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1.
J Allergy Clin Immunol ; 151(2): 572-578.e1, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36243222

RESUMO

BACKGROUND: The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2-/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function. OBJECTIVE: Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies. METHODS: Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro. RESULTS: The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2V205fs mutant failed to suppress T-cell proliferation. CONCLUSIONS: We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient.


Assuntos
Autoanticorpos , Linfócitos T Reguladores , Camundongos , Humanos , Animais , Células HEK293 , Ativação Linfocitária , Mutação , Fibrinogênio/genética , Fibrinogênio/metabolismo
2.
J Clin Immunol ; 43(6): 1360-1366, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37145392

RESUMO

BACKGROUND AND AIMS: Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG. METHODS: In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG. RESULTS: Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0-14 years). The patients' diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5-125 months). The QoL score showed a significant improvement in the patients' global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients' general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively). CONCLUSIONS: This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20% SCIG.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Masculino , Feminino , Humanos , Criança , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulina G/uso terapêutico , Qualidade de Vida , Arábia Saudita , Estudos Prospectivos , Síndromes de Imunodeficiência/terapia , Síndromes de Imunodeficiência/tratamento farmacológico , Doenças da Imunodeficiência Primária/tratamento farmacológico , Infusões Subcutâneas
3.
J Clin Immunol ; 43(2): 479-484, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36348183

RESUMO

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disorder affecting roughly 1:50,000 individuals. It is commonly characterized by swelling of the larynx, gastrointestinal tract, extremities, and skin. There is growing genetic heterogeneity associated with this disease but more than 95% of mutations are found in SERPING1, the gene which encodes complement 1 inhibitor (C1-INH). HAE cohorts from several populations have been published but no large scale study has been reported from the Arab world to date. Here we document the clinical and genetic findings of HAE patients from a single Saudi institution, which is a major referral center at the national level. A total of 51 patients across 17 unrelated families were recruited including two large multi-generational families, of which one contained an in-frame exonic deletion that was resolved through MLPA. Two cases were negative for all the genes we tested (including F12, PLG, ANGPT1, MYOF, KNG1, and HS3ST6). The predominant HAE subtype in our cohort was type I, at 76%. We were able to uncover a mutation in 49 patients (96%). No type III (normal C1-INH) patients were encountered in the clinic, suggesting that this subtype does not play a major role in HAE pathogenesis in Saudi Arabia. Additionally, the existence of four patients with consistently normal complement 4 (C4) levels alongside abnormal C1-INH profiles highlights the utility of dual screening for both proteins in suspected patients.


Assuntos
Angioedemas Hereditários , Humanos , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/epidemiologia , Angioedemas Hereditários/genética , Arábia Saudita/epidemiologia , Proteína Inibidora do Complemento C1/genética , Mutação/genética , Deleção de Sequência , Genótipo
4.
J Immunol ; 207(1): 133-152, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34183371

RESUMO

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfo-Histiocitose Hemofagocítica , Infecções por Mycobacterium , Mycobacterium bovis , Humanos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo
5.
Blood ; 135(12): 954-973, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31932845

RESUMO

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Antígenos de Histocompatibilidade Classe II/genética , Idade de Início , Alelos , Biomarcadores , Criança , Pré-Escolar , Feminino , Genótipo , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Cuidados Paliativos , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Condicionamento Pré-Transplante , Doadores não Relacionados
6.
J Clin Immunol ; 40(6): 833-839, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32514656

RESUMO

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency accounts for about 4% of severe combined immunodeficiency diseases. PNP deficiency is a variable disease with recurrent infections and neurodevelopmental delay. Autoimmunity and malignancy can still occur in one-third of patients. METHODS: Case report. CASE PRESENTATION: An 8-year-old Saudi female who was apparently healthy presented at the age of 7 years with confirmed systemic lupus erythematosus (SLE) and lupus nephritis that were poorly controlled with conventional therapy. She also had frequent sinopulmonary and varicella infections. Preliminary immunological workup showed severe lymphopenia and depressed lymphocyte proliferation assay. The uric acid was within normal levels at 179 µmol/L (normal range, 150 to 350 µmol/L) 6 weeks after blood transfusion. Genetic study revealed a homozygous missense mutation c.265G>A in the PNP gene, resulting in a substitution of glutamic acid to lysine at amino acid 89 of the encoded protein (E89K). The PNP serum level was 798 nmol/h/mg (normal level 1354 ± 561 nmol/h/mg) 6 weeks after blood transfusion. Hematopoietic stem cell transplantation (HSCT) was planned from a matched unrelated donor; however, she developed an EBV and varicella meningoencephalitis. Atypical malignant cells suggestive of lymphoma were discovered, likely induced by EBV, and suspicious lesions were shown on brain MRI and PET scan. Unfortunately, she passed away before HSCT due to multiorgan failure. CONCLUSION: This report emphasizes the challenges in recognizing PNP deficiency in a patient suffering from SLE.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Linfoma/complicações , Linfoma/genética , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/etiologia , Purina-Núcleosídeo Fosforilase/deficiência , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/etiologia , Alelos , Autoimunidade , Biomarcadores , Criança , Suscetibilidade a Doenças , Feminino , Transplante de Células-Tronco Hematopoéticas , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Mutação , Tomografia por Emissão de Pósitrons , Doenças da Imunodeficiência Primária/terapia , Purina-Núcleosídeo Fosforilase/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/terapia
7.
J Clin Immunol ; 40(8): 1103-1110, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32851577

RESUMO

PURPOSE: Combined immunodeficiency (CID), due to mutations in TFRC gene that encodes the transferrin receptors (TfR1), is a rare monogenic disorder. In this study, we further characterize the clinical and immunological phenotypes in a cohort of eight patients. METHODS: A retrospective review of clinical and immunological features of patients diagnosed with a TFRC gene mutation between 2015 and 2019 in three tertiary centers. RESULTS: Eight patients from six unrelated families were enrolled. The patients had a median age of 7 years (4-32 years). All patients presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. Less common features were skin abscesses, conjunctivitis, global developmental delay, optic nerve atrophy, vitiligo, multinodular goiter, and hemophagocytic lymphohistiocytosis-like symptoms. All patients had intermittent neutropenia and 87% of the patients had recurrent thrombocytopenia. Anemia was found in 62%. All patients had hypogammaglobinemia and one had a persistent high IgM level. All patients had impaired function of T cells. The same homozygous missense mutation c.58T>C:p.Y20H, in the TFRC gene, was detected in all patients. Stem cell transplantation from matched donors was successful in two patients. Five patients did not receive stem cell transplantation, and they are on prophylactic treatment. One patient died due to severe sepsis and neurological complications. CONCLUSION: This report provides a large cohort with a long follow up of patients with this disease. Our cohort showed variable disease severity.


Assuntos
Antígenos CD/genética , Mutação , Fenótipo , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Receptores da Transferrina/genética , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adolescente , Adulto , Biomarcadores , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Estudos Retrospectivos , Adulto Jovem
8.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.


Assuntos
Ligante de CD40/deficiência , Transplante de Células-Tronco Hematopoéticas , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Resultado do Tratamento , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/mortalidade
9.
J Clin Immunol ; 39(4): 414-420, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31041574

RESUMO

BACKGROUND: One of the limiting factors for successful hematopoietic stem cell transplantation (HSCT) is graft versus host disease (GVHD). The EBMT/ESID guidelines for HSCT in severe combined immunodeficiency (SCID) recommend no GVHD prophylaxis for a matched sibling donor (MSD). OBJECTIVE: To determine the risk of GVHD in MSD HSCT for SCID patients compared to matched related donor (MRD). METHODS: This retrospective cohort study compares MSD with MRD and the outcome of GVHD in all SCID patients who underwent HSCT between 1993 and 2013. All statistical analyses were done using IBM SPSS statistics software. RESULTS: One hundred forty-five SCID patients underwent 152 HSCTs while 82 (54%) received GVHD prophylaxis. GVHD occurred in 48 patients (31.5%); 20/48 (42%) had GVHD prophylaxis compared to 28/48 (58%) that did not, P = 0.022. Acute GVHD occurred at a higher trend in MSD, 37/120 (30.8%), compared to MRD, 6/32 (18.8%), P = 0.17. We also analyzed the outcome according to the period of HSCT. The first period was 1993 to 2003, 48 HSCTs, 43 MSD, 5 MRD; all patients had GVHD prophylaxis, and there was no difference in GVHD. The second period was 2004 to 2013: of 104 HSCTs, 77 had MSD and 27 had MRD; GVHD prophylaxis was used in 22.1% of MSD and 63% of MRD, P = 0.000. GVHD was significantly higher in the MSD (40.2%) compared to MRD (18.5%) patients, P = 0.041. CONCLUSION: GVHD prophylaxis in MSD transplant should be considered in SCID patients.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunodeficiência Combinada Severa/complicações , Irmãos , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Imunodeficiência Combinada Severa/terapia , Resultado do Tratamento
10.
J Allergy Clin Immunol ; 141(3): 1050-1059.e10, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28601686

RESUMO

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) deficiencies give rise to overlapping phenotypes of immune dysregulation and autoimmunity, with dramatically increased frequencies of circulating follicular helper T (cTFH) cells. OBJECTIVE: We sought to determine the mechanisms of cTFH cell dysregulation in patients with LRBA deficiency and the utility of monitoring cTFH cells as a correlate of clinical response to CTLA4-Ig therapy. METHODS: cTFH cells and other lymphocyte subpopulations were characterized. Functional analyses included in vitro follicular helper T (TFH) cell differentiation and cTFH/naive B-cell cocultures. Serum soluble IL-2 receptor α chain levels and in vitro immunoglobulin production by cultured B cells were quantified by using ELISA. RESULTS: cTFH cell frequencies in patients with LRBA or CTLA4 deficiency sharply decreased with CTLA4-Ig therapy in parallel with other markers of immune dysregulation, including soluble IL-2 receptor α chain, CD45RO+CD4+ effector T cells, and autoantibodies, and this was predictive of favorable clinical responses. cTFH cells in patients with LRBA deficiency were biased toward a TH1-like cell phenotype, which was partially reversed by CTLA4-Ig therapy. LRBA-sufficient but not LRBA-deficient regulatory T cells suppressed in vitro TFH cell differentiation in a CTLA4-dependent manner. LRBA-deficient TFH cells supported in vitro antibody production by naive LRBA-sufficient B cells. CONCLUSIONS: cTFH cell dysregulation in patients with LRBA deficiency reflects impaired control of TFH cell differentiation because of profoundly decreased CTLA4 expression on regulatory T cells and probably contributes to autoimmunity in patients with this disease. Serial monitoring of cTFH cell frequencies is highly useful in gauging the clinical response of LRBA-deficient patients to CTLA4-Ig therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Antígeno CTLA-4 , Doenças do Sistema Imunitário , Linfócitos T Auxiliares-Indutores/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Criança , Feminino , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Masculino , Linfócitos T Auxiliares-Indutores/patologia
12.
Int Arch Allergy Immunol ; 177(4): 350-359, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30184525

RESUMO

BACKGROUND: The timing of the introduction of egg to an infant's diet is of current interest, as new evidence raises questions regarding the benefit of delaying egg introduction. The objective of this study was to systematically review the existing literature regarding the effect of the early introduction of egg on the development of egg allergy. METHODS: Literature searches were conducted in MEDLINE, EMBASE, and CENTRAL, and trial protocols were searched in Meta Register and OpenGREY. Only randomized controlled trials (RCTs) comparing early (between 3 and 6 months of age) egg introduction to no early introduction were included. The primary outcome was the development of egg allergy. RESULTS: Of the 416 articles identified and screened, 6 RCTs met the eligibility criteria for data extraction. Allergic outcomes were evaluated in a total of 3,032 participants. A low to moderate level of evidence showed a benefit of the early introduction of egg (relative risk, RR 0.60, 95% CI 0.44-0.82, p = 0.002, mild heterogeneity, I2 = 23%). The absolute risk reduction for a population with an incidence of egg allergy of 9.3% was 37 fewer cases (95% CI 17-52) per 1,000 people. Consumption of < 4,000 mg/week of egg protein had a greater preventive effect than a higher dose. CONCLUSION: This systematic review and meta-analysis showed an association between the early introduction of egg and a lower risk of egg allergy. Furthermore, the nature and dose of egg protein exposure may play a role. These findings should be addressed in the context of primary studies.


Assuntos
Dietoterapia , Hipersensibilidade a Ovo/epidemiologia , Alérgenos/imunologia , Proteínas do Ovo/imunologia , Ovos , Humanos , Incidência , Lactente , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco
13.
Hum Genet ; 136(8): 921-939, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28600779

RESUMO

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.


Assuntos
Exoma , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/epidemiologia , Genoma Humano , Consanguinidade , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Anotação de Sequência Molecular , Morbidade , Mutação , Fenótipo , Reprodutibilidade dos Testes , Arábia Saudita/epidemiologia , Análise de Sequência de DNA
14.
J Allergy Clin Immunol ; 137(6): 1780-1787, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26915675

RESUMO

BACKGROUND: Molecular genetics techniques are an essential diagnostic tool for primary immunodeficiency diseases (PIDs). The use of next-generation sequencing (NGS) provides a comprehensive way of concurrently screening a large number of PID genes. However, its validity and cost-effectiveness require verification. OBJECTIVES: We sought to identify and overcome complications associated with the use of NGS in a comprehensive gene panel incorporating 162 PID genes. We aimed to ascertain the specificity, sensitivity, and clinical sensitivity of the gene panel and its utility as a diagnostic tool for PIDs. METHODS: A total of 162 PID genes were screened in 261 patients by using the Ion Torrent Proton NGS sequencing platform. Of the 261 patients, 122 had at least 1 known causal mutation at the onset of the study and were used to assess the specificity and sensitivity of the assay. The remaining samples were from unsolved cases that were biased toward more phenotypically and genotypically complicated cases. RESULTS: The assay was able to detect the mutation in 117 (96%) of 122 positive control subjects with known causal mutations. For the unsolved cases, our assay resulted in a molecular genetic diagnosis for 35 of 139 patients. Interestingly, most of these cases represented atypical clinical presentations of known PIDs. CONCLUSIONS: The targeted NGS PID gene panel is a sensitive and cost-effective diagnostic tool that can be used as a first-line molecular assay in patients with PIDs. The assay is an alternative choice to the complex and costly candidate gene approach, particularly for patients with atypical presentation of known PID genes.


Assuntos
Marcadores Genéticos , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Biologia Computacional , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Síndromes de Imunodeficiência/imunologia , Mutação , Polimorfismo de Nucleotídeo Único , Fluxo de Trabalho
16.
Genet Med ; 18(6): 554-62, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26355662

RESUMO

PURPOSE: Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large cohort of RD patients. METHODS: We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel. RESULTS: Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia. CONCLUSION: Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.Genet Med 18 6, 554-562.


Assuntos
Caderinas/genética , Carboxipeptidases/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Distrofias Retinianas/genética , Feminino , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Fenótipo , Retina/patologia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/patologia , Sequenciamento do Exoma
17.
J Clin Immunol ; 35(7): 651-60, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26395454

RESUMO

PURPOSE: Primary immunodeficiencies (PID) are a group of heterogeneous diseases. Epidemiological studies from databases worldwide show geographical variation. In this study the objective is to determine the spectrum of PID in Saudi Arabia by analyzing the database in a referral tertiary hospital. METHODS: This is a prospective data collection by interviews and medical chart review for all PID patients followed at the King Faisal Specialist Hospital & Research Center (KFSH&RC) from May 2010 to April 2013. RESULTS: A total of 502 patients presented (53 % male and 47 % female). Combined immunodeficiencies were the most common (59.7 %), followed by predominantly antibody deficiencies (12.3 %), congenital defects of phagocyte (9.4 %), combined immunodeficiencies with associated or syndromic features (6.2 %), disease of immune dysregulation (6 %), complement deficiencies (5.8), and defects in innate immunity (0.6 %). The most common combined immunodeficiencies phenotype was T-B-SCID (17 %). The patients' ages ranged from less than 1 year old to 78 years, and 394 patients (78.2 %) are in the paediatrics age group (<14 years). The overall mean age of symptoms onset was 17 months and the overall mean delay in diagnosis was 21.6 months. Recurrent infections were the most common occurring clinical presentation (66 %), followed by family history (26 %). Consanguinity was found in 75 % of the patients. A total of 308 (61 %) patients had undergone stem cell transplantation (SCT). CONCLUSION: The study revealed that combined immunodeficiencies are not uncommon and are the most frequent occurring diagnosis in our patient population. This study is a prerequisite to establish a national registry of primary immunodeficiency in Saudi Arabia.


Assuntos
Linfócitos B/fisiologia , Síndromes de Imunodeficiência/epidemiologia , Infecções/epidemiologia , Linfócitos T/fisiologia , Centros de Atenção Terciária , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Lactente , Infecções/diagnóstico , Infecções/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Arábia Saudita , Transplante de Células-Tronco , Adulto Jovem
18.
Pediatr Transplant ; 19(6): 634-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26073206

RESUMO

HIGMI is a disease with a high risk for morbidity and mortality. HSCT has been shown to be a curative option. This study retrospectively reviewed and analyzed data from five patients who received HSCT at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia, between 2005 and 2013. Five patients with HIGMI syndrome underwent HSCT at a median age of 41 months (range, 9-72 months). The median time from diagnosis to transplantation was 30 months (range, 5-58 months). For all five patients, the donors were HLA-identical siblings. In three patients, the conditioning regimen was composed of BU and CY. Fludarabine and melphalan with either ATG or alemtuzumab was used in two patients. For GVHD prophylaxis, cyclosporine was used in two patients, and the combination of cyclosporine and MTX was used in three patients. The survival rate was 100%, with a median follow-up of 69 months (range, 13-100 months). All patients engrafted. Two patients developed acute GVHD. Four patients showed complete immune recovery with positive CD40L expression in activated T cells and discontinued IVIG replacement. HSCT in early stage from an HLA-matched sibling donor is potentially effective at curing the disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/terapia , Ligante de CD40/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Marcadores Genéticos , Doença Enxerto-Hospedeiro , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/genética , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/mortalidade , Lactente , Masculino , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento
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