RESUMO
Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.
Assuntos
Bancos de Espécimes Biológicos , Genética Médica , Genoma Humano , Genômica , Hispânico ou Latino , Humanos , Glicemia/genética , Glicemia/metabolismo , Estatura/genética , Índice de Massa Corporal , Interação Gene-Ambiente , Marcadores Genéticos/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/classificação , Hispânico ou Latino/genética , Homozigoto , México , Fenótipo , Triglicerídeos/sangue , Triglicerídeos/genética , Reino Unido , Genoma Humano/genéticaRESUMO
INTRODUCTION: Isolated SHOX haploinsufficiency is a common monogenic cause of short stature. Few studies compare untreated and rhGH-treated patients up to adult height (AH). Our study highlights a growth pattern from childhood to AH in patients with SHOX haploinsufficiency and analyzes the real-world effectiveness of rhGH alone or plus GnRH analog (GnRHa). METHODS: Forty-seven patients (18 untreated and 29 rhGH-treated) with SHOX haploinsufficiency were included in a longitudinal retrospective study. Adult height was attained in 13 untreated and 18 rhGH-treated (rhGH alone [n = 8] or plus GnRHa [n = 10]) patients. RESULTS: The untreated group decreased height SDS from baseline to AH (-0.8 [-1.1; -0.4]), with an increase in the prevalence of short stature from 31% to 77%. Conversely, the rhGH-treated group had an improvement in height SDS from baseline to AH (0.6 [0.2; 0.6]; p < 0.001), with a reduction in the prevalence of short stature (from 61% to 28%). AH in the rhGH-treated patients was 1 SD (6.3 cm) taller than in untreated ones. Regarding the use of GnRHa, the subgroups (rhGH alone or plus GnRHa) attained similar AH, despite the higher prevalence of pubertal patients and worse AH prediction at the start of rhGH treatment in patients who used combined therapy. CONCLUSION: The use of rhGH treatment improves AH in patients with SHOX haploinsufficiency, preventing the loss of height potential during puberty. In peripubertal patients, the addition of GnRHa to rhGH allows AH attainment similar to the AH of patients who start rhGH alone in the prepubertal age.
Assuntos
Estatura , Nanismo , Hormônio do Crescimento Humano , Proteína de Homoeobox de Baixa Estatura , Adulto , Estatura/genética , Criança , Nanismo/tratamento farmacológico , Hormônio Liberador de Gonadotropina , Haploinsuficiência , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Estudos Retrospectivos , Proteína de Homoeobox de Baixa Estatura/genéticaRESUMO
Treatment with recombinant growth hormone, or somatropin, increases linear growth and is effective in improving final height in children with isolated growth hormone deficiency (IGHD), however, the available information of these results in the Latin population is scarce. OBJECTIVE: To evaluate the effect of somatropin on growth velocity and final height in Mexican children with IGHD, as well as to determine the factors associated with final height. PATIENTS AND METHOD: A retrospective study was conducted in 50 children with isolated and severe growth hormone deficiency treated with somatro pin. Auxological characteristics were assessed before somatropin and at final height. Only patients with severe GH deficiency, with a peak GH value < 5 µg/L, were included. RESULTS: 40% (n = 20) were girls. The basal height Z-score was -2.6 ± 0.4 vs final height Z-score 1.6 ± 0.7, with a Z-score of height in crease of 1 ± 0.6. Ninety-two percent (n = 46) reached their genetic potential; somatropin dose was 33 ± 0.5 µg/kg/d, with a treatment duration of 4.16 ± 1.5 years. The highest growth velocity was observed during the first year. In the multivariate analysis, the association between final height, mid-parental target height (r = 0.30; p = 0.03, ß = 0.7; p = 0.001), and somatropin dose (r = 0.63; p = 0.001, ß = 0.30; p = 0.028) was observed. CONCLUSIONS: Somatropin treatment allows normalization of linear growth and the achievement of genetic height potential in most Mexican children with IGHD. Final height is associated with mid-parental height and somatropin dose, highlighting the importance of genetic potential and the dose-response effect of somatropin in establishing height prognosis.
Assuntos
Nanismo Hipofisário , Hormônio do Crescimento Humano , Criança , Feminino , Humanos , Masculino , Estatura/genética , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento Humano/farmacologia , Estudos RetrospectivosRESUMO
Covariance components were estimated for growth traits (BW, birth weight; WW, weaning weight; YW, yearling weight), visual scores (BQ, breed quality; CS, conformation; MS, muscling; NS, navel; PS, finishing precocity), hip height (HH), and carcass traits (BF, backfat thickness; LMA, longissimus muscle area) measured at yearling. Genetic gains were obtained and validation models on direct and maternal effects for BW and WW were fitted. Genetic correlations of growth traits with CS, PS, MS, and HH ranged from 0.20 ± 0.01 to 0.94 ± 0.01 and were positive and low with NS (0.11 ± 0.01 to 0.20 ± 0.01) and favorable with BQ (0.14 ± 0.02 to 0.37 ± 0.02). Null to moderate genetic correlations were obtained between growth and carcass traits. Genetic gains were positive and significant, except for BW. An increase of 0.76 and 0.72 kg is expected for BW and WW, respectively, per unit increase in estimated breeding value (EBV) for direct effect and an additional 0.74 and 1.43, respectively, kg per unit increase in EBV for the maternal effect. Monitoring genetic gains for HH and NS is relevant to maintain an adequate body size and a navel morphological correction, if necessary. Simultaneous selection for growth, morphological, and carcass traits in line with improve maternal performance is a feasible strategy to increase herd productivity.
Assuntos
Peso ao Nascer/genética , Constituição Corporal/genética , Estatura/genética , Bovinos/crescimento & desenvolvimento , Bovinos/genética , Estudos de Associação Genética/veterinária , Característica Quantitativa Herdável , Animais , Cruzamento , Feminino , Humanos , Masculino , Herança Materna/genética , FenótipoRESUMO
Puberty is a complex developmental process that varies considerably among individuals and populations. Genetic factors explain a large proportion of the variability of several pubertal traits. Recent genome-wide association studies (GWAS) have identified hundreds of variants involved in traits that result from body growth, like adult height. However, they do not capture many genetic loci involved in growth changes over distinct growth phases. Further, such GWAS have been mostly performed in Europeans, but it is unknown how these findings relate to other continental populations. In this study, we analyzed the genetic basis of three pubertal traits; namely, peak height velocity (PV), age at PV (APV) and height at APV (HAPV). We analyzed a cohort of 904 admixed Chilean children and adolescents with European and Mapuche Native American ancestries. Height was measured on roughly a [Formula: see text]month basis from childhood to adolescence between 2006 and 2019. We predict that, in average, HAPV is 4.3 cm higher in European than in Mapuche adolescents (P = 0.042), and APV is 0.73 years later in European compared with Mapuche adolescents (P = 0.023). Further, by performing a GWAS on 774, 433 single-nucleotide polymorphisms, we identified a genetic signal harboring 3 linked variants significantly associated with PV in boys (P [Formula: see text]). This signal has never been associated with growth-related traits.
Assuntos
Indígenas Sul-Americanos/genética , Puberdade/genética , Adolescente , Desenvolvimento do Adolescente , Adulto , Envelhecimento/genética , Estatura/genética , Chile , Estudos de Coortes , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , População Branca/genéticaRESUMO
Growth is the task of children. We review the normal process of linear growth from the fetus through adolescence and note that growth is the result of age- and gender-dependent interactions among key genetic, environmental, dietary, socioeconomic, developmental, behavioral, nutritional, metabolic, biochemical, and hormonal factors. We then define the wide range of normative data at each stage of growth and note that a pattern within this range is generally indicative of good general health and that growth significantly slower than this range may lead to growth faltering and subsequent short stature. Although not often emphasized, we detail how to properly measure infants and children because height velocity is usually determined from two height measurements (both relatively large values) to calculate the actual height velocity (a relatively much smaller number in comparison). Traditionally the physiology of growth has been taught from an endocrine-centric point-of-view. Here we review the hypothalamic-pituitary-end organ axes for the GH/IGF-1 and gonadal steroid hormones (hypothalamic-pituitary-gonadal axis), both during "mini"-puberty as well as at puberty. However, over the past few decades much more emphasis has been placed on the growth plate and its many interactions with the endocrine system but also with its own intrinsic physiology and gene mutations. These latter, whether individually (large effect size) or in combination with many others including endocrine system-based, may account in toto for meaningful differences in adult height. The clinical assessment of children with short stature includes medical, social and family history, physical exam and importantly proper interpretation of the growth curve. This analysis should lead to judicious use of screening laboratory and imaging tests depending on the pre-test probability (Bayesian inference) of a particular diagnosis in that child. In particular for those with no pathological features in the history and physical exam and a low, but normal height velocity, may lead only to a bone age exam and reevaluation (re-measurement), perhaps 6 months later. he next step depends on the comfort level of the primary care physician, the patient, and the parent; that is, whether to continue with the evaluation with more directed, more sophisticated testing, again based on Bayesian inference or to seek consultation with a subspecialist pediatrician based on the data obtained. This is not necessarily an endocrinologist. The newest area and the one most in flux is the role for genetic testing, given that growth is a complex process with large effect size for single genes but smaller effect sizes for multiple other genes which in the aggregate may be relevant to attained adult height. Genetics is a discipline that is rapidly changing, especially as the cost of exome or whole gene sequencing diminishes sharply. Within a decade it is quite likely that a genetic approach to the evaluation of children with short stature will become the standard, truncating the diagnostic odyssey and be cost effective as fewer biochemical and imaging studies are required to make a proper diagnosis.
Assuntos
Transtornos do Crescimento/diagnóstico , Crescimento/fisiologia , Adolescente , Determinação da Idade pelo Esqueleto/métodos , Teorema de Bayes , Estatura/genética , Estatura/fisiologia , Criança , Pré-Escolar , Feminino , Interação Gene-Ambiente , Testes Genéticos/tendências , Crescimento/genética , Transtornos do Crescimento/etiologia , Hormônio do Crescimento/metabolismo , Lâmina de Crescimento/fisiologia , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Lactente , Recém-Nascido , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Anamnese , Exame Físico , Puberdade/fisiologia , Fatores SexuaisRESUMO
Acid-labile subunit (ALS) deficiency (ACLSD) constitutes the first monogenic defect involving a member of the Insulin-like Growth Factor (IGF) binding protein system. The lack of ALS completely disrupts the circulating IGF system. Autocrine/paracrine action of local produced IGF-I could explain the mild effect on growth. In the present work we have revised the more relevant clinical and biochemical consequences of complete ACLSD in 61 reported subjects from 31 families. Low birth weight and/or length, reduced head circumference, height between -2 and -3 SD, pubertal delay and insulin resistance are commonly observed. Partial ACLSD could be present in children initially labeled as idiopathic short stature, presenting low IGF-I levels, suggesting that one functional IGFALS allele is insufficient to stabilize ternary complexes. Dysfunction of the GH-IGF axis observed in ACLSD may eventually result in increased risk for type-2 diabetes and tumor progression. Consequently, long term surveillance is recommended in these patients.
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Proteínas de Transporte/fisiologia , Glicoproteínas/fisiologia , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Estatura/efeitos dos fármacos , Estatura/genética , Proteínas de Transporte/genética , Proteínas de Transporte/farmacologia , Criança , Feminino , Glicoproteínas/deficiência , Glicoproteínas/genética , Glicoproteínas/farmacologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Masculino , Puberdade Tardia/genética , Puberdade Tardia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.
Assuntos
Estatura/genética , Fibrilina-1/genética , Mutação de Sentido Incorreto , Seleção Genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Indígenas Sul-Americanos/genética , Masculino , Microfibrilas/química , Microfibrilas/genética , PeruRESUMO
CONTEXT: Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach. OBJECTIVE: To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder. DESIGN: Screening by karyotype (n = 42), chromosome microarray analyses (CMA) (n = 16), MS-MLPA (n = 2) targeted panel (n = 12) and whole-exome sequencing (n = 31). PATIENTS AND METHODS: We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups. MAIN OUTCOME MEASURES: Frequencies of pathogenic findings. RESULTS: We identified two patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith-Wiedemann syndrome by targeted MS-MLPA analysis and nine cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1, MC4R = 1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients. CONCLUSION: A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.
Assuntos
Gigantismo/genética , Transtornos do Crescimento/genética , Adolescente , Adulto , Estatura/genética , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Heterozigoto , Humanos , Cariótipo , Cariotipagem , Pessoa de Meia-Idade , Estudos Prospectivos , Proteína de Homoeobox de Baixa Estatura/genética , Sequenciamento do Exoma/métodos , Adulto JovemRESUMO
Short stature is a common feature, and frequently remains without a specific diagnosis after conventional clinical and laboratorial evaluation. Longitudinal growth is mainly determined by genetic factors, and hundreds of common variants have been associated to height variability among healthy individuals. Although isolated short stature may be caused by the combination of variants, with a deleterious impact on the growth of individuals with polygenic inheritance, recent studies have pointed out some monogenic defects as the cause of the growth disorder observed in nonsyndromic children. The majority of these defects are in genes related to the growth plate cartilage and in the growth hormone (GH) - insulin-like growth factor 1 (IGF-1) axis. Affected patients usually present the mildest spectrum of some forms of skeletal dysplasia, or subtle abnormalities of laboratory tests, suggesting hormonal resistance or insensibility. The lack of specific characteristics, however, does not allow formulation of a definitive diagnosis without the use of broad genetic studies. Thus, molecular genetic studies including panels of genes or exome analysis will become essential in investigating and identifying the causes of isolated short stature in children, with a crucial impact on treatment and follow-up.