Supplementary Table 1. Clinical and genetic characteristics of patients with LRBA deficiency
Previously reported patientsP1 / P2 / P3 / P4 / P5 / P6 / P7 / P8 / P9 / P10 / P11 / P12 / P13 / P14 / P15 / P16 / P17 / P18 / P19 / P20 / P21 / P22 / P23
Mutation / p.I2657S a
(p.I2646S) / p.I2657S a
(p.I2646S) / p.R1683X / p.E59X / Exon 1-2 deletion / p.E2219D
fs*3 / p.E2219D
fs*3 / p.E2219D
fs*3 / p.E2219D
fs*3 / p.E2219Dfs*3 / Exons 1-30 deletion / p.T2388P
fs*7 / p.T2388P
fs*7 / p.I2824P / p.Q678X / p.C289Cfs*3 / p.C289Cfs*3 / p.I1837X / p. R2203X / p.I2657S a
(p.I2646S) / p.S2713fs13 / p.S2713fs13 / p.S2713fs13
Exon(s) affected / Exon 53 / Exon 53 / Exon 30 / Exon 2 / Exons 1-2 / Exon 43 / Exon 43 / Exon 43 / Exon 43 / Exon 43 / Exon 1-30 / Exon 47 / Exon 47 / Exon 57 / Exon 16 / Exon 7 / Exon 7 / Exon 30 / Exon 43 / Exon 54 / Exon 56 / Exon 56 / Exon 56
Ethnic Origin / Arabian / Arabian / Sicilian / Iranian / Iranian / Arabian / Arabian / Arabian / Arabian / Arabian / Pakistani / Kurdish / Kurdish / Turkish / Arabian / Lebanese / Lebanese / NA / North African / Palestinian / Palestinian / Palestinian / Palestinian
Consanguinity / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
Sex / Male / Female / Male / Male / Female / Male / Female / Female / Female / Female / Female / Female / Female / Female / Male / Male / Female / Female / Female / Male / Male / Male / Male
Presenting age / 1 year / 1 year / 12 years / 2 year / 2 years / 2 months / 2 years / 4 years / 3 years / 2 years / 4 years / 2 years / 5 years / 6 months / 3 months / 7 years / 10 years / 6 years / Early infancy / 3 years / 6 years / Asymptomatic
(2 year follow-up, now age 9) / 1.5 years
Growth retardation / Yes / Yes / Yes / Yes / - / GH deficiency / Yes$ / - / - / - / Yes / Yes / - / - / Yes / - / Yes / - / - / - / -
Hypogammaglobulinemia / Yes / Yes / Yes / Yes / Yes / - / - / Yes / Yes / Yes / - / - / Yes / - / - / Yes / - / - / Yes / Yes (gradual) / - / - / -
Respiratory features / LRTI, LIP, BE / OTM, BA, BE, pneumonia, empyema / URTI, LIP, recurrent pneumonia / URTI, LRTI, BE / URTI, LRTI, BE / URTI, LRTI / - / Recurrent OTM, LRTI, BE / - / - / - / URTI / - / - / - / URTI, LRTI, fibrosing pneumonitis / LRTI / Recurrent infections, BE / - / Pneumonia, BE / - / - / -
Finger clubbing / Yes / - / - / Yes / - / - / Yes / Yes / - / - / - / - / - / Yes / - / - / - / Yes / - / - / - / - / -
Organomegaly / - / - / LN / HSM / - / - / - / - / - / - / - / HSM / HM / SM / HSM, LN / LN / HSM / SM, LN / SM / LN, SM / - / LN, SM
Other hematological/lymphoid features / Pan-cytopenia / TCP / TCP / TCP / - / TCP, NP / - / - / TCP / - / TCP, NP / TCP, NP, LPD / - / - / - / TCP, NP / TCP, NP / - / - / TCP, NP / TCP / - / -
Rheumatological manifestations / - / Reactive mono-arthritis / - / - / - / - / - / Recurrent arthritis / - / - / Transient arthritis / - / Gonococcal arthritis / - / - / - / - / - / - / - / - / - / -
Autoimmune disease / ITP, AIHA / ITP / ITP, AIHA / ITP, AIHA, AIE / AITD, MG / - / - / - / AIHA / - / AIHA / ITP, vitiligo / AIHA / AITH, T1DM / AIHA, AITH, T1DM, AIE / - / - / Celiac disease / - / ITP, AIHA
(ALPS-like disorder) / ITP, AIHA
(ALPS-like disorder) / - / ITP, AIHA
(ALPS-like disorder)
Neurological features / Cerebral granuloma,
strabismus, hemiplegia / - / Cerebral granuloma,
seizures / - / MG / - / - / - / - / - / - / - / - / Cerebral and cerebellar atrophy / - / - / - / - / - / - / - / - / -
Chronic diarrhea / - / - / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes / - / Yes / Yes / - / - / - / -
Colitis / - / - / Yes / - / - / - / Yes / Yes / Yes / - / - / - / IBD, vasculitis / IBD-like disease / - / - / - / Severe colitis / CMV-colitis / - / - / - / -
Other GIT features / - / - / Atrophic gastritis / Recurrent infections, AIE / Villous atrophy / Villous atrophy / Villous atrophy / - / Villous atrophy / - / AIE / - / - / Anal fissures, villous atrophy / AIE / - / Biliary atresia, PT / Celiac disease / Normal villi / - / - / - / -
Dermatologic features / - / - / Warts / Urticaria / Allergic dermatitis / - / - / - / - / - / Erythema nodosum, recurrent cellulitis§ / Vitiligo / - / - / - / - / - / - / - / - / - / - / -
Treatment / IVIG / IVIG, CST, antibiotics, antifungals / IVIG, CST, infliximab / IVIG, antibiotics / IVIG, CST / IVIG, CST / CST, AZA, vitamin B12 / IVIG, CST / IVIG / IVIG / MMF, Rituximab, IVIG / IVIG, CST, HSCT / IVIG, CST, TPN / CsA, CST, thyroxine / - / IVIG, CST, Infliximab, AZA / IVIG, CST , Kasai procedure / HSCT / IVIG, Rituximab, total colectomy / CST, MMF, Sirolimus, IVIG / CST, MMF, Sirolimus / - / CST, MMF
Other features & complications / - / - / Sub-maxillary abscess / Conjunctivitis, cardiac failure / Death from respiratory failure / EBV-LPD
(spontaneous resolution) / Megaloblastic anemia, B12 deficiency, / - / - / - / Recurrent penumo-coccal sepsis§,
reccurrent epyema§, psoas abscess / Recurrent URI, hepatitis / URI, Adenovirus infection, Norovirus infection / Renal, respiratory and cardiac failure / Septic shock / Conjunctiv-itis granulomatous disease / Conjunctiv-itis / Renal Tubulopathy / EBV-MZL, death from septicemia and multi-organ failure / - / - / - / -
a First published based on the Ensembl record for transcript ENST00000357115.
§ Developed after withdrawal of IVIG and receiving mycophenolate mofetil therapy.
$Poor weight gain at 18 years of age.
AIE, autoimmune enteropathy; AIHA, autoimmune hemolytic anemia; ALPS, autoimmune lymphoproliferative syndrome; AITD, autoimmune thyroid disease; AZA, azathioprine; BA, bronchial asthma; BE, bronchiectasis; CMV, cytomegalovirus; CsA, cyclosporin A; CST, corticosteroids; EBV, Epstein–Barr virus; FTT, failure to thrive; GCSF, granulocyte colony stimulating factor; GH, growth hormone; HM, hepatomegaly; HSCT, Hematopoietic stem cell transplantation; HSM, hepatosplenomegaly; IBD, inflammatory bowel disease; ITP, immune thrombocytopenic purpura; JIA, juvenile idiopathic arthritis; LIP, lymphoid interstitial pneumonia; LN, lymphadenopathy; LPD, lymphoproliferative disease; LRTI, lower respiratory tract infections; OTM, otitis media; MTZ, metronidazole; MG, myasthenia gravis; MMF, mycophenolate mofetil, MZL, marginal zone lymphoma; NP, neutropenia; PT, portal hypertension; SM, splenomegaly; T1DM, type 1 diabetes mellitus; TCP, thrombocytopenia; TPN, total parenteral nutrition; URTI, upper respiratory tract infections; UTI, urinary tract infection; WB, Western blot.
Supplementary Table 1 continued. Clinical and genetic characteristics of patients with LRBA deficiency
P24 / P25 / P26 / P27 / P28 / P29 / P30 / P31
Mutation / c.1014+1 C>T
(splice site) / p.S1605X / p.S1605X / p.R182X / Not detected (absent LRBA on WB) / p.N988fs*7 / c.4729+2insA
(splice site) / c.4729+2insA
(splice site)
Exon(s) affected / Exons 8-9 / Exon 30 / Exon 30 / Exon 5 / Not detected / Exon 23 / Exon 29-30 / Exon 29-30
Ethnic Origin / Iranian / Iranian / Iranian / Iranian / Iranian / Lebanese / Iranian / Iranian
Consanguinity / Yes / Yes / Yes / Yes / Yes / Yes / Yes / Yes
Sex / Female / Male / Male / Male / Male / Female / Female / Female
Presenting age / 3 years / 2 years / NA / 2 years / 2 months / 3 years / 6 years / 10 years
Growth retardation / - / Yes / - / - / - / Yes / Yes / -
Hypogammaglobulinemia / Yes / Yes / - / Yes / Yes / Yes / Yes / -
Respiratory features / URTI, BE, recurrent pneumonia, lobar emphysema / BE, recurrent sinusitis and pneumonia / URTI / - / Sinusitis, recurrent Pneumonia / Recurrent OTM, recurrent Pneumonia / URTI, pneumonia, BA, BE / URTI, OTM,
sinusitis
Finger clubbing / Yes / Yes / - / - / - / - / -
Organomegaly / HSM, LN / HM, LN / - / HM / HSM / LN, HSM / HSM / LN, SM
Other hematological/lymphoid features / - / - / - / - / TCP, petechiae, purpura / NP / TCP / TCP
Rheumatological manifestations / JIA / Arthralgia / - / JIA / - / Arthralgia / -
Autoimmune disease / JIA / - / - / JIA / - / - / AITD, AIHA / ITP, AIHA
(ALPS-like disorder)
Neurological features / - / - / - / - / Unilateral optic nerve atrophy / Seizures, parietal lobe lesion / - / Unilateral optic nerve demyelination and atrophy, granuloma-like lesion, viral meningitis
Chronic diarrhea / - / Yes / - / Yes / Yes / - / Yes / -
Colitis / - / - / - / - / - / - / - / -
Other GIT features / - / Giardiasis, Trichomonas hominis infection / - / Tricho-strongylus ova, bloody stool / Rectorrhagia / - / - / -
Dermatologic features / Warts / Hyper-pigmented lesions / - / - / Bullous and necrotic lesions / - / Atopic dermatitis / -
Treatment / IVIG / IVIG, CST, MTZ / - / IVIG / IVIG, CST, CsA, GCSF, platelets
Antibiotics, Rituximab / IVIG, antibiotics / IVIG / Splenectomy, antibiotics, IVIG, CST
Other features & complications / Conjunctivitis,
death from respiratory failure / - / - / Multiple granuloma-like lesions / Septicemia, hypersplenism / - / - / Hypersplenism