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1.
J Clin Immunol ; 44(7): 151, 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38896336

RESUMEN

A cell's ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.


Asunto(s)
ADN Ligasa (ATP) , Homocigoto , Mutación , Inmunodeficiencia Combinada Grave , Femenino , Humanos , Masculino , ADN Ligasa (ATP)/genética , ADN Ligasa (ATP)/metabolismo , Fibroblastos , Simulación de Dinámica Molecular , Mutación/genética , Inmunodeficiencia Combinada Grave/genética , Lactante
2.
J Allergy Clin Immunol ; 151(2): 572-578.e1, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36243222

RESUMEN

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.


Asunto(s)
Autoanticuerpos , Linfocitos T Reguladores , Ratones , Humanos , Animales , Células HEK293 , Activación de Linfocitos , Mutación , Fibrinógeno/genética , Fibrinógeno/metabolismo
3.
J Clin Immunol ; 43(2): 479-484, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36348183

RESUMEN

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.


Asunto(s)
Angioedemas Hereditarios , Humanos , Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/epidemiología , Angioedemas Hereditarios/genética , Arabia Saudita/epidemiología , Proteína Inhibidora del Complemento C1/genética , Mutación/genética , Eliminación de Secuencia , Genotipo
4.
J Allergy Clin Immunol ; 146(1): 192-202, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31862378

RESUMEN

BACKGROUND: The gene AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival. OBJECTIVE: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection. METHODS: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function. RESULTS: We identified 2 different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function. CONCLUSIONS: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.


Asunto(s)
Adenilato Quinasa/genética , Linfocitos B/inmunología , Homocigoto , Activación de Linfocitos/genética , Mutación Missense , Inmunodeficiencia Combinada Grave/genética , Adenilato Quinasa/inmunología , Adulto , Sustitución de Aminoácidos , Niño , Preescolar , Femenino , Humanos , Masculino , Inmunodeficiencia Combinada Grave/inmunología , Linfocitos T/inmunología
5.
Mod Rheumatol ; 31(6): 1171-1178, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33563058

RESUMEN

OBJECTIVES: To report the phenotypic, genetic findings and outcome of children with lupus manifestations associated with primary immunodeficiency diseases (PIDs). METHODS: Data are retrospectively collected on patients with lupus manifestations and PIDs seen between 1998 and 2019. Data comprised the clinical findings and genetic testing, the response to treatment and the accrual damage related to SLE. RESULTS: A total of 39 patients (22 female) were reviewed. Thirty-four patients had lupus manifestations and six patients with SLE-like manifestations. Genetic analysis was performed in 25 patients. Complement deficiency was the most frequent PIDs; 26 patients were C1q deficient, three patients had C3 deficiency, two patients had C4 deficiency and one patient with heterozygous C8b variant. The other seven patients had different PIDs genetic defects that include SCID caused by PNP deficiency, CGD, CVID (PIK3CD), IL-2RB mutation, DNase II deficiency, STAT1 mutation, ISG15 mutation and Griscelli syndrome type 3. Mucocutaneous lesions, arthritis and lung involvement were the main clinical features. 84.1% experienced recurrent infections. The mean accrual damage was 2.7 ± 2.2. There were five deaths because of infection. CONCLUSION: This study suggests that patients with lupus manifestations and early onset disease, family history of SLE or recurrent infections should undergo immunological work-up and genetic testing to rule out PIDs.


Asunto(s)
Lupus Eritematoso Sistémico , Enfermedades de Inmunodeficiencia Primaria , Errores Innatos del Metabolismo de la Purina-Pirimidina , Niño , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , Mutación , Purina-Nucleósido Fosforilasa , Estudios Retrospectivos
6.
J Clin Immunol ; 40(8): 1103-1110, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32851577

RESUMEN

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.


Asunto(s)
Antígenos CD/genética , Mutación , Fenotipo , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/genética , Receptores de Transferrina/genética , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Adolescente , Adulto , Biomarcadores , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Estudios Retrospectivos , Adulto Joven
7.
Hum Genet ; 138(1): 105-107, 2019 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30483960

RESUMEN

ISLR2 (immunoglobulin superfamily containing leucine-rich repeat 2), encodes a protein involved in axon guidance in brain development (hence the other name leucine-rich repeat domain- and immunoglobulin domain-containing axon extension proteins; LINX). A recently described mouse knockout displays hydrocephalus. However, the corresponding phenotype in humans is unknown. Here, we describe a multiplex consanguineous family in which a homozygous truncating variant in ISLR2 segregates with severe congenital hydrocephalus, arthrogryposis multiplex congenita and abdominal distension. We suggest this syndrome may represent the human "knockout" phenotype for ISLR2.


Asunto(s)
Abdomen/anomalías , Artrogriposis/genética , Biomarcadores/análisis , Eliminación de Gen , Genes Recesivos , Hidrocefalia/genética , Inmunoglobulinas/genética , Abdomen/patología , Artrogriposis/patología , Femenino , Homocigoto , Humanos , Hidrocefalia/patología , Lactante , Masculino , Linaje , Fenotipo , Pronóstico , Síndrome
8.
Hum Genet ; 138(3): 231-239, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30778726

RESUMEN

Pseudouridylation is the most common post-transcriptional modification, wherein uridine is isomerized into 5-ribosyluracil (pseudouridine, Ψ). The resulting increase in base stacking and creation of additional hydrogen bonds are thought to enhance RNA stability. Pseudouridine synthases are encoded in humans by 13 genes, two of which are linked to Mendelian diseases: PUS1 and PUS3. Very recently, PUS7 mutations were reported to cause intellectual disability with growth retardation. We describe two families in which two different homozygous PUS7 mutations (missense and frameshift deletion) segregate with a phenotype comprising intellectual disability and progressive microcephaly. Short stature and hearing loss were variable in these patients. Functional characterization of the two mutations confirmed that both result in decreased levels of Ψ13 in tRNAs. Furthermore, the missense variant of the S. cerevisiae ortholog failed to complement the growth defect of S. cerevisiae pus7Δ trm8Δ mutants. Our results confirm that PUS7 is a bona fide Mendelian disease gene and expand the list of human diseases caused by impaired pseudouridylation.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Discapacidad Intelectual/genética , Microcefalia/genética , Mutación , Seudouridina/genética , Adolescente , Secuencia de Aminoácidos , Niño , Mapeo Cromosómico , Consanguinidad , Femenino , Genes Recesivos , Humanos , Masculino , Microcefalia/diagnóstico , Linaje , Fenotipo , ARN de Transferencia/genética , Secuenciación del Exoma
9.
Genet Med ; 21(3): 545-552, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30214071

RESUMEN

PURPOSE: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. METHODS: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. RESULTS: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. CONCLUSION: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect.


Asunto(s)
Microcefalia/genética , Microcefalia/fisiopatología , Adulto , Niño , Preescolar , Enanismo/genética , Femenino , Genómica/métodos , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Mutación/genética , Linaje , Fenotipo , Secuenciación del Exoma/métodos
10.
BMC Med Genet ; 20(1): 119, 2019 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-31272422

RESUMEN

BACKGROUND: Mutations in ARL6IP1, which encodes a tetraspan membrane protein localized to the endoplasmic reticulum (ER), have been recently described in a large family with a complicated form of hereditary spastic paraplegia (HSP). CASE PRESENTATION: We sought to expand the HSP phenotype associated with ARL6IP1 variants by examining a Saudi kindred with a clinically more severe presentation, which resulted in spontaneous neonatal death of both affected siblings. Clinical features encompassed not only spastic paraplegia but also developmental delay, microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures, spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and respiratory distress. We performed clinical assessment and radiological studies of this family, in addition to homozygosity mapping and whole exome sequencing (WES) to identify the disease-associated variant. Homozygosity mapping localized the causative gene to a region on chromosome 16 harboring ARL6IP1. WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1 that segregated with the phenotype and was predicted to result in loss of the protein. Allelic expression analysis of the parents demonstrated downward pressure on the mutant allele, suggestive of nonsense-mediated decay. CONCLUSIONS: Our report shows that the phenotype associated with ARL6IP1 variants may be broader and more acute than so far reported and identifies fatal HSP as the severe end of the phenotypic spectrum of ARL6IP1 variants.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Variación Genética , Proteínas de la Membrana/genética , Mutación , Paraplejía Espástica Hereditaria/genética , Alelos , Preescolar , Retículo Endoplásmico/metabolismo , Femenino , Regulación de la Expresión Génica , Homocigoto , Humanos , Masculino , Mutación/genética , Linaje , Fenotipo , Arabia Saudita , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Paraplejía Espástica Hereditaria/fisiopatología , Secuenciación del Exoma
11.
Allergy ; 74(2): 370-379, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30252138

RESUMEN

BACKGROUND: Hyper-IgE syndromes (HIES) are a clinically overlapping, heterogeneous group of inborn errors of immunity characterized by elevated serum IgE level, eosinophilia, atopy, and immune dysregulation. Deficiency of DOCK8 protein is potentially a life-threatening autosomal recessive HIES and only curable with bone marrow transplantation. Hence, the diagnosis of DOCK8 deficiency is critical and should be sought at an early stage to initiate definitive therapy. METHODS: Serum samples from patients with DOCK8 deficiency and atopic dermatitis were profiled on a cytokine/chemokine panel for potential differential expression. RESULTS: CXCL10 and TNF-A were upregulated in DOCK8 patients when compared to AD, possibly contributing toward increased susceptibility to infections and cancer. In contrast, epidermal growth factor (EGF) was significantly downregulated in a subgroup of DOCK8-deficient and AD patients, while IL-31 expression was comparable between both DOCK8-deficient and AD cohorts, possibly contributing toward pruritus seen in both groups. CONCLUSION: This comprehensive cytokine profile in HIES patients reveals distinctive biomarkers that differentiate between the DOCK8-deficient and AD patients. The unique expression profile of various inflammatory cytokines in patients with DOCK8 deficiency vs atopic dermatitis likely reflects disease-specific perturbations in multiple cellular processes and pathways leading to a predisposition to infections and allergies seen in these patients. These data agree with the role for EGF replacement therapy in EGF-deficient individuals with AD as well as DOCK8 deficiency through a potential shared pathway. In addition, these novel biomarkers may be potentially useful in distinguishing DOCK8 deficiency from AD allowing early-targeted treatment options.


Asunto(s)
Quimiocinas/metabolismo , Citocinas/metabolismo , Dermatitis Atópica/etiología , Dermatitis Atópica/metabolismo , Factores de Intercambio de Guanina Nucleótido/deficiencia , Adolescente , Adulto , Biomarcadores , Línea Celular , Niño , Dermatitis Atópica/diagnóstico , Susceptibilidad a Enfermedades , Femenino , Humanos , Inmunoglobulina E/inmunología , Masculino , Mutación , Curva ROC , Adulto Joven
12.
Am J Hum Genet ; 97(6): 862-8, 2015 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-26608784

RESUMEN

Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.


Asunto(s)
Proteínas Portadoras/genética , Enanismo/genética , Mutación , Secuencia de Aminoácidos , Animales , Encéfalo/anomalías , Encéfalo/metabolismo , Proteínas de Ciclo Celular , Niño , Preescolar , Consanguinidad , Enanismo/patología , Exoma , Exones , Expresión Génica , Homocigoto , Humanos , Intrones , Masculino , Microcefalia/genética , Microcefalia/patología , Datos de Secuencia Molecular , Linaje , Alineación de Secuencia
14.
Genet Med ; 20(12): 1609-1616, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29620724

RESUMEN

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.


Asunto(s)
Exoma/genética , Heterogeneidad Genética , Predisposición Genética a la Enfermedad , Anomalías Musculoesqueléticas/genética , Alelos , Proteínas Sanguíneas/genética , Hidrolasas de Éster Carboxílico , Estudios de Cohortes , Exorribonucleasas/genética , Femenino , Proteínas Fetales/genética , Efecto Fundador , Genética de Población , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Proteínas de la Membrana/genética , Anomalías Musculoesqueléticas/clasificación , Anomalías Musculoesqueléticas/patología , Proteínas de Neoplasias/genética , Proteínas Oncogénicas/genética , Fenotipo , Receptores de Superficie Celular/genética , Proteína Wnt3A/genética
15.
J Clin Immunol ; 37(6): 575-581, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28741180

RESUMEN

INTRODUCTION: Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS: Patients' clinical, immunological, and laboratory features were examined. Samples were subjected to targeted next-generation sequencing (NGS). The pathogenic change in NHEJ1 was confirmed by Sanger sequencing, then further assessed at the RNA and protein levels. RESULTS: Patients were found to have a homozygous splice site mutation immediately downstream of exon 3 in NHEJ1 (c.390 + 1G > C). This led to two distinct mRNA products, one of which demonstrated skipping of the last 69 basepairs (bp) of exon 3 while the other showed complete skipping of the entire exon. Although both deletions were in-frame, immunoblotting did not reveal any NHEJ1 protein products in patient cells, indicating a null phenotype. CONCLUSION: Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.


Asunto(s)
Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Discapacidades del Desarrollo/genética , Síndromes de Inmunodeficiencia/genética , Microcefalia/genética , Mutación/genética , Isoformas de Proteínas/genética , Sitios de Empalme de ARN/genética , Adolescente , Adulto , Empalme Alternativo , Niño , Familia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Masculino , Linaje , Fenotipo , Hermanos
16.
Hum Genomics ; 10(1): 32, 2016 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-27671536

RESUMEN

BACKGROUND: Fifty random genetically unstudied families (limb-girdle muscular dystrophy (LGMD)/myopathy) were screened with a gene panel incorporating 759 OMIM genes associated with neurological disorders. Average coverage of the CDS and 10 bp flanking regions of genes was 99 %. All families were referred to the Neurosciences Clinic of King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Patients presented with muscle weakness affecting the pelvic and shoulder girdle. Muscle biopsy in all cases showed dystrophic or myopathic changes. Our main objective was to evaluate a neurological gene panel as a first-line diagnostic test for LGMD/myopathies. RESULTS: Our panel identified the mutation in 76 % of families (38/50; 11 novel). Thirty-four families had mutations in LGMD-related genes with four others having variants not typically associated with LGMD. The majority of cases had recessive inheritance with homoallelic pathogenic variants (97.4 %, 37/38), as expected considering the high rate of consanguinity in the study population. In one case, we detected a heterozygous mutation in DNAJB responsible for LGMD-1E. Our cohort included seven different subtypes of LGMD2. Mutations of DYSF were the most commonly identified cause of disease followed by that in CAPN3 and FKRP. Non-LGMD myopathies were due to mutations in genes associated with congenital disorder of glycosylation (ALG2), rigid spine muscular dystrophy 1 (SEPN1), inclusion body myopathy2/Nonaka myopathy (GNE), and neuropathy (WNK1). Whole exome sequencing (WES) of patients who remained undiagnosed with the neurological panel did not improve our diagnostic yield. CONCLUSIONS: Our neurological panel achieved a high clinical sensitivity (76 %) and is an effective first-line laboratory test in patients with LGMD and other myopathies. This sensitive, cost-effective, and rapid assay significantly assists clinical practice especially in these phenotypically and genetically heterogeneous disorders. Moreover, the application of the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) guidelines applied in the classification of variant pathogenecity provides a clear interpretation for physicians on the relevance of such findings.

17.
Clin Exp Rheumatol ; 35(2): 327-329, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28134088

RESUMEN

Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency causes common variable immunodeficiency (CVID) disorders and autoimmunity. LRBA deficiency has become a clinically variable syndrome with a wide spectrum of clinical manifestations. We report a patient with LRBA deficiency associated chronic non-erosive arthritis. This report highlights the spectrum of arthritis in such patients and the potential causative role of LRBA gene in juvenile arthritis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Artritis Juvenil/genética , Inmunodeficiencia Variable Común/genética , Mutación , Abatacept/administración & dosificación , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/inmunología , Adolescente , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/inmunología , Artrografía , Enfermedad Crónica , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/tratamiento farmacológico , Inmunodeficiencia Variable Común/inmunología , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Humanos , Inmunosupresores/administración & dosificación , Articulación de la Rodilla/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Fenotipo , Resultado del Tratamiento
18.
BMC Genomics ; 17(Suppl 9): 749, 2016 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-27766953

RESUMEN

BACKGROUND: Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. METHODS: Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7). RESULTS: Depletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts. CONCLUSIONS: Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.


Asunto(s)
Estudios de Asociación Genética , Ribonucleoproteínas/deficiencia , Telómero/genética , Adulto , Línea Celular , Niño , Estudios de Cohortes , Consanguinidad , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Hibridación Fluorescente in Situ , Masculino , Modelos Genéticos , Mutación , Linaje , Fenotipo , Homeostasis del Telómero/genética
19.
Hum Genet ; 135(5): 525-540, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27023906

RESUMEN

Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.


Asunto(s)
Enfermedades del Tejido Conjuntivo/genética , Heterogeneidad Genética , Marcadores Genéticos/genética , Anomalías Cutáneas/genética , Secuencia de Aminoácidos , Estudios de Cohortes , Enfermedades del Tejido Conjuntivo/patología , Exoma/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Homología de Secuencia de Aminoácido
20.
Am J Med Genet A ; 170A(5): 1142-7, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26842963

RESUMEN

ADAT3-related intellectual disability has been recently described in 24 individuals from eight Saudi families who had cognitive impairment and strabismus. Other common features included growth failure, microcephaly, tone abnormalities, epilepsy, and nonspecific brain abnormalities. A single homozygous founder mutation (c.382G>A:p.(V128M)) in the ADAT3 gene, which encodes a protein that functions in tRNA editing, was identified in all affected individuals. In this report, we present additional 15 individuals from 11 families (10 Saudis and 1 Emirati) who are homozygous for the same founder mutation. In addition to the universal findings of intellectual disability and strabismus, the majority exhibited microcephaly and growth failure. Additional features not reported in the original cohort include dysmorphic facial features (prominent forehead, up-slanted palpebral fissures, epicanthus, and depressed nasal bridge), behavioral problems (hyperactivity and aggressiveness), recurrent otitis media, and growth hormone deficiency. ADAT3-related intellectual disability is an important recognizable cause of intellectual disability in Arabia.


Asunto(s)
Adenosina Desaminasa/genética , Disfunción Cognitiva/genética , Discapacidad Intelectual/genética , Estrabismo/genética , Adolescente , Adulto , Niño , Preescolar , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/fisiopatología , Femenino , Efecto Fundador , Hormona del Crecimiento/genética , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/fisiopatología , Masculino , Fenotipo , Estrabismo/complicaciones , Estrabismo/fisiopatología
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