 25 to 33 | n = 1 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | |||
c.709G > T, p.Glu237Ter | n = 2 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.949C > T, p.Arg317Ter | n = 1 |
Nonsense
| rs113432057 | Pathogenic | NA | NA | NA | 0.00000398 | |||
c.3037 T > C, p.Phe1013Leu | n = 1 |
Missense
| rs779343060 | VUS | Neutral | Tolerated | 0.209 | 0.0000557 | |||
c.3460C > T, p.Arg1154Cys | n = 1 |
Missense
| rs34390308 | VUS-LP | Deleterious | Damaging | 1.000 | 0.00086 | |||
c.3165_3167delCTT, p.Phe1055del | n = 2 |
Deletion
| - | VUS | Deleterious | NA | NA | - | |||
c.3135delT, p.Phe1045LeufsTer2 | n = 5 |
Deletion
| rs748134881 | pathogenic | NA | NA | NA | 0 | |||
c.5132C > A, p.Ser1711Ter | n = 6 |
Nonsense
| rs1554707993 | Pathogenic | NA | NA | NA | - | |||
c.5864_5866dupAGA, p.Lys1955dup | n = 1 |
Insertion
| - | Likely pathogenic | NA | NA | NA | - | |||
c.4627-1G > C | n = 1 |
Intronic
| - | Pathogenic | NA | NA | NA | - | |||
c.5962-1G > A | n = 1 |
Intronic
| - | Pathogenic | NA | NA | NA | - | |||
RFXANK (AR) | 2♂/3♀ | c.247_250delTCAG, p.Ser83LeufsTer6 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | Sanger (n = 1) WES (n = 4) |
c.431 T > C, p.Leu144Pro | n = 2 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | |||
c.600delG, p.Asn201ThrfsTer3 | n = 2 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
CIITA (AR) | 1♂ | c.929delA, p.Asn310ThrfsTer2 | n = 1 |
Deletion
| - | Likely pathogenic | NA | NA | NA | - | WES (n = 1) |
RFX5 (AR) | 3♂ | c.116 + 1G > A | n = 1 |
Intronic
| rs972632936 | Pathogenic | NA | NA | NA | 0.00000398 | NGS (n = 1) WES (n = 2) |
c.455G > T, p.Gly152Val | n = 1 |
Missense
| rs1043385719 | VUS | Deleterious | Damaging | 1.000 | - | |||
c.715C > T, p.Arg239Ter | n = 1 |
Nonsense
| rs1233130743 | Pathogenic | NA | NA | NA | 0.00000399 | |||
ARPC1B (AR) | 1♀ | c.91G > T, p.Glu31Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | NGS (n = 1) |
CD40L (XL) | 1♂ | c.346G > T, p.Gly116Cys | n = 1 |
Missense
| - | Pathogenic | Deleterious | Damaging | 1.000 | - | NGS (n = 1) |
ZAP70 (AR) | 1♀ | c.261C > G, p.Tyr87Ter | n = 1 |
Nonsense
| - | Likely pathogenic | NA | NA | NA | - | NGS (n = 1) |
STK4 (AR) | 1♂ | NA | n = 1 | WES (n = 1) | |||||||
CARD11 (AR) | 1♂/1♀ | c.2839G > A, p.Glu947Lys | n = 1 |
Missense
| - | Pathogenic | Neutral | Tolerated | 0.06 | - | NGS (n = 2) |
c.1703C > G, p.Pro568Arg | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
DOCK2 (AR) | 1♂/2♀ | c.316dupT, p.Tyr106Leu fsTer35 | n = 2 |
Insertion
| - | Pathogenic | NA | NA | NA | - | NGS (n = 3) |
c.2541delC, p.Phe848LeufsTer18 | n = 1 |
Deletion
| - | Likely pathogenic | NA | NA | NA | - | |||
II. CID with associated or syndromic features (n = 24) | |||||||||||
WAS (XL) | 6♂ | c.274-2A > G | n = 1 |
Intronic
| - | Pathogenic | NA | NA | NA | - | Sanger (n = 1) NGS (n = 3) WES (n = 2) |
c.347_348insT, p.Phe117LeufsTer5 | n = 1 |
Intronic
| - | Pathogenic | NA | NA | NA | - | |||
c.1031delC, p.Pro344LeufsTer101 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
c.177del, p.Gly60GlufsTer16 | n = 1 |
Deletion
| - | Likely Pathogenic | NA | NA | NA | - | |||
c.773 + 3_777 + 6delGAGT | n = 2 |
Intronic
| - | VUS | NA | NA | NA | - | |||
PNP (AR) | 3♂/2♀ | c.172C > T, p.Arg58Ter | n = 1 |
Nonsense
| rs104894460 | Pathogenic | NA | NA | NA | 0.0000438 | Sanger (n = 3) NGS (n = 1) WES (n = 1) |
c.452delA, p.Asn151Met fsTer20 | n = 3 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
c.682G > C, p.Ala228Pro | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | |||
DiGeorge | 3♂/1♀ | Del 22q11.2 | n = 4 |
Deletion
| - | Pathogenic | NA | NA | NA | - | FISH (n = 4) |
ATM (AR) | 2♀ | c.3894dup, p.Ala1299CysfsTer3 | n = 1 |
Insertion
| rs587781823 | Pathogenic | NA | NA | NA | 0.00000796 | NGS (n = 2) |
c.6346delA, p.Ser2116AlafsTer4 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
c.1388C > G, p.Ala463Glu | n = 1 |
Missense
| rs1468739528 | Likely pathogenic | Neutral | Damaging | 1.000 | 0.00000398 | |||
c.370A > G, p.Ile124Val | n = 1 | Missense | rs148590073 | Likely pathogenic | Neutral | Tolerated | 0.001 | 0.00181 | |||
STAT3
(AD LOF) | 2♂ | c.1909G > A, p.Val637Met | n = 1 |
Missense
| rs113994139 | Pathogenic | Deleterious | Damaging | 1.000 | - | NGS (n = 2) |
c.1703C > A, p.Pro98Thr | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 0.998 | - | |||
PGM3 (AR) | 1♂ | c.975 T > G, p.Asp325Glu | n = 1 |
Missense
| rs587777415 | Pathogenic | Deleterious | Damaging | 1.000 | - | NGS (n = 1) |
TCN2 (AR) | 1♀ | c.1195C > T, p.Arg399Ter | n = 1 |
Nonsense
| rs769817524 | Pathogenic | NA | NA | NA | 0.00000398 | WES (n = 1) |
IKBKG (XL) | 1♂ | deletion Exon 9 | n = 1 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | NGS (n = 1) |
ORAI-1 (AR) | 1♂ | NA | n = 1 | - | NGS (n = 1) | ||||||
IL6R (AR) | 1♂ | c.10_11delGT, p.Val4FsTer128 | n = 1 |
Deletion
| - | Likely pathogenic | NA | NA | NA | - | WES (n = 1) |
III. Predominantly antibody deficiencies (n = 13) | |||||||||||
BTK (XL) | 4♂ | c.82C > T, p.Arg28Cys | n = 1 |
Missense
| - | Pathogenic | Deleterious | Damaging | 1.000 | - | NGS (n = 4) |
c.1085A > T, p.His362Leu | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
c.523A > T, p.Lys175Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.1697C > G, p.Pro566Arg | n = 1 |
Missense
| rs1057521814 | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
AICDA (AR) | 1♂/2♀ | c.331G > A, p.Ala111Thr | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 0.997 | - | NGS (n = 3) |
c.406delT, p.Ile136Ter | n = 2 |
Deletion
| rs1453843217 | Pathogenic | NA | NA | NA | 0.00000404 | |||
MSH6 (AR) | 2♂ | c.1904G > C, p.Arg635Thr | n = 1 |
Missense
| - | VUS | Neutral | Damaging | 0.254 | - | NGS (n = 2) |
c.453dupT, p.Thr152TyrfsTer20 | n = 1 |
Insertion
| - | Pathogenic | NA | NA | NA | - | |||
PIK3CD
(AD GOF) | 1♂ | c.3061G > A, p.Glu1021Lys | n = 1 |
Missense
| rs397518423 | Pathogenic | Deleterious | Damaging | 0.999 | 0 | NGS (n = 1) |
NFKB1 (AD) | 1♂ | c.2634A > T, p.Arg878Ser | n = 1 |
Missense
| rs751865962 | VUS | Neutral | Tolerated | 0.1 | 0.00000398 | NGS (n = 1) |
NFKB2 (AD) | 1♀ | c.2557C > T, p.Arg853Ter | n = 1 |
Nonsense
| rs397514332 | Pathogenic | NA | NA | NA | - | NGS (n = 1) |
CR2 (AR) | 1♂ | c.1676G > A, p.Gly559Glu | n = 1 |
Missense
| rs143614333 | VUS | Deleterious | Damaging | 0.999 | 0.000848 | NGS (n = 1) |
IV. Diseases of immune dysregulation (n = 39) | |||||||||||
LRBA (AR) | 14♂/7♀ | Deletion Exon 1–22 | n = 1 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | NGS (n = 21) |
Deletion Exon 3–37 | n = 1 |
Deletion Exon
| - | pathogenic | NA | NA | NA | - | |||
c.491dupT, p.Leu164PhefsTer12 | n = 2 |
Insertion
| - | Pathogenic | NA | NA | NA | - | |||
c. 2170A > G, p.Ile724Val | n = 1 |
Missense
| rs72719663 | Benign | Neutral | Tolerated | 0.000 | 0.0212 | |||
c.2212 C > T, p.Gln738Ter | n = 2 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.2368-2A > G | n = 1 |
Intronic
| - | Pathogenic | NA | NA | NA | - | |||
c.2447delC, p.Pro816LeufsTer4 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
c.3229G > T, p.Glu1077Ter | n = 2 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.3286_3287delTT, p.Phe1096LeufsTer3 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
Deletion Exon35 | n = 1 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | |||
c.6587delG, p.Arg2196LeufsTer4 | n = 2 |
Deletion
| - | Pathogenic | NA | NA | NA | ||||
c.6760G > T, p.Glu2254Ter | n = 3 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.8335_8336delGA, p.Asp2779Ter | n = 3 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
SLC7A7 (AR) | 3♂ | c.1381_1384delATCA, p.Ile461GlufsTer57 | n = 2 |
Deletion
| - | Pathogenic | NA | NA | NA | - | WES (n = 3) |
c.404delT, p.Ile135MetfsTer35 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
AIRE (AR) | 3♂ | c.47C > T, p.Thr16Met | n = 1 |
Missense
| rs179363877 | Likely pathogenic | Deleterious | Damaging | 1.000 | - | NGS (n = 3) |
c.91delG, p.Val31SerfsTer158 | n = 1 |
Deletion
| rs140965390 | Benign | NA | NA | NA | 0.00268 | |||
c.755C > T, p.Pro252Leu | n = 1 |
Missense
| rs34397615 | Benign | Neutral | Tolerated | 0.000 | 0.00259 | |||
c.274C > T, p.Arg92Trp | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
FOXP3 (XL) | 3♂ | c.61G > C, p.Gly21Arg | n = 1 |
Missense
| rs782138321 | VUS | Neutral | Damaging | 1.000 | - | WES (n = 1) NGS (n = 2) |
c.1040G > A, p.Arg347His | n = 1 |
Missense
| rs1557115786 | pathogenic | Deleterious | Damaging | 0.993 | - | |||
c.1190G > A, p.Arg397Gln | n = 1 |
Missense
| rs1057520529 | Likely pathogenic | Deleterious | Damaging | 0.997 | - | |||
IL10RA (AR) | 2♂ | c.499 T > C, p.Tyr167His | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | NGS (n = 2) |
c.632C > T, p.Ser211Phe | n = 1 |
Missense
| rs143645358 | VUS | Deleterious | Damaging | 1.000 | 0.00000398 | |||
IL10RB (AR) | 1♂/1♀ | c.610 T > C, p.Trp204Arg | n = 1 |
Missense
| - | VUS | Deleterious | Tolerated | 0.921 | 0.00000698 | NGS (n = 2) |
c.627 T > A, p.Cys209Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
RIPK1 (AR) | 1♀ | NA | n = 1 | - | WES (n = 1) | ||||||
UNC13D (AR) | 1♂ | c.1193C > T, p.Ser398Leu | n = 1 |
Missense
| rs747756030 | VUS | Deleterious | Damaging | 1.000 | 0.00000399 | WES (n = 1) |
SH2D1A (XL) | 1♂ | c.245dupA, p.Asn82LysTer22 | n = 1 |
Insertion
| - | Pathogenic | NA | NA | NA | - | WES (n = 1) |
FAS | 1♂ | c.52delT, p.Leu18TyrfsTer10 | n = 1 |
Deletion
| - | Likely pathogenic | NA | NA | NA | - | NGS (n = 1) |
PRKCD (AR) | 1♂ | c.1013G > A, p.Trp338Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | NGS (n = 1) |
V. Congenital defects of phagocyte no., function or both (n = 60) | |||||||||||
CYBA (AR) | 8♂/14♀ | c.160_161 InsC, p.Tyr54SerfsTer159 | n = 1 |
Insertion
| - | Pathogenic | NA | NA | NA | - | Sanger (n = 21) WES (n = 1) |
c.295_301delGTGCCCG, p.Val99ProfsTer90 | n = 20 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
c.383_393delCACTGCTCGCC, p.Gly128AspfsTer81 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | |||
NCF1 (AR) | 7♂/6♀ | c.75_76delGT, p.Tyr26HisfsTer26 | n = 12 |
Deletion
| rs4029402 | Pathogenic | NA | NA | NA | 0.00018 | Sanger (n = 13) |
NCF2 (AR) | 1♂/1♀ | c.239 T > C, p.Leu80Pro | n = 1 |
Missense
| - | VUS | Deleterious | Tolerated | 0.996 | - | Sanger (n = 2) |
c.574C > T, p.Gln192Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
CYBB (XL) | 7♂ | c.337 + 1G > A | n = 1 |
Intronic
| - | Pathogenic | NA | NA | NA | - | Sanger (n = 7) |
c.271C > T, p.Arg91Ter | n = 1 |
Nonsense
| rs886041192 | Pathogenic | NA | NA | NA | - | |||
c.359 T > C, p.Leu120Pro | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
c.1139G > A, p.Trp380Ter | n = 1 |
Nonsense
| rs1602183244 | Pathogenic | NA | NA | NA | - | |||
Deletion Exon 2 | n = 1 |
Deletion Exon
| - | Pathogenic | NA | NA | NA | - | |||
c.1598_1600delGAG, p.Gly533del | n = 2 |
Deletion In frame
| - | Likely pathogenic | Deleterious | NA | NA | - | |||
ITGB2 (AR) | 4♂/6♀ | c.1377C > A, p.Cys459Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | Sanger (n = 10) |
c.500G > T, p.Gly167Val | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
c.505G > A, p.Gly169Arg | n = 3 |
Missense
| rs137852612 | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
c.652C > T, p.Gln218Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | |||
c.307delG, p.Val103Ter | n = 1 |
Nonsense
| - | Likely pathogenic | NA | NA | NA | - | |||
c.185G > A, p.Cys62Tyr | n = 2 |
Missense
| - | VUS-LP | Deleterious | Damaging | 0.977 | - | |||
c.306dup, p.Val103SerfsTer39 | N = 1 |
Insertion
| - | Pathogenic | NA | NA | NA | - | |||
ELANE (AD) | 3♀ | c.452G > C, p.Cys151Ser | n = 1 |
Missense
| - | Pathogenic | Deleterious | Damaging | 0.998 | - | WES (n = 3) |
c.640G > A, p.Gly214Arg | n = 1 |
Missense
| rs137854451 | Pathogenic | Deleterious | Damaging | 1.000 | - | |||
c.607G > C, p.Gly203Arg | n = 1 |
Missense
| - | Likely pathogenic | Deleterious | Damaging | 1.000 | - | |||
CLPB
| 1♀ | c.2099-2100delCT, p.Pro700ArgfsTer22 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | WES (n = 1) |
JAGN1 (AR) | 1♂/1♀ | NA | n = 2 | - | WES (n = 2) | ||||||
VI. Defects in intrinsic and innate immunity (n = 16) | |||||||||||
IL12RB1 (AR) | 5♂/1♀ | c.1791 + 2 T > G | n = 1 |
Intronic
| rs554063682 | Pathogenic | NA | NA | NA | 0.000111 | WES (n = 6) |
c.643C > T, p.Arg215Trp | n = 1 |
Missense
| Rs750667928 | VUS | Deleterious | Damaging | 0.72 | 0.00000806 | |||
c.64 + 2 T > G | n = 4 |
Intronic
| rs765825621 | Pathogenic | NA | NA | NA | 0.00000416 | |||
STAT1
(AD GOF) | 3♂/1♀ | c.862A > C, p.Thr288Pro | n = 1 |
Missense
| - | Pathogenic | Deleterious | Damaging | 0.283 | - | Sanger (n = 4) |
c.1154C > T, p.Thr385Met | n = 1 |
Missense
| rs587777630 | Pathogenic | Deleterious | Damaging | 1.000 | - | |||
c.1198C > G, p.Leu400Val | n = 1 |
Missense
| - | VUS | Neutral | Damaging | 1.000 | - | |||
c.1199 T > A, p.Leu400Gln | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | |||
STAT2 (AR) | 1♀ | c.512A > T, p.Asp171Val | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | WES (n = 1) |
IFNGR2 (AR) | 1♂ | c.371C > T, p.Ser124Phe | n = 1 |
Missense
| - | VUS | Deleterious | Damaging | 1.000 | - | WES (n = 1) |
IFNGR1 (AR) | 1♀ | NA | n = 1 | WES (n = 1) | |||||||
CARD9 (AR) | 2♂./1♀ | c.1546C > T, p.Arg516Trp | n = 1 |
Missense
| rs773889930 | VUS | Neutral | Damaging | 0.978 | - | NGS (n = 3) |
c.442C > T, p.Arg148Trp | n = 1 |
Missense
| rs149206311 | VUS | Deleterious | Tolerated | 0.088 | 0.0000811 | |||
c.1442-5G > C | n = 1 |
Intronic
| rs553995269 | VUS | NA | NA | NA | 0.0000129 | |||
c.807 + 8C > T | n = 1 |
Intronic
| rs372934669 | Likely benign | NA | NA | NA | 0.0000228 | |||
VII. Auto-inflammatory disorders (n = 6) | |||||||||||
NLRP3 (AD) | 1♂ | c.584C > T, p.Thr195Met | n = 1 |
Missense
| rs76291085 | Likely benign | Neutral | Tolerated | 0.001 | 0.0000358 | NGS (n = 1) |
NLRP12 (AD) | 1♀ | c.209G > A, p.Trp70Ter | n = 1 |
Nonsense
| - | Pathogenic | NA | NA | NA | - | NGS (n = 1) |
PLCG2 (AD) | 1♂ | c.886delT, p.Ser296HisfsTer19 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | NGS (n = 1) |
STING1 (AD) | 1♂ | c.575G > T, p.Gly192Val | n = 1 |
Missense
| rs201096097 | Benign | Neutral | Tolerated | 0.970 | 0.000266 | NGS (n = 1) |
PSTPIP1 (AD) | 1♂ | c.59C > T, p.Thr20Met | n = 1 |
Missense
| rs553718554 | Benign | Neutral | Damaging | 0.616 | 0.000102 | NGS (n = 1) |
SH3BP2 (AD) | 1♂ | c.1103delC, p.Pro368GlnfsTer21 | n = 1 |
Deletion
| - | Pathogenic | NA | NA | NA | - | NGS (n = 1) |
VIII. Complement deficiencies (n = 1) | |||||||||||
CD59 (AR) | 1♂ | c.80delA, p.Gln27ArgfsTer53 | n = 1 |
Deletion
| - | Likely pathogenic | NA | NA | NA | - | WES (n = 1) |
Others | |||||||||||
THEMIS
| 1♀ | c.1004C > A, p.Pro335His | n = 1 |
Missense
| - | VUS-LP | Deleterious | Damaging | 0.981 | - | WES (n = 1) |
Clinical diagnosis | Preliminary test | Genes | Genetic test |
---|---|---|---|
Omenn syndrome (n = 8) | Lymphocyte enumeration, RTE, immunoglobulin level | RAG1 | Sanger (n = 5) |
RAG2 | Sanger (n = 3) | ||
SCID (n = 76) | Lymphocyte enumeration, RTE, immunoglobulin level T & B cell subpopulations when indicated, ADA, CD127 expression when suspected | RAG1 | Sanger (n = 10), WES (n = 1) |
RAG2 | Sanger (n = 20), WES (n = 1) | ||
DCLRE1C | NGS (n = 4) | ||
ADA | Sanger (n = 6), NGS (n = 2), WES (n = 1) | ||
LAT | WES (n = 1) | ||
JAK3 | Sanger (n = 1), WES (n = 11) | ||
IL2RG | WES (n = 8) | ||
IL7RA | WES (n = 4) | ||
CD247 | WES (n = 1) | ||
CD3E | WES (n = 1) | ||
DOCK2 | WES (n = 1) | ||
THEMIS | WES (n = 1) | ||
PNP | NGS n = 1, WES n = 1 | ||
Atypical SCID/CID (n = 7) | Lymphocyte enumeration, RTE, immunoglobulin level T & B cell subpopulations | RAG1 | Sanger (n = 1), NGS (n = 1) |
RAG2 | Sanger (n = 1) | ||
NHEJ1 | NGS (n = 1) | ||
RFXANK | WES (n = 2) | ||
RFX5 | WES (n = 1) | ||
SCID/Atypical SCID with Microcephaly (n = 2) | Lymphocyte enumeration, immunoglobulin level, BTK expression | LIG4 | NGS (n = 1) |
NHEJ1 | NGS (n = 1) | ||
DiGeorge syndrome (n = 4) | Lymphocyte enumeration | Del 22q11.2 | FISH (n = 4) |
CID/Immune dysregulation (n = 2) | Lymphocyte enumeration, Tregs, double negative TCRαβ T cells | DCLRE1C | NGS (n = 1) |
SH3BP2 | NGS (n = 1) | ||
CID/HIES (n = 23) | Lymphocyte enumeration, B cells differentiation, immunoglobulin level, Defective DOCK8 expression | DOCK8 | NGS (n = 23) |
HIES (n = 4) | Lymphocyte enumeration, B cells differentiation, immunoglobulin level, Normal DOCK8 expression | STAT3 | NGS (n = 2) |
IL6R | WES (n = 1) | ||
LRBA | NGS (n = 1) | ||
HIGM/CID (n = 4) | Lymphocyte enumeration, B cells differentiation, immunoglobulin level, CD40/CD40L expression | CD40LG | NGS (n = 1) |
AICDA | NGS (n = 3) | ||
CID (n = 23) | Lymphocyte enumeration, RTE, HLADR expression | RFXANK | WES (n = 2) |
RFX5 | NGS (n = 1), WES (n = 1) | ||
CIITA | WES (n = 1) | ||
Lymphocyte enumeration, RTE, T cell differentiation, LRBA expression when suspected | DOCK2 | NGS (n = 1), WES (n = 1) | |
Zap70 | WES (n = 1) | ||
ARPC1B | NGS (n = 1) | ||
STK4 | WES (n = 1) | ||
WAS | Sanger (n = 1) | ||
ATM | NGS (n = 2) | ||
ORAI 1 | NGS (n = 1) | ||
PNP | Sanger (n = 1) | ||
STAT2 | WES (n = 1) | ||
PSTPIP1 | NGS (n = 1) | ||
CARD11 | NGS (n = 2) | ||
CD59 | WES (n = 1) | ||
CR2 | NGS (n = 1) | ||
LRBA | NGS (n = 2) | ||
WAS (n = 6) | Lymphocyte enumeration, immunoglobulin level, WASP expression, platelet count, mean platelet volume | WAS | NGS (n = 3), WES (n = 2) |
PGM3 | NGS (n = 1) | ||
MSMD (n = 7) | Lymphocyte enumeration, DHR | IL12RB1 | WES (n = 5) |
IFNGR1 | WES (n = 1) | ||
IFNGR2 | WES (n = 1) | ||
CMC (n = 6) | Lymphocyte enumeration, DHR | STAT1 | Sanger (n = 4) |
SLC7A7 | WES (n = 2) | ||
LAD (n = 10) | CD18/CD11b expression | ITGB2 | Sanger (n = 10) |
CGD (n = 44) | Defective DHR with bimodal maternal pattern | CYBB | Sanger (n = 7) |
Defective DHR, FCM defective CYBA | CYBA | Sanger (n = 21), WES (n = 1) | |
Defective DHR, FCM defective NCF1 | NCF1 | Sanger (n = 13) | |
Defective DHR, FCM defective NCF2 | NCF2 | Sanger (n = 2) | |
Neutropenia (n = 6) | CBC, Lymphocyte enumeration, anti-neutrophil antibodies | ELANE | WES (n = 3) |
JAGN1 | WES (n = 2) | ||
CLPB | WES (n = 1) | ||
Bone marrow failure syndrome (n = 1) | Lymphocyte enumeration | TCN2 | WES (n = 1) |
XLA (n = 4) | Lymphocyte enumeration, immunoglobulin level, BTK expression | BTK | NGS (n = 4) |
Immune dysregulation (n = 11) | Lymphocyte enumeration, Tregs enumeration | IKBKG | NGS (n = 1) |
NFKB1 | NGS (n = 1) | ||
PIK3CD | NGS (n = 1) | ||
STING1 | NGS (n = 1) | ||
PLCG2 | NGS (n = 1) | ||
NLRP12 | NGS (n = 1) | ||
LRBA | NGS (n = 5) | ||
EO-IBD (n = 5) | Lymphocyte enumeration, B cell differentiation | IL10RA | NGS (n = 2) |
IL10RB | NGS (n = 2) | ||
RIPK1 | NGS (n = 1) | ||
IBD (n = 1) | Lymphocyte enumeration, LRBA expression | LRBA | NGS (n = 1) |
CVID (n = 3) | Lymphocyte enumeration, B cell differentiation, immunoglobulin level | NFKB2 | NGS (n = 1) |
LRBA | NGS (n = 2) | ||
APECD (n = 2) | Lymphocyte enumeration, Tregs | AIRE | NGS (n = 2) |
IPEX (n = 3) | Lymphocyte enumeration, Tregs | FOXP3 | NGS (n = 2), WES (n = 1) |
IPEX like (n = 3) | Lymphocyte enumeration, Tregs, LRBA expression | LRBA | NGS (n = 3) |
Evans syndrome (n = 1) | Lymphocyte enumeration | LRBA | NGS (n = 1) |
Autoinflammatory disorder (n = 1) | Lymphocyte enumeration | NLRP3 | NGS (n = 1) |
ORAI (n = 1) | Lymphocyte enumeration, DHR | SLC7A7 | NGS (n = 1) |
Lymphoproliferative disorder (n = 1) | Lymphocyte enumeration, double negative TCRαβ T cells | SH2D1A | NGS (n = 1) |
ALPS like (n = 2) | Lymphocyte enumeration, double negative TCRαβ T cells | IL12RB1 | WES (n = 1) |
UNC13D | WES (n = 1) | ||
ALPS (n = 5) | Lymphocyte enumeration, double negative TCRαβ T cells | FAS | NGS (n = 1) |
PRKCD | NGS (n = 1) | ||
LRBA | NGS (n = 3) | ||
Screened patients (n = 6) | Tested according to affected proband phenotype | Sanger (n = 3), NGS (n = 3) |