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1.
Biochemistry ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682116

RESUMO

The diversity of the cellular proteome substantially exceeds the number of genes coded by the DNA of an organism because one or more residues in a majority of eukaryotic proteins are post-translationally modified (PTM) by the covalent conjugation of specific chemical groups. We now know that PTMs alter protein conformation and function in ways that are not entirely understood at the molecular level. NMR spectroscopy has been particularly successful as an analytical tool in elucidating the themes underlying the structural role of PTMs. In this Perspective, we focus on the NMR-based characterization of three abundant PTMs: phosphorylation, acetylation, and glycosylation. We detail NMR methods that have found success in detecting these modifications at a site-specific level. We also highlight NMR studies that have mapped the conformational changes ensuing from these PTMs as well as evaluated their relation to function. The NMR toolbox is expanding rapidly with experiments available to probe not only the average structure of biomolecules but also how this structure changes with time on time scales ranging from picoseconds to seconds. The atomic resolution insights into the biomolecular structure, dynamics, and mechanism accessible from NMR spectroscopy ensure that NMR will continue to be at the forefront of research in the structural biology of PTMs.

2.
Genome Res ; 29(7): 1057-1066, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160375

RESUMO

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.

3.
Folia Phoniatr Logop ; : 1-9, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31132766

RESUMO

BACKGROUND: Recent models of speech production suggest a link between speech production and perception. Persons with stuttering are known to have deficits in sensorimotor timing and exhibit auditory processing problems. Most of the earlier studies have focused on assessing temporal ordering in adults who stutter (AWS), but limited attempts have been made to document temporal resolution abilities in AWS. METHODS: A group of 16 AWS and 16 age- and gender-matched adults who do not stutter (AWNS) were recruited for the study. Temporal resolution abilities were assessed using the Gap Detection Test and temporal modulation transfer function (TMTF). RESULTS: The results revealed significant differences in TMTF between AWS and AWNS, but no differences were found in the gap detection thresholds. CONCLUSIONS: Results suggest that the sensory representations of the temporal modulations are compromised in AWS, which may contribute to the programming of rhythmic movements during speech planning.

4.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
6.
Endocr Connect ; 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30694796

RESUMO

OBJECTIVE: Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare in children. A large proportion of these are now understood to be due to underlying germline mutations. Here we focus on SDHB gene mutations carriers as these tumours carry a high risk of malignant transformation. There remains no current consensus with respect to optimal surveillance for asymptomatic carriers and those in whom the presenting tumour has been resected. METHOD: We undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed-up in a single UK tertiary referral centre. This included index cases that pre-dated the introduction of surveillance screening and asymptomatic carriers identified through cascade genetic testing. We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations. RESULTS: Clinical outcomes of a total of 38 children are presented: 8 index cases and 30 mutation positive asymptomatic carriers with 175 patient years of follow-up data . Three of the eight index cases developed metachronous disease and two developed metastatic disease. Of the 30 asymptomatic carriers, 3 were found to have PGLs on surveillance screening. CONCLUSIONS: Surveillance screening was well tolerated in our paediatric cohort and asymptomatic paediatric subjects. Screening can identify tumours before they become secretory and/or symptomatic, thereby facilitating surgical resection and reducing the chance of distant spread. We propose a regular screening protocol commencing at age 5 years in this at-risk cohort of patients.

7.
Am J Hum Genet ; 103(1): 3-18, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29909963

RESUMO

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

8.
Wellcome Open Res ; 3: 46, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900417

RESUMO

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS.

9.
Int J Endocrinol ; 2018: 8581626, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849625

RESUMO

Introduction: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations are responsible for 15-30% of familial isolated pituitary adenomas (FIPAs). We report a FIPA kindred with a heterozygous deletion in AIP, aiming to highlight the indications and benefits of genetic screening, variability in clinical presentations, and management challenges in this setting. Patients: An 18-year-old male was diagnosed with a clinically nonfunctioning pituitary adenoma (NFPA). Two years later, his brother was diagnosed with a somatolactotrophinoma, and a small Rathke's cleft cyst and a microadenoma were detected on screening in their 17-year-old sister. Following amenorrhoea, their maternal cousin was diagnosed with hyperprolactinaemia and two distinct pituitary microadenomas. A 12-year-old niece developed headache and her MRI showed a microadenoma, not seen on a pituitary MRI scan 3 years earlier. Discussion: Out of the 14 members harbouring germline AIP mutations in this kindred, 5 have pituitary adenoma. Affected members had different features and courses of disease. Bulky pituitary and not fully suppressed GH on OGTT can be challenging in the evaluation of females in teenage years. Multiple pituitary adenomas with different secretory profiles may arise in the pituitary of these patients. Small, stable NFPAs can be present in mutation carriers, similar to incidentalomas in the general population. Genetic screening and baseline review, with follow-up of younger subjects, are recommended in AIP mutation-positive families.

11.
Oman J Ophthalmol ; 11(1): 78-81, 2018 Jan-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29563705

RESUMO

To discuss diagnostic strategies and management options in cases with suspected valsalva maculopathy (VM), to optimize visual outcome. We describe six cases with suspected VM. The preretinal hemorrhage resolved spontaneously in four out of six patients, without any intervention. One patient underwent neodymium-doped yttrium aluminum garnet hyaloidotomy and the other proceeded to have a vitrectomy for persistent diffuse vitreous hemorrhage. Considering the evidence available and the outcomes of our patients, we have devised a treatment algorithm for treating VM, which is elaborated in this article.

12.
Am J Med Genet A ; 176(4): 925-935, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436146

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

13.
Neurology ; 90(1): e55-e66, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29196579

RESUMO

OBJECTIVE: To characterize the phenotypic spectrum, molecular genetic findings, and functional consequences of pathogenic variants in early-onset KCNT1 epilepsy. METHODS: We identified a cohort of 31 patients with epilepsy of infancy with migrating focal seizures (EIMFS) and screened for variants in KCNT1 using direct Sanger sequencing, a multiple-gene next-generation sequencing panel, and whole-exome sequencing. Additional patients with non-EIMFS early-onset epilepsy in whom we identified KCNT1 variants on local diagnostic multiple gene panel testing were also included. When possible, we performed homology modeling to predict the putative effects of variants on protein structure and function. We undertook electrophysiologic assessment of mutant KCNT1 channels in a xenopus oocyte model system. RESULTS: We identified pathogenic variants in KCNT1 in 12 patients, 4 of which are novel. Most variants occurred de novo. Ten patients had a clinical diagnosis of EIMFS, and the other 2 presented with early-onset severe nocturnal frontal lobe seizures. Three patients had a trial of quinidine with good clinical response in 1 patient. Computational modeling analysis implicates abnormal pore function (F346L) and impaired tetramer formation (F502V) as putative disease mechanisms. All evaluated KCNT1 variants resulted in marked gain of function with significantly increased channel amplitude and variable blockade by quinidine. CONCLUSIONS: Gain-of-function KCNT1 pathogenic variants cause a spectrum of severe focal epilepsies with onset in early infancy. Currently, genotype-phenotype correlations are unclear, although clinical outcome is poor for the majority of cases. Further elucidation of disease mechanisms may facilitate the development of targeted treatments, much needed for this pharmacoresistant genetic epilepsy.

14.
Mol Genet Genomic Med ; 5(5): 608-613, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28944244

RESUMO

BACKGROUND: Microdeletions of 2q23.1 disrupting MBD5 and loss of function mutations of MBD5 cause MBD5-Associated Neurodevelopmental disorders (MAND). Nearly all reported patients have been isolated cases of de novo origin. METHODS: This study investigates three families with inherited MBD5 mutations from three different Regional Genetics Centres in the UK. RESULTS: Two of the parents in the study had MBD5 deletions in a mosaic form. The parent with an MBD5 deletion in an apparently nonmosaic form has a psychiatric disorder in the absence of developmental delay or dysmorphism. CONCLUSIONS: Inherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought.

15.
J Int Adv Otol ; 13(1): 83-87, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28555599

RESUMO

OBJECTIVE: The study investigated the effect of noise on syllable perception in individuals with Auditory Neuropathy Spectrum Disorder (ANSD) and compared that with the normal hearing individuals. MATERIALS AND METHODS: A total of 54 participants were considered, out of which 26 individuals were diagnosed with ANSD and 28 with normal hearing sensitivity. Syllable identification and discrimination were assessed in both the groups in quiet as well as +10 dB SNR. RESULTS: All the individuals with ANSD performed poorer on syllable identification and syllable discrimination tasks compared to individuals with normal hearing. Information transfer and d-prime analyses revealed that noise affects the perception of voicing information in individuals with ANSD compared to place and manner information. Among the consonants tested, /pa/ was more resistant to noise. CONCLUSION: Noise had deleterious effects on speech perception in individuals with ANSD. Low-frequency information appears to be more susceptible to the effects of noise in individuals with ANSD.


Assuntos
Limiar Auditivo , Potenciais Evocados Auditivos , Perda Auditiva Central/diagnóstico , Ruído , Percepção da Fala , Adulto , Estudos de Casos e Controles , Feminino , Perda Auditiva Central/reabilitação , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença
16.
J Int Adv Otol ; 13(1): 118-127, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28555603

RESUMO

OBJECTIVE: Localization involves processing of subtle yet highly enriched monaural and binaural spatial cues. Remediation programs aimed at resolving spatial deficits are surprisingly scanty in literature. The present study is designed to explore the changes that occur in the spatial performance of normal-hearing listeners before and after subjecting them to virtual acoustic space (VAS) training paradigm using behavioral and electrophysiological measures. MATERIALS AND METHODS: Ten normal-hearing listeners participated in the study, which was conducted in three phases, including a pre-training, training, and post-training phase. At the pre- and post-training phases both behavioral measures of spatial acuity and electrophysiological P300 were administered. The spatial acuity of the participants in the free field and closed field were measured apart from quantifying their binaural processing abilities. The training phase consisted of 5-8 sessions (20 min each) carried out using a hierarchy of graded VAS stimuli. RESULTS: The results obtained from descriptive statistics were indicative of an improvement in all the spatial acuity measures in the post-training phase. Statistically, significant changes were noted in interaural time difference (ITD) and virtual acoustic space identification scores measured in the post-training phase. Effect sizes (r) for all of these measures were substantially large, indicating the clinical relevance of these measures in documenting the impact of training. However, the same was not reflected in P300. CONCLUSION: The training protocol used in the present study on a preliminary basis proves to be effective in normal-hearing listeners, and its implications can be extended to other clinical population as well.


Assuntos
Testes de Impedância Acústica , Percepção Auditiva , Audição , Processamento Espacial , Testes de Impedância Acústica/métodos , Adulto , Limiar Auditivo , Feminino , Voluntários Saudáveis , Humanos , Masculino
18.
Ambio ; 46(5): 613-620, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28247341

RESUMO

The relative impacts of hunting and habitat on waterbird community were studied in agricultural wetlands of southern India. We surveyed wetlands to document waterbird community, and interviewed hunters to document hunting intensity, targeted species, and the motivations for hunting. Our results show that hunting leads to drastic declines in waterbird diversity and numbers, and skew the community towards smaller species. Hunting intensity, water spread, and vegetation cover were the three most important determinants of waterbird abundance and community structure. Species richness, density of piscivorous species, and medium-sized species (31-65 cm) were most affected by hunting. Out of 53 species recorded, 47 were hunted, with a preference for larger birds. Although illegal, hunting has increased in recent years and is driven by market demand. This challenges the widely held belief that waterbird hunting in India is a low intensity, subsistence activity, and undermines the importance of agricultural wetlands in waterbird conservation.


Assuntos
Aves , Ecossistema , Áreas Alagadas , Animais , Conservação dos Recursos Naturais , Índia
19.
Clin Endocrinol (Oxf) ; 86(2): 286-296, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27678251

RESUMO

OBJECTIVE: For 'asymptomatic carriers' of the succinate dehydrogenase subunit B (SDHB) gene mutations, there is currently no consensus as to the appropriate modality or frequency of surveillance imaging. We present the results of a surveillance programme of SDHB mutation carriers. DESIGN: Review of clinical outcomes of a surveillance regimen in patients identified to have an SDHB gene mutation, based on annual MRI, in a single UK tertiary referral centre. PATIENTS: A total of 92 patients were identified with an SDHB gene mutation. a total of 27 index patients presented with symptoms, and 65 patients were identified as asymptomatic carriers. MEASUREMENTS: Annual MRI of the abdomen, with alternate year MRI of the neck, thorax and pelvis. Presence of an SDHB-related tumour included paraganglioma (PGL), phaeochromocytoma (PCC), renal cell carcinoma (RCC) and gastrointestinal stromal tumour (GIST). RESULTS: A total of 43 PGLs, eight PCCs and one RCC occurred in the 27 index patients (23 solitary, four synchronous, five metachronous). A further 15 SDHB-related tumours (11 PGLs, three RCCs, one GIST) were identified in the asymptomatic carriers on surveillance screening (25% of screened carriers): 10 on the first surveillance imaging and five on subsequent imaging 2-6 years later. A total of 11 patients had malignant disease. CONCLUSIONS: SDHB-related tumours are picked up as early as 2 years after initial negative surveillance scan. We believe the high malignancy rate and early identification rate of tumours justifies the use of 1-2 yearly imaging protocols and MRI-based imaging could form the mainstay of surveillance in this patient group thereby minimizing radiation exposure.


Assuntos
Monitoramento Epidemiológico , Heterozigoto , Mutação , Succinato Desidrogenase/genética , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/patologia , Reino Unido/epidemiologia , Adulto Jovem
20.
Hum Mutat ; 38(1): 78-85, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27650164

RESUMO

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.


Assuntos
Acromegalia/epidemiologia , Acromegalia/genética , Predisposição Genética para Doença , Gigantismo/epidemiologia , Gigantismo/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Acromegalia/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Mapeamento Cromossômico , Estudos Transversais , Feminino , Frequência do Gene , Genótipo , Gigantismo/diagnóstico , Heterozigoto , Humanos , Irlanda/epidemiologia , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Fenótipo , Risco , Adulto Jovem
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