RESUMO
Mental health and neurodevelopmental disorders are highly heritable and can affect morbidity and mortality. A large, growing body of evidence has implicated both common and rare variation in the risk of these disorders. Testing for rare variants, such as copy number variants, has been available in clinical practice for some time in the context of developmental disorders. However, until recently, individuals with mental health and neurodevelopmental disorders in the UK have not tended to access genetic counselling and testing. Here, we describe the development of the All Wales Psychiatric Genomics Service, a collaborative effort between psychiatric and clinical genetics services and the first of its kind in the UK. We provide an overview of the structure and function of the service, our referral criteria, a summary of the 40 referrals we have received to date and our future plans.
RESUMO
Individuals with the three base pair deletion NM_000267.3(NF1):c.2970_2972del p.(Met992del) have been recognised to present with a milder neurofibromatosis type 1 (NF1) phenotype characterised by café-au-lait macules (CALs) and intertriginous freckling, as well as a lack of cutaneous, subcutaneous and plexiform neurofibromas and other NF1-associated complications. Examining large cohorts of patients over time with this specific genotype is important to confirm the presentation and associated risks of this variant across the lifespan. Forty-one individuals with the in-frame NF1 deletion p.Met992del were identified from 31 families. Clinicians completed a standardised clinical questionnaire for each patient and the resulting data were collated and compared to published cohorts. Thirteen patients have been previously reported, and updated clinical information has been obtained for these individuals. Both CALs and intertriginous freckling were present in the majority of individuals (26/41, 63%) and the only confirmed features in 11 (27%). 34/41 (83%) of the cohort met NIH diagnostic criteria. There was a notable absence of all NF1-associated tumour types (neurofibroma and glioma). Neurofibroma were observed in only one individual-a subcutaneous lesion (confirmed histologically). Nineteen individuals were described as having a learning disability (46%). This study confirms that individuals with p.Met992del display a mild tumoural phenotype compared to those with 'classical', clinically diagnosed NF1, and this appears to be the case longitudinally through time as well as at presentation. Learning difficulties, however, appear to affect a significant proportion of NF1 subjects with this phenotype. Knowledge of this genotype-phenotype association is fundamental to accurate prognostication for families and caregivers.
Assuntos
Neurofibroma , Neurofibromatose 1 , Manchas Café com Leite/genética , Estudos de Associação Genética , Humanos , Estudos Longitudinais , Neurofibroma/genética , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neurofibromatose 1/patologiaRESUMO
Quality improvement in specialist services such as clinical genetics is challenging largely due to the complexity of the service and the difficulty in obtaining accurate, reproducible, and measurable data. The objectives were to evaluate the pattern of referrals to the All Wales Medical Genetics Service (AWMGS) North Wales Genetics team based in three separate hospitals, define the capacity of the team and implement change to improve equity, timeliness and efficiency of care delivery to patients. The methodology required collating the monthly referral rates retrospectively for each center over a 2.5-year period and plotting on statistical process control charts. Process mapping of the referral process in each center was undertaken, differences documented and a common pathway implemented. "Did not attend" and "time to first appointment" rates were also measured in one center. PDSA methodology was used to implement "patient focused booking." The results show that the range for referral rates in any given month for each center was 3-33 referrals. The range for referral rate for the whole team was 18-64 per month. Since January 2004 the average number of monthly referrals to the North Wales service has increased by 50%. The potential range in monthly referrals varies between centers and the range of the variability has also increased also in two out of the three centers. Introduction of Patient Focused Booking reduced the "Failed to Attend" rate and 100% of patients were offered a choice of appointments. In addition 100% had a first face-to-face contact within 6 weeks if they chose. The measurement of improvement involved firstly introducing a series of continuous measures to provide a baseline for the process prior to the implementation of any changes and secondly to indicate the impact of the changes following implementation. The measures implemented included process (referrals numbers, percentage of patients offered a choice of appointments), outcome (percentage of patients seen within 6 weeks and the percentage failing to attend), and balancing measures (percentage declining the service or failing to respond). It was concluded that general tools of quality improvement can be used to good effect within specialist services. Good processes and accurate, reproducible and measurable data are essential. Small changes can have a major impact both on the quality of the service offered and the ability to deliver the service.
Assuntos
Serviços em Genética/organização & administração , Padrões de Prática Médica/normas , Garantia da Qualidade dos Cuidados de Saúde , Encaminhamento e Consulta , Serviços de Saúde Comunitária/normas , Atenção à Saúde , Aconselhamento Genético , Humanos , Avaliação de Resultados em Cuidados de Saúde , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Medicina Estatal , Fatores de Tempo , País de GalesRESUMO
It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.
Assuntos
Insuficiência Adrenal/congênito , Deleção Cromossômica , Mutação da Fase de Leitura , Haploinsuficiência , Síndromes Mielodisplásicas/genética , Proteínas/genética , Insuficiência Adrenal/genética , Insuficiência Adrenal/mortalidade , Cromossomos Humanos Par 7 , Estudos de Coortes , Mutação da Fase de Leitura/genética , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Síndromes Mielodisplásicas/mortalidadeRESUMO
The proximal promoter region of the human pituitary expressed growth hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Variação Genética , Haplótipos/genética , Hormônio do Crescimento Humano/genética , Região de Controle de Locus Gênico/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Adulto , Estatura/genética , Mapeamento Cromossômico/métodos , Mapeamento Cromossômico/estatística & dados numéricos , Ensaio de Desvio de Mobilidade Eletroforética/estatística & dados numéricos , Evolução Molecular , Frequência do Gene/genética , Transtornos do Crescimento/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Valor Preditivo dos Testes , Reino Unido/etnologia , População Branca/genéticaRESUMO
Subtle mutations in the growth hormone 1 (GH1) gene have been regarded as a comparatively rare cause of short stature. Such lesions were sought in a group of 41 individuals selected for short stature, reduced height velocity, and bone age delay; a group of 11 individuals with short stature and idiopathic growth hormone deficiency (IGHD); and a group of 154 controls. Heterozygous mutations were identified in all three groups but disproportionately in the individuals with short stature, both with (odds ratio 25.2; 95% CI, 5.1-132.2) and without (odds ratio 3.6; 95% CI, 1.0-12.9) IGHD. Twenty-four novel GH1 gene lesions were found. Thirteen novel missense mutations were characterized by assaying the signal transduction activity of in vitro expressed variants; six (T27I, K41R, N47D, S71F, S108R, and T175A) exhibited a reduced ability to activate the JAK/STAT pathway. Molecular modeling suggested that both K41R and T175A might compromise GH receptor binding. Seven GH variants (R16C, K41R, S71F, E74K, Q91L, S108C, and a functional polymorphism, V110I) manifested reduced secretion in rat pituitary cells after allowance had been made for the level of expression attributable to the associated GH1 proximal promoter haplotype. A further leader peptide variant (L-11P) was not secreted. Eleven novel mutations in the GH1 gene promoter were assessed by reporter gene assay but only two, including a GH2 gene-templated gene conversion, were found to be associated with a significantly reduced level of expression. Finally, a novel intron 2 acceptor splice-site mutation, detected in a family with autosomal dominant type II IGHD, was shown to lead to the skipping of exon 3 from the GH1 transcript. A total of 15 novel GH1 gene mutations were thus considered to be of probable phenotypic significance. Such lesions are more prevalent than previously recognized and although most may be insufficient on their own to account for the observed clinical phenotype, they are nevertheless likely to play a contributory role in the etiology of short stature.
Assuntos
Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Seleção de Pacientes , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Feminino , Variação Genética , Genótipo , Transtornos do Crescimento/etiologia , Haplótipos/genética , Hormônio do Crescimento Humano/fisiologia , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Fenótipo , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/fisiologia , Splicing de RNA/genética , Splicing de RNA/fisiologia , RNA Mensageiro/genética , População Branca/genéticaRESUMO
The pituitary-expressed GH1 gene was screened for mutation in a group of 74 children with familial short stature. Two novel mutations were identified: an Ile179Met substitution and a -360A-->G promoter variant. The Ile179Met variant was shown to exhibit a similar degree of resistance to proteolysis as wild-type GH, indicating that the introduction of Met does not cause significant misfolding. Secretion of Ile179Met GH from rat pituitary cells was also similar to that of wild type. Although receptor binding studies failed to show any difference in binding characteristics, molecular modeling studies suggested that the Ile179Met substitution might nevertheless perturb interactions between GH and the GH receptor loop containing the hotspot residue Trp169, thereby affecting signal transduction. The ability of the Ile179Met variant to activate a signal transducer and activator of transcription (STAT) 5-responsive luciferase reporter gene and induce phosphorylation of STAT 5 and ERK was therefore studied. In contrast to its ability to activate STAT 5 normally, activation of ERK by the Ile179Met variant was reduced to half that observed with wild type. Although differential effects on the activation of distinct signaling pathways by a mutant receptor agonist are unprecedented, these findings also suggest that the ERK pathway could play a role in mediating the action of GH.
Assuntos
Estatura/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Hormônio do Crescimento Humano/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Criança , Cristalografia por Raios X , Testes Genéticos , Transtornos do Crescimento/metabolismo , Hormônio do Crescimento Humano/química , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação Puntual , Regiões Promotoras Genéticas/genética , Estrutura Terciária de ProteínaRESUMO
An increased prevalence of both hypertension and cerebrovascular stroke is apparent in growth hormone (GH) deficiency whilst hypertension is a frequent complication in acromegaly. This has suggested a possible link between GH, stature and arterial function. Since the risk of both hypertension and stroke also appears to be inversely correlated with adult height, we have instigated an exploratory study to assess whether inter-individual variation in the genes encoding human growth hormone (GH1) and the GH receptor (GHR) might be associated with an increased risk of hypertension and stroke. GH1 promoter haplotypes were found to differ significantly not only between hypertensive patients (n = 111) and controls (n = 121) but also between stroke patients (n = 155) and controls (n = 158). Intriguingly, the association between GH1 promoter haplotype and risk of hypertension was much greater in females than in males. An inverse correlation between height and central systolic blood pressure was apparent in both hypertensive patients and normal controls but was much stronger in individuals carrying at least one GH1 promoter risk haplotype. The GH1 genotype therefore constitutes a risk factor for hypertension that interacts with stature. A strong association was found between the presence of at least one GH1 risk haplotype and a family history of stroke at an early age (odds ratio: 9.07, 95% confidence interval: 1.14-72.22). Three novel GH variants (Arg16His, Phe176Cys, Cys189Arg) were identified during the course of this study. Although two exhibited markedly reduced biological activity in vitro, their clinical significance remains unclear. No association was found between GHR genotype and either hypertension or stroke, nor was any interaction noted between GHR and GH1 genotypes in terms of a disease association. However, an association between GHRd3 genotype and hypertension was observed among stroke patients, particularly females. Elevated HDL was found to be a risk factor for hypertension in individuals lacking a copy of the GHRd3 allele. Weak associations with GHR genotype were also noted for peripheral systolic and diastolic blood pressure in hypertensive patients. Although the underlying mechanisms are still unclear, our findings are consistent with a complex relationship between height, hypertension, GH1 promoter haplotype, GHR polymorphism and the risk of stroke.