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. 2017 Jul 27;12(7):e0181874. doi: 10.1371/journal.pone.0181874

Table 3. Clinical features and genetic variants identified in patients with unknown diagnoses.

Patient no. Ethnicity Consan Sex Age** (yrs) Gene Nucleotide change* Amino acid change* Predicted pathogenicity† Zygosity Variant classific-ation
(LoE‡)		 Clinical features and treatment Clinical impact of VIP
23 White N M 4 C5 715G>A G239S B/T/N Het 3 Cutaneous Vasculitis, communication disorder, macrocephaly, recurrent upper respiratory tract infections and severe croup
Normal CRP/SAA
Vasculitis resolved following tonsillectomy		 Diagnosis of Cowden syndrome; entry into cancer screening programme; genetic counselling (this was found to be a de novo mutation in this patient)
CBS 833T>C I278T P/D/A Het 3
PLCG2 1565C>G P522R B/T/N Het 3
PTEN 650T>A V217D [27] D/D/D Het 5(S)
TGFBR1 51_59del:
GGCGGCGGC		 17_20del -/-/- Het 3
TGFBR2 449delA E150fs -/-/- Het 3
TRAP1 1946C>T A649V B/T/N Het 3
24 White N F 5 CASP8 1415A>G K472R D/D/D Het 3 Uveitis, mouth ulcers, vasculitic rash,
High ESR, normal CRP/SAA
Hydroxychloroquine unresponsive
 Diagnosis of A20 haploinsufficiency [HA20]; genetic counselling; and consideration of IL-1 blockade
COL4A1 1246C>G P416A P/T/D Het 3
CTC1 26C>A P9H B/D/N Het 3
LYST 9017A>G K3006R B/T/D Het 3
NCF1 269G>A R90H B/D/D Het 3
NOTCH3 509A>G H170R P/T/D Het 3
STXBP2 503A>G Q168R B/T/N Het 3
TNFAIP3 811C>T R271X [28] T/-/D Het 5(VS +S)
25 White N M 17 C5 1060C>A L354M D/D/D Het 3 Familial moyamoya disease and systemic hypertension; multiple cerebral artery stenoses; father and sister also affected
Blood pressure controlled with anti-hypertensives		 RNF213- associated familial moyamoya disease; genetic counselling
NCF1 269G>A R90H B/D/D Het 3
RNF213 12037G>A D4013N [29] D/T/N Het 5(S)
TGFBR1 51_59del:
GGCGGCGGC		 17_20del -/-/- Het 3
WAS 995T>C V332A B/T/N Hom 3
26 White
 N F 9 NCF1 292T>G C98G D/D/D Het 3 Unclassified AID with erythema nodosum (histology revealing septal panniculitis) from age 3 months; elevated acute phase reactants including SAA; no evidence of HLH;
partial response to colchicine; good serological response to tocilizumab but no effect on cutaneous lesions		 Unclassified AID; carrier for UNC13D mutation
NLRP12 2188dupG V730fs -/-/- Het 3
TGFBR2 449delA E150fs -/-/- Het 3
TTC37 4187A>G N1396S B/T/D Het 3
UNC13D 2896C>T R966W [30] D/T/D Het 5(S)
27 Mixed White/
Chinese/Malaysian
 N F 2 DNASE1 358_360del:GAT 120_120del
 -/-/- Het 3 HLH with no evidence of viral trigger; abnormal T cell (but not NK cell) CD107a granule release; good response to high-dose corticosteroids, etoposide and ciclosporin; not yet required HSCT Probable primary HLH (heterozygous UNC13D class 5 mutation)
DOCK8 2666C>T A889V B/T/D Het 3
FASLG 280T>G L94V D/D/D Het 3
NCF1 269G>A R90H P/D/D Het 3
TGFBR2 449delA E150fs -/-/- Het 3
UNC13D 2896C>T R966W [30] D/T/D Het 5(S)
28 White
 N F 22 C7 1912G>A D638N B/T/N Het 3 Unclassified autoinflammation, elevated acute phase reactants including SAA; normal platelet count; no evidence of recurrent infection; no males in family for eight generations;
Good response to colchicine		 Suspected autoinflammation caused by heterozygous WAS mutation in a female; genetic counselling
CTC1 2497G>C D833H P/T/N Het 3
NCF1 269G>A R90H P/D/D Het 3
PLOD1 1675C>T R559C B/D/D Het 3
TRAP1 1406G>A R469H D/D/D Het 3
WAS 391G>A E131K [31] D/D/D Het 5(VS+S)
29
 Indian N F 8 LPIN2 1876C>T P626S B/T/N Het 4(S) Periodic fevers, intestinal inflammation, CRMO, failure to thrive Microcytic anaemia, chronically elevated CRP/SAA
Anakinra responsive		 Diagnosis of Majeed syndrome; continue anakinra; genetic counselling
LPIN2 608C>T S203F P/T/D Het 4(S)
PTEN 236C>T A79V -/-/- Het 3
FAS A136A>C T46P D/T/N Het 3
30 White
 N F 6 C6 2087A>G D696G B/T/D Het 3 Infantile panniculitis and erythema nodosum, arthritis, uveitis, autoimmune hepatitis, splenomegaly;
High SAA/CRP; elevated double negative T cells; elevated serum vitamin B12; impairment of functional apoptosis assay
CS-responsive; partial response to MTX; recently commenced mycophenolate mofetil		 Diagnosis of Autoimmune lymphoprolifer-ative syndrome Type 2a; screening of other family members and genetic counselling; change of treatment to mycophenolatemofetil
CASP10 295A>G K99E B/D/N Het 4(S)
CFP 391C>G Q131E B/T/N Het 3
LPIN2 1876C>T P626S B/T/N Het 4(S)
31 White N M 5 CFHR5 480dupA P160fs -/-/- Het 3 Periodic fevers, cold-induced urticaria, arthralgia
High CRP/SAA with fevers
Anakinra responsive		 Diagnosis of APLAID; genetic counselling; continue anakinra
CFHR5 622T>C C208R D/D/N Het 3
HPS6 698T>G L233R B/T/N Het 3
NCF1 269G>A R90H B/D/D Het 3
NOTCH3 3130G>A A1044T D/D/D Het 3
PLCG2 1444T>C Y482H D/T/D Het 4(S)
PLCG2 1712A>G N571S B/D/D Het 4(S)
TGFBR2 449delA E150fs -/-/- Het 3
TRAP1 1728G>C E576D B/T/D Het 3
32 White N M 15 CBS T833T>C I278T P/D/A Het 3 Recurrent fevers, panniculitis, abdominal pain, headaches, conjunctivitis, arthralgia, mouth ulcers
intermittently elevated CRP/SAA
Anakinra and tocilizumab unresponsive
Colchicine partial response		 Suspected LYN-associated AID@
LYN 1523A>T Y508F D/D/D Het 4(S)
NCF1 269G>A R90H B/D/D Het 3
NLRP3 292C>G R98G B/T/N Het 3
TGFBR2 449delA E150fs -/-/- Het 3
33 Mixed
(White/
Asian)		 N F 6 C6 2087A>G D696G B/T/D Het 3 MAS (cause undetermined), livedo racemosa, hepatosplenomegaly
periodic fevers
Cytopenias, hyperferritinaemia, high ESR/CRP/SAA, high IgG
Anakinra and CS responsive		 Diagnosis of DADA; consideration of anti-TNF treatment should there be escape of efficacy of anakinra; ongoing clinical monitoring for neurological deterioration
CECR1 1208T>C M403T B/T/N Het 4(M)
CECR1 -12233delC (5UTR) n/a -/-/- Het 4(S)
GLA C525C>G D175E B/T/N Het 3
NCF1 269G>A R90H B/D/D Het 3
NOTCH3 5296A>G M1766V B/T/D Het 3
RET 2554A>G I852V D/T/D Het 3
TGFBR2 449delA E150fs -/-/- Het 3
TTC37 4061A>G K1354R P/T/N Het 3
TTC37 4348G>T A1450S D/T/D Het 3
34 Pakist Y M 8 DOCK8 3079G>A V1027I B/T/D Het 4(S) Intermittent fevers, colitis, arthritis, oral ulcers
High ESR/CRP/SAA, and high IgE
CS and MTX-responsive		 Diagnosis of Hyper IgE syndrome; genetic counselling
DOCK8 4041C>A D1347E B/T/D Het 4(S)
MASP2 467G>A C156Y D/D/D Het 3
MVK 1156G>A D386N B/T/N Het 3
NCF1 269G>A R90H B/D/D Het 3
NLRP12 2206G>A G736R D/T/D Het 3
PRF1 755A>G N252S B/T/A Het 3
35 White
 N F 16 C6 2087A>G D696G B/T/D Het 3 Unknown cause for autoinflammation from the age of 3 years; splenomegaly; erythema nodosum and livedo racemosa; anaemia, cause uncertain; granulomatous hepatitis on liver biopsy;
Elevated acute phase reactants including SAA;
Poorly responsive to adalimumab		 DADA suspected, not yet proven (await ADA2 enzyme activity)
CECR1 937A>G I313V B/T/N Het 4(M)
CECR1 -12233delC (5UTR) - -/-/- Het 4(S)
NLRP6 1957C>G R653G D/T/N Het 3
SH3BP2 1686A>G X562W -/-/D Het 3
36 White
 N F 27 CFP 521G>T C174F D/D/D Het 3 Unclassified autoinflammation, fever, rash, recurrent aseptic meningitis, raised intracranial pressure;
elevated acute phase reactants including SAA;
Poor response to anakinra		 Suspected LYN associated autoinflammation@
ELN 2318G>A G773D P/-/- Het 3
HPS4 751TA> T251S B/T/N Het 3
LYN 359A>T K120I B/D/D Het 4(M)
NCF1 269G>A R90H B/D/D Het 3
NCF1 299C>T T100M P/D/N Het 3
TRAP1 1330T>A Y444N D/D/D Het 3
37 White
 N F 3 ADAM17 2017G>A V673I D/T/D Het 3 Clinical diagnosis of R92Q TNF receptor associated periodic syndrome (TRAPS; detected on Sanger sequencing);
elevated acute phase reactants including SAA;
complete therapeutic response to anakinra		 Diagnosis of R92Q TRAPS confirmed
BMPR2 2867T>C I956T B/-/D Het 3
LYST 5945C>T T1982I B/T/D Het 3
NCF1 269G>A R90H B/D/D Het 3
TNFRSF1A 362G>A R121Q [R92Q] B/T/N Het 4(S)
TRAP1 237G>C E79D B/D/D Het 3
38 White
 N F 44 CYBA 179A>C K60T B/T/N Het 3 V198M CAPS: autoinflammation, hyperostosis of distal femur, urticaria, normal hearing;
high acute phase reactants including SAA;
Poor response to colchicine; not yet tried IL1-blockade
 Diagnosis of NLRP3 V198M CAPS confirmed
GUCY2C 2350C>A Q784K B/T/N Het 3
NCF1 269G>A R90H B/D/D Het 3
NLRP12 910C>T H304Y D/D/N Het 3
NLRP3 598G>A V198M B/T/N Het 4(S)
NOTCH1 2542G>A E848K D/T/D Het 3
TGFBR1 51_59del:GGCGGCGGC p.17_20del -/-/- Het 3
TGFBR2 449delA E150fs -/-/- Het 3
VPS13B 8903A>G N2968S D/D/A Het 3
39 White
 N F 40 COL7A1 1907G>T G636V P/D/D Het 3 Unclassified autoinflammation, fever, cervical lymphadenopathy, arthralgia;
elevated acute phase reactants including SAA; partial response to corticosteroids;
complete response to anakinra		 Suspected TRAP1 autoinflammati-on©
CYBB 1090G>C G364R P/T/D Het 3
FERMT1 1600G>A A534T B/T/D Het 3
GUCY2C 2350C>A Q784K B/T/N Het 3
NCF1 269G>A R90H B/D/D Het 3
NLRP7 1520A>T E507V B/T/N Het 3
SKI 985C>T P329S D/T/D Het 3
TMEM173 761C>T A254V B/T/N Het 3
TRAP1 1330T>A Y444N D/D/D Het 3
TRAP1 947G>A R316H P/D/D Het 3
TRAP1 383G>A R128H© D/D/D Het 4 (S)

*Since each gene may have multiple splicing isoforms, the variants were annotated according to the RefSeq transcript in S1 and S2 Tables.

**Age at the time of this study.

†Prediction (polyphen2/SIFT/MutationTaster); B = Benign, D = damaging or deleterious, P = probably damaging, T = tolerated, n = neutral, A = disease causing automatic for MutationTaster.

Class 4 and 5 variants are indicated in bold with references added for class 5 variants. LoE

‡: Level of evidence based on reference 21; S = strong; VS = very strong; M = moderate. Abbreviations: Pakist = Pakistani, CRP = C-reactive protein, SAA = Serum amyloid A, ESR = erythrocyte sedimentation rate, MTX = Methotrexate, DMARDS = Disease-modifying anti-rheumatic drugs, IgE = Immunoglobulin E, AID = autoinflammatory disease, APLAID = autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation, TRAPS = TNF receptor-associated autoinflammatory syndrome, HLH = Haemophagocytic Lymphohistiocytosis, MAS = macrophage activation syndrome, DADA = Deficiency of Adenosine Deaminase, CAPS = Cryopyrin-Associated Autoinflammatory Syndromes, CRMO = Chronic recurrent multifocal osteomyelitis, Consan = Consanguinity (Y = yes, N = no, U = unknown), Sex (F = female, M = male). HSCT = Haematopoietic stem cell transplantation, CS = corticosteroid (including pulses of intravenous methylprednisolone or oral prednisolone); CYC = intravenous cyclophosphamide; EPO = intravenous epoprostenol; hep = heparin; asp = aspirin (antiplatelet dose), GI = gastrointestinal, PRAAS = Proteasome Associated Autoinflammatory Syndromes.

©Discovered by our group to cause a novel recessive AID (manuscript in preparation).

@ Described in abstract (manuscript in preparation): De Jesus AA, Montealegre G, Liu Y, Marrero B, Kuehn H, Calvo K et al. A de novo nonsense mutation in the tyrosine kinase lyn in a patient with an early onset autoinflammatory phenotype. Pediatr Rheumatol Online J 2014; 12 (Suppl 1):O25.