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1.
Nature ; 583(7814): 96-102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581362

RESUMO

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.


Assuntos
Internacionalidade , Programas Nacionais de Saúde , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Bases de Dados Factuais , Eritrócitos/metabolismo , Fator de Transcrição GATA1/genética , Humanos , Fenótipo , Locos de Características Quantitativas , Receptores de Trombopoetina/genética , Medicina Estatal , Reino Unido
2.
Brain ; 146(6): 2285-2297, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36477332

RESUMO

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.


Assuntos
Microcefalia , Animais , Humanos , Microcefalia/genética , Claudina-5/genética , Claudina-5/metabolismo , Peixe-Zebra/metabolismo , Barreira Hematoencefálica/metabolismo , Convulsões/genética , Síndrome
3.
J Allergy Clin Immunol ; 152(1): 257-265, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36828084

RESUMO

BACKGROUND: Cystic fibrosis (CF) is one of the most common life-limiting autosomal-recessive disorders and is caused by genetic defects in the CF transmembrane conductance regulator (CFTR) gene. Some of the features of this multisystem disease can be present in primary immunodeficiency (PID). OBJECTIVE: We hypothesized that a carrier CFTR status might be associated with worse outcome regarding structural lung disease in patients with PID. METHODS: A within-cohort and population-level statistical genomic analysis of a large European cohort of PID patients was performed using genome sequence data. Genomic analysis of variant pathogenicity was performed. RESULTS: Compared to the general population, p.Phe508del carriage was enriched in lung-related PID. Additionally, carriage of several pathogenic CFTR gene variants were increased in PID associated with structural lung damage compared to PID patients without the structural lung damage. We identified 3 additional biallelic cases, including several variants not traditionally considered to cause CF. CONCLUSION: Genome sequencing identified cases of CFTR dysfunction in PID, driving an increased susceptibility to infection. Large national genomic services provide an opportunity for precision medicine by interpreting subtle features of genomic diversity when treating traditional Mendelian disorders.


Assuntos
Bronquiectasia , Fibrose Cística , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Prevalência , Mutação , Bronquiectasia/epidemiologia , Bronquiectasia/genética , Fibrose Cística/epidemiologia , Fibrose Cística/genética
4.
Clin Immunol ; 215: 108443, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32353633

RESUMO

A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.


Assuntos
Adenosina Desaminase/deficiência , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/patogenicidade , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/metabolismo , Adulto , Humanos , Masculino
5.
Sci Immunol ; 7(74): eabn3800, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-35960817

RESUMO

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.


Assuntos
Neoplasias , Fator 3 Associado a Receptor de TNF , Autoimunidade/genética , Linfócitos B , Humanos , Mutação , Neoplasias/patologia , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo
6.
Eur J Hum Genet ; 23(12): 1744-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26264437

RESUMO

Neonatal diabetes is a highly genetically heterogeneous disorder. There are over 20 distinct syndromic and non-syndromic forms, including dominant, recessive and X-linked subtypes. Biallelic truncating or mis-sense mutations in the DNA-binding domain of the RFX6 transcription factor cause an autosomal recessive, syndromic form of neonatal diabetes previously described as Mitchell-Riley syndrome. In all, eight cases have been reported, with the age at onset of diabetes in the first 2 weeks of life. Here we report two individuals born to double first cousins in whom intestinal atresias consistent with a diagnosis of Mitchell-Riley syndrome were diagnosed at birth, but in whom diabetes did not present until the ages of 3 and 6 years. Novel compound heterozygous RFX6 nonsense mutations (p.Arg726X/p.Arg866X) were identified at the 3' end of the gene. The later onset of diabetes in these patients may be due to incomplete inactivation of RFX6. Genetic testing for RFX6 mutations should be considered in patients presenting with intestinal atresias in the absence of neonatal diabetes.


Assuntos
Códon sem Sentido , Proteínas de Ligação a DNA/genética , Diabetes Mellitus/genética , Doenças da Vesícula Biliar/genética , Atresia Intestinal/genética , Fatores de Transcrição/genética , Adolescente , Alelos , Criança , Diabetes Mellitus/diagnóstico , Feminino , Doenças da Vesícula Biliar/diagnóstico , Heterozigoto , Humanos , Atresia Intestinal/diagnóstico , Masculino , Fatores de Transcrição de Fator Regulador X
7.
Nat Genet ; 46(1): 61-64, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24212882

RESUMO

The contribution of cis-regulatory mutations to human disease remains poorly understood. Whole-genome sequencing can identify all noncoding variants, yet the discrimination of causal regulatory mutations represents a formidable challenge. We used epigenomic annotation in human embryonic stem cell (hESC)-derived pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. This analysis uncovered six different recessive mutations in a previously uncharacterized ~400-bp sequence located 25 kb downstream of PTF1A (encoding pancreas-specific transcription factor 1a) in ten families with pancreatic agenesis. We show that this region acts as a developmental enhancer of PTF1A and that the mutations abolish enhancer activity. These mutations are the most common cause of isolated pancreatic agenesis. Integrating genome sequencing and epigenomic annotation in a disease-relevant cell type can thus uncover new noncoding elements underlying human development and disease.


Assuntos
Elementos Facilitadores Genéticos/genética , Mutação , Pâncreas/anormalidades , Pancreatopatias/congênito , Fatores de Transcrição/genética , Cromossomos Humanos Par 10 , Células-Tronco Embrionárias/fisiologia , Epigenômica/métodos , Feminino , Genes Recessivos , Humanos , Masculino , Pancreatopatias/genética , Linhagem
8.
Nat Genet ; 46(8): 812-814, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25038750

RESUMO

Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.


Assuntos
Doenças Autoimunes/genética , Mutação em Linhagem Germinativa , Fator de Transcrição STAT3/genética , Sequência de Aminoácidos , Linhagem Celular , Predisposição Genética para Doença , Células HEK293 , Humanos , Síndrome de Job/genética , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
9.
Nat Genet ; 44(1): 20-22, 2011 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-22158542

RESUMO

Understanding the regulation of pancreatic development is key for efforts to develop new regenerative therapeutic approaches for diabetes. Rare mutations in PDX1 and PTF1A can cause pancreatic agenesis, however, most instances of this disorder are of unknown origin. We report de novo heterozygous inactivating mutations in GATA6 in 15/27 (56%) individuals with pancreatic agenesis. These findings define the most common cause of human pancreatic agenesis and establish a key role for the transcription factor GATA6 in human pancreatic development.


Assuntos
Fator de Transcrição GATA6/genética , Haploinsuficiência , Pâncreas/anormalidades , Humanos , Fenótipo
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