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1.
Mol Genet Genomic Med ; 10(4): e1901, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35235708

RESUMO

OBJECTIVE: Craniosynostosis is the result of the early fusion of cranial sutures. Syndromic craniosynostosis includes but not limited by Crouzon syndrome and Pfeiffer syndrome. Considerable phenotypic overlap exists among these syndromes and mutations in FGFR2 may cause different syndromes. This study aims to investigate the explanation of the phenotypic variability via clinical and genetic evaluation for eight patients in a large pedigree. METHODS: For each patient, comprehensive physical examination, cranial plain CT scan with three-dimensional CT reconstruction (3D-CT), and eye examinations were conducted. Whole exome sequencing was applied for genetic diagnosis of the proband. Variants were analyzed and interpreted following the ACMG/AMP guidelines. Sanger sequencing was performed to reveal genotypes of all the family members. RESULTS: A pathogenic variant in the FGFR2 gene, c.833G > T (p.C278F), was identified and proved to be co-segregate with the disease. Some symptoms of head, hearing, vision, mouth, teeth expressed differently by affected individuals. Nonetheless, all the eight patients manifested core symptoms of Crouzon syndrome without abnormality in the limbs, which could exclude diagnosis of Pfeiffer syndrome. CONCLUSION: We have established clinical and genetic diagnosis of Crouzon syndrome for eight patients in a five-generation Chinese family. Variability of clinical features among these familial patients was slighter than that in previously reported sporadic cases.


Assuntos
Acrocefalossindactilia , Disostose Craniofacial , Craniossinostoses , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Acrocefalossindactilia/genética , Variação Biológica da População , Disostose Craniofacial/genética , Craniossinostoses/genética , Humanos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Síndrome
2.
Orphanet J Rare Dis ; 17(1): 139, 2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35346302

RESUMO

BACKGROUND: Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities. RESULTS: From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700). CONCLUSIONS: This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.


Assuntos
Neurofibromatose 1 , Osteogênese Imperfeita , Diagnóstico Duplo (Psiquiatria) , Humanos , Osteogênese Imperfeita/genética , Fenótipo , Sequenciamento Completo do Exoma
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(11): 1051-1054, 2021 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-34729741

RESUMO

OBJECTIVE: To analyze the metabolic profile and genetic variants for newborns with primary carnitine deficiency (PCD) from Guangxi, China. METHODS: From January 2014 to December 2019, 400 575 newborns from the jurisdiction of Guangxi Zhuang Autonomous Region Newborn Screening Center were subjected to tandem mass spectrometry (MS/MS) analysis. Newborns with positive results for PCD and their mothers were recalled for retesting. Those who were still positive were subjected to sequencing of the SLC22A5 gene. RESULTS: Twenty-two newborns and 9 mothers were diagnosed with PCD, which gave a prevalence rate of 1/18 208. Sequencing of 18 newborns and 4 mothers have identified 14 types of SLC22A5 gene variants, with the common ones including c.51C>G (10/44, 22.7%), c.1195C>T (9/44, 20.5%) and c.1400C>G (7/44, 15.9%), The c.517delC(p.L173Cfs*3) and c.1031C>T(p.T344I) were unreported previously and predicted to be pathogenic (PVS1+PM2_supporting+PM3+PP4) and likely pathogenic (PM1+PM2_supporting+PM3+PP3+PP4) based on the American College of Medical Genetics and Genomics standards and guidelines. CONCLUSION: c.51C>G, c.1195C>T and c.1400C>G are the most common variants underlying PCD in Guangxi.


Assuntos
Metaboloma , Espectrometria de Massas em Tandem , Cardiomiopatias , Carnitina/deficiência , China , Humanos , Hiperamonemia , Recém-Nascido , Doenças Musculares , Mutação , Membro 5 da Família 22 de Carreadores de Soluto/genética
4.
JAMA Netw Open ; 4(10): e2131040, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34698846

RESUMO

Importance: Obesity is a public health challenge in China, but the geographical profiles of overweight and obesity among Chinese children are limited. Objective: To examine regional disparities in the prevalence of obesity among the heterogeneous population of Chinese children and adolescents to provide a more accurate profile of obesity among children in China. Design, Setting, and Participants: The Prevalence and Risk Factors for Obesity and Diabetes in Youth (PRODY) study was a cross-sectional survey study conducted from January 1, 2017, to December 31, 2019, among 201 098 children aged 3 to 18 years from 11 provinces, autonomous regions, and municipalities that produced a sample of Chinese children with a full range of ages and wide geographical coverage using a multistage, stratified, cluster-sampling design. Exposures: Five regions geographically representative of China (northern, eastern, southern, western, and central). Main Outcomes and Measures: The body weights and heights of all participants were measured. Multilevel, multinomial logistic regression models were used to estimate the prevalence of overweight and obesity. Results: Among 201 098 healthy children (105 875 boys [52.6%]; mean [SD] age, 9.8 [3.8] years) from eastern, southern, northern, central, and western China, the highest obesity prevalence was estimated for children aged 8 to 13 years in northern China (from 18.8% [95% CI, 16.2%-21.7%] to 23.6% [95% CI, 20.5%-26.9%]) and for boys aged 3 to 6 years in western China (from 18.1% [95% CI, 10.4%-29.4%] to 28.6% [95% CI, 14.3%-49.0%]). Boys had a higher prevalence than girls of obesity only in eastern and northern China, with a mean difference in prevalence of 4.6% (95% CI, 3.8%-5.4%) and 7.6% (95% CI, 6.5%-8.6%), respectively. Conclusions and Relevance: In this survey study, substantial geographic disparities in the prevalence of obesity and overweight were found among the heterogeneous population of Chinese children. The results suggest that special attention should be paid to vulnerable children and that regionally adapted interventions are needed to efficiently mitigate obesity in children.


Assuntos
Disparidades nos Níveis de Saúde , Obesidade Pediátrica/epidemiologia , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino
5.
Front Endocrinol (Lausanne) ; 12: 711991, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34589056

RESUMO

Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis. Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis. Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients. Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.


Assuntos
Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Sequenciamento Completo do Exoma , Criança , Pré-Escolar , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , DNA/sangue , Análise Mutacional de DNA , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Proteínas com Homeodomínio LIM/genética , Masculino , RNA Polimerase III/genética , Proteínas Repressoras/genética , Estudos Retrospectivos , Fatores de Transcrição/genética
6.
Front Endocrinol (Lausanne) ; 12: 583114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211433

RESUMO

Purpose: To investigate the features and treatment status of children with type 1 diabetes mellitus (T1DM) in China. Methods: We recruited patients <14 years of age with T1DM from 33 medical centers in 25 major cities of China between January 2012 and March 2015. All patients completed a questionnaire that was conducted by their pediatric endocrinologists at all centers. Results: A total of 1,603 children (755 males and 848 females) with T1DM participated in this survey. Of these, 834 (52.03%) of the patients exhibited diabetic ketoacidosis (DKA) at onset, while 769 patients (47.97%) did not exhibit DKA (non-DKA) at onset. There was a higher proportion of females (55.71%) in the cohort of patients exhibiting DKA at onset than in the non-DKA cohort (49.33%). The mean age of patients exhibiting DKA at presentation was 7.12 ± 0.14 years; this was significantly younger than that in non-DKA group (7.79 ± 0.15 years; P < 0.005). The frequency of DKA in 3 years old, 3-7 years old, and 7 years old or more was 77.21%, 26.17%, and 37.62%, respectively. Upon initial diagnosis, 29.4%, 15.2% and 11.8% of patients showed positivity for glutamic acid decarboxylase antibody (GADA), Insulin autoantibodies (IAA), or islet cell antibody (ICA), respectively. During six months follow-up, 244 patients (15.21%) reported receiving insulin pump therapy, and more than 60% of patients monitored their blood glucose levels less than 35 times per week. Although the majority of patients had no problems with obtaining insulin, 4.74% of the children surveyed were not able to receive insulin due to financial reasons, a shortage of insulin preparations, or the failure of the parents or guardians to acquire the appropriate medicine. Conclusion: DKA is more common in very young children. Treatment and follow-up of T1DM in China still face very serious challenges.


Assuntos
Glicemia , Diabetes Mellitus Tipo 1/diagnóstico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adolescente , Criança , Pré-Escolar , China , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/sangue , Cetoacidose Diabética/diagnóstico , Feminino , Humanos , Sistemas de Infusão de Insulina , Masculino , Resultado do Tratamento
7.
J Genet Genomics ; 48(5): 396-402, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34006472

RESUMO

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing (ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group (group I, n = 257) and an apparently syndromic short stature group (group II, n = 304). Causal variants were identified in 135 of 561 (24.1%) patients. In group I, 29 of 257 (11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304 (34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellular process played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.


Assuntos
Nanismo/diagnóstico , Nanismo/genética , Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Sequenciamento Completo do Exoma , Adolescente , Alelos , Criança , Pré-Escolar , China , Variações do Número de Cópias de DNA , Gerenciamento Clínico , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Genótipo , Humanos , Masculino , Mutação , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Síndrome
8.
Front Cell Dev Biol ; 9: 661747, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937263

RESUMO

PURPOSE: ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of ROR2 in children with short stature and to identify the underlying molecular mechanisms. METHODS: We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of ROR2. We subsequently examined the changes in protein expression and subcellular location in ROR2 caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a-ROR2 pathway was also examined. RESULTS: We identified 12 mutations in ROR2 in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments in vitro. The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2. CONCLUSION: We expanded the mutational spectrum of ROR2 in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in ROR2 might affect the expression of downstream Wnt5a-ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.

9.
Front Endocrinol (Lausanne) ; 12: 603277, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935963

RESUMO

Aims: Findings from previous studies about the association of preterm birth as well as birth weight with the risk of T1DM were still inconsistent. We aimed to further clarify these associations based on Chinese children and explore the role of gender therein. Methods: A nationwide multicenter and population-based large cross-sectional study was conducted in China from 2017 to 2019. Children aged between 3 and 18 years old with complete information were included in this analysis. Multiple Poisson regression models were used for evaluating the associations of birth weight as well as preterm birth with T1DM in children. Results: Out of 181,786 children, 82 childhood T1DM cases were identified from questionnaire survey. Children with preterm birth (<37 weeks) had higher risk of type 1 diabetes (OR: 3.17, 95%CI: 1.76-5.71). Children born with high birth weight (≥4,000g) had no statistically significant risk of T1DM (OR:1.71, 95%CI: 0.90-3.22). However, children's gender might modify the effect of high birth weight on T1DM (girls: OR: 3.15, 95%CI: 1.33-7.47; boys: OR: 0.99, 95%CI: 0.38-2.55, p for interaction=0.065). In addition, children with low birth weight were not associated with T1DM (OR: 0.70, 95%CI: 0.24-2.08). The findings from matched data had the similar trend. Conclusions: In China mainland, preterm birth increased the risk of childhood T1DM, but high birth weight only affected girls. Therefore, early prevention of T1DM may start with prenatal care to avoid adverse birth outcomes and more attention should be paid to children with preterm birth and girls with high birth weight after birth.


Assuntos
Peso ao Nascer/fisiologia , Diabetes Mellitus Tipo 1/epidemiologia , Nascimento Prematuro/epidemiologia , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 1/etiologia , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Fatores de Risco
10.
Chin Med J (Engl) ; 134(10): 1152-1159, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33813517

RESUMO

BACKGROUND: Compared to adult studies, studies which involve the treatment of pediatric congenital hypogonadotropic hypogonadism (CHH) are limited and no universal treatment regimen is available. The aim of this study was to evaluate the feasibility of human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) therapy for treating male adolescents with CHH. METHODS: Male adolescent CHH patients were treated with hCG/hMG (n = 20) or a gonadotropin-releasing hormone (GnRH) pump (n = 21). The treatment was divided into a study phase (0-3 months) and a follow-up phase (3-12 months). The testicular volume (TV), penile length (PL), penis diameter (PD), and sex hormone levels were compared between the two groups. The TV and other indicators between the groups were analyzed using a t-test (equal variance) or a rank sum test (unequal variance). RESULTS: Before treatment, there was no statistical difference between the two groups in terms of the biochemistry, hormones, and other demographic indicators. After 3 months of treatment, the TV of the hCG/hMG and GnRH groups increased to 5.1 ±â€Š2.3 mL and 4.1 ±â€Š1.8 mL, respectively; however, the difference was not statistically significant (P > 0.05, t = 1.394). The PL reached 6.9 ±â€Š1.8 cm and 5.1 ±â€Š1.6 cm (P < 0.05, t = 3.083), the PD reached 2.4 ±â€Š0.5 cm and 2.0 ±â€Š0.6 cm (P < 0.05, t = 2.224), respectively, in the two groups. At the end of 6 months of treatment, biomarkers were in normal range in the two groups. Compared with the GnRH group, the testosterone (T) level and growth of PL and PD were significantly greater in the hCG/hMG group (all P < 0.05). While the TV of both groups increased, the difference was not statistically significant (P > 0.05, t = 0.314). After 9 to 12 months of treatment, the T level was higher in the hCG/hMG group. Other parameters did not exhibit a statistical difference. CONCLUSIONS: The hCG/hMG regimen is feasible and effective for treating male adolescents with CHH. The initial 3 months of treatment may be a window to optimally observe the strongest effects of therapy. Furthermore, results from the extended time-period showed positive outcomes at the 1-year mark; however, the long-term effectiveness, strengths, and weaknesses of the hCG/hMG regimen require further research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02880280; https://clinicaltrials.gov/ct2/show/NCT02880280.


Assuntos
Hipogonadismo , Menotropinas , Adolescente , Adulto , Criança , Gonadotropina Coriônica/uso terapêutico , Hormônio Liberador de Gonadotropina , Humanos , Hipogonadismo/tratamento farmacológico , Masculino , Menotropinas/uso terapêutico , Espermatogênese , Testosterona
11.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
12.
Eur J Hum Genet ; 29(1): 194-204, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32884118

RESUMO

In this study, we performed a spinal muscular atrophy carrier screening investigation with NGS-based method. First, the validation for NGS-based method was implemented in 2255 samples using real-time PCR. The concordance between the NGS-based method and real-time PCR for the detection of SMA carrier and patient were up to 100%. Then, we applied this NGS-based method in 10,585 self-reported normal couples (34 Chinese ethnic groups from 5 provinces in South China) for SMA carrier screening. The overall carrier frequency was 1 in 73.8 (1.4%). It varied substantially between ethnic groups, highest in Dai ethnicity (4.3%), and no significant difference was found between five provinces. One couple was detected as carriers with an elevated risk of having an SMA affected baby. The distribution of SMN1:SMN2 genotype was also revealed in this study. Among the individuals with normal phenotype, the exon 7 copy-number ratio of SMN1 to SMN2 proved the gene conversion between them. With NGS-based method, we investigated SMA carrier status in Chinese population for the first time, and our results demonstrated that it is a promising alternative for SMA carrier screening and could provide data support and reference for future clinical application.


Assuntos
/genética , Frequência do Gene , Triagem de Portadores Genéticos/estatística & dados numéricos , Atrofia Muscular Espinal/genética , China , Feminino , Conversão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Atrofia Muscular Espinal/etnologia , Análise de Sequência de DNA/estatística & dados numéricos , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética
13.
BMC Med Genomics ; 13(1): 181, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33276791

RESUMO

BACKGROUND: Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants. METHODS: In our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature. RESULTS: A novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years. CONCLUSIONS: Here we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.


Assuntos
Facies , Histona-Lisina N-Metiltransferase/genética , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Mutação com Perda de Função , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , /genética , Pré-Escolar , Nanismo/tratamento farmacológico , Nanismo/genética , Feminino , Seguimentos , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/genética , Histona-Lisina N-Metiltransferase/deficiência , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Linhagem , Fenótipo , Proteínas Repressoras/deficiência , Resultado do Tratamento , Sequenciamento Completo do Exoma , Síndrome de Wolf-Hirschhorn/tratamento farmacológico
14.
J Paediatr Child Health ; 56(10): 1590-1596, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32767607

RESUMO

AIM: This study investigated the pattern of liver enzymes in a large cohort of Chinese children and adolescents, including 16 383 individuals aged 4-18 years old recruited at six medical centres in China. METHODS: Clinical data were collected including weight, height, blood pressure, alanine aminotransferase, aspartate aminotransferase and fasting lipid panel. We used an unsupervised machine learning algorithm, the K-means clustering method, to identify different patterns of increased liver enzymes. RESULTS: Six clusters of elevated enzymes patterns were identified. The most common in 2.18% (325) of youth was elevated transaminases in the absence of features of metabolic syndrome(MetS), and they were thinner, and more likely to be from urban areas. The second cluster, with 1.47% (n = 220) youth had the most notable MetS features. They were older, obese and had central obesity, higher BP, triglycerides cholesterol and lower high-density lipoprotein cholesterol. Cluster 3 (0.6%, N = 90) had mild MetS, and cluster 4 (0.06%, N = 9), 5 (0.03%, N = 5) and 6 (0.007%, N = 1) were not related to MetS. CONCLUSIONS: We identified two distinct groups of children with both increased liver enzymes and MetS features in this population sample of Chinese children. One of the two groups had increased liver enzymes as the predominant clinical features at a younger age, suggesting genetic susceptibility to the condition. Further work to understand the increased MetS risk in cluster 2 is warranted.


Assuntos
Síndrome Metabólica , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , China/epidemiologia , Humanos , Fígado , Síndrome Metabólica/epidemiologia , Prevalência , Fatores de Risco
15.
Proc Natl Acad Sci U S A ; 117(23): 12868-12876, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32457162

RESUMO

Fine-resolution differentiation trajectories of adult human hematopoietic stem cells (HSCs) involved in the generation of red cells is critical for understanding dynamic developmental changes that accompany human erythropoiesis. Using single-cell RNA sequencing (scRNA-seq) of primary human terminal erythroid cells (CD34-CD235a+) isolated directly from adult bone marrow (BM) and umbilical cord blood (UCB), we documented the transcriptome of terminally differentiated human erythroblasts at unprecedented resolution. The insights enabled us to distinguish polychromatic erythroblasts (PolyEs) at the early and late stages of development as well as the different development stages of orthochromatic erythroblasts (OrthoEs). We further identified a set of putative regulators of terminal erythroid differentiation and functionally validated three of the identified genes, AKAP8L, TERF2IP, and RNF10, by monitoring cell differentiation and apoptosis. We documented that knockdown of AKAP8L suppressed the commitment of HSCs to erythroid lineage and cell proliferation and delayed differentiation of colony-forming unit-erythroid (CFU-E) to the proerythroblast stage (ProE). In contrast, the knockdown of TERF2IP and RNF10 delayed differentiation of PolyE to OrthoE stage. Taken together, the convergence and divergence of the transcriptional continuums at single-cell resolution underscore the transcriptional regulatory networks that underlie human fetal and adult terminal erythroid differentiation.


Assuntos
Diferenciação Celular/genética , Eritroblastos/fisiologia , Eritropoese/genética , Adulto , Apoptose/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sangue Fetal/citologia , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Família Multigênica , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , RNA-Seq , Análise de Célula Única , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Transcrição Genética
16.
Medicine (Baltimore) ; 99(15): e19751, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282736

RESUMO

RATIONALE: This case report expands the mutation and phenotypic spectra of Beaulieu-Boycott-Innes syndrome (BBIS), and will be valuable for mutation-based pre- and post-natal screening of BBIS when conducting a genetic diagnosis. PATIENT CONCERNS: A 4-year old boy from Guilin City, Guangxi Zhuang Autonomous Region, China, was referred to our clinic for clarification of his diagnosis because he showed moderate intellectual disability. DIAGNOSIS: Two novel compound heterozygous mutations of THOC6, c.664T>C (p.Trp222Arg) and c.945+1 G>A were identified in this patient by whole exome sequencing. The two mutations were evaluated as pathogenic and likely pathogenic respectively according to the American College of Medical Genetics guidelines. This is the first case displaying the BBIS phenotype reported in the Chinese population. These two mutations have not been reported previously. INTERVENTIONS: Symptomatic treatment and rehabilitation training for patients. OUTCOMES: The genetic cause of the disease was identified. The family received scientific genetic counseling. LESSONS: BBIS is a rare syndromic autosomal recessive disease with intellectual disability and it is normally difficult for clinicians to recognize it. Whole exome sequencing is an efficient way to identify the gene which causes a particular disease in patients.


Assuntos
Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Proteínas de Ligação a RNA/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/reabilitação , Anormalidades Múltiplas/terapia , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/reabilitação , Deficiências do Desenvolvimento/terapia , Facies , Aconselhamento Genético/normas , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/reabilitação , Deficiência Intelectual/terapia , Masculino , Atrofia Muscular/diagnóstico , Atrofia Muscular/reabilitação , Atrofia Muscular/terapia , Mutação/genética , Fenótipo , Síndrome , Sequenciamento Completo do Exoma/métodos
17.
BMC Pediatr ; 20(1): 138, 2020 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-32222149

RESUMO

BACKGROUND: To evaluate the efficacy of GH in improving FAH in ISS children in a multicenter study. METHODS: A real-world observation was carried out. Children with ISS in seven hospitals in China were enrolled. The height gains standard deviation score and the height gain over the target height were evaluated. RESULTS: There were 344 ISS patients (217 boys and 127 girls). The baseline average age of boys and girls was 12.7 and 11.7 years, with bone age of 11.7 and 10.1 years, respectively. The baseline height SDS of boys and girls was - 3.07 and - 2.74, and the FAH SDS was - 1.91 and - 1.38, respectively. Compared with the baseline height SDS, the FAH SDS was significantly increased in both boys and girls (both P = 0.0000). The FAH SDS was the highest (gain by 1.54 SD) in the ≥2y treatment course group. Two hundred eighteen patients (218/344, 63.4%) had a FAH SDS > - 2 SD. Among these patients, girls in the 1-2y treatment course group and ≥ 2y group had a FAH SDS higher than TH SDS. Even in the control group, a spontaneous catch-up growth of 1.16 SD was observed. A multivariate linear regression model was used to analyze the results, with FAH SDS as the dependent variable. It was found that the treatment course and baseline height SDS in the boys' model were statistically significant (P < 0.05), whereas the baseline height SDS and baseline bone age significantly affected the girls' FAH SDS (P < 0.05). CONCLUSIONS: Both girls and boys of ISS improved FAH by GH therapy even if treatments begin over 10 years old and majority of them reached TH. Some peri-puberty ISS will have a spontaneous height gain. We recommend the course of GH treatment more than 2 years for girls, and longer courses for boys.


Assuntos
Estatura , Transtornos do Crescimento , Hormônio do Crescimento Humano , Adulto , Criança , China , Feminino , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Puberdade
18.
Clin Chim Acta ; 500: 128-134, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31654632

RESUMO

Myhre syndrome is a rare autosomal dominant multi-organ disorder characterized by growth retardation, skeletal anomalies, muscular hypertrophy, joint stiffness, facial dysmorphism, deafness, cardiovascular disease, and abnormal sexual development. Here we described the first two Chinese Myhre syndrome patients diagnosed by whole-exome sequencing. They both had de novo c.1498A > G (p.Ile500Val) variant in SMAD4 and presented with key characteristics of Myhre syndrome but also revealed uncommon features (polydactyly in the girl and precocious puberty in the boy). We performed functional analysis on four previously reported SMAD4 pathogenic variants in Myhre syndrome patients using dual-luciferase assay. Our results revealed that the pathogenic variants resulted in a variable degree of increased transcription activity of target genes that contain the minimal SMAD binding elements in their promoter regions. The boy responded to the recombinant human growth hormone treatment with improved height but also led to hyperinsulinemia and advanced bone age. Because of his precocious puberty, we subsequently combined the recombinant human growth hormone and gonadotrophin-releasing hormone agonist treatments, which resulted in overall improved height. We reviewed the sexual features of reported Myhre syndrome cases and discussed the possible mechanism of SMAD4 variants in Myhre syndrome that lead to the abnormal hypothalamic-pituitary-gonadal axis.


Assuntos
Criptorquidismo/genética , Criptorquidismo/metabolismo , Variação Genética , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Sequência de Bases , Pré-Escolar , China , Criptorquidismo/patologia , Facies , Feminino , Transtornos do Crescimento/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Gravidez
19.
Child Obes ; 15(7): 459-467, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408357

RESUMO

Background: Despite perceiving their child as being above a healthy weight, many parents do not intervene. Little is known about the factors influencing parental action. We assessed parental perception of child's weight status, the prevalence of mitigating parental action, and the underlying factors. Methods: We studied 20,242 children and adolescents from 6 centers across China. Anthropometry was measured by research nurses. Parents answered questionnaires, including their perception of their child's weight status, and any subsequent weight treatment. Results: A total of 3254 children had obesity (16.1%), with 63.0% correctly perceived as overweight by their parents. These children were more likely to be older (≥8 years; p < 0.0001), have severe obesity [adjusted relative risk (aRR) 1.41; p < 0.0001], and have mothers with overweight/obesity (aRR 1.15; p < 0.0001). In particular, parents of children aged <8 years were over five times more likely to perceive their child with overweight/obesity as "thin" than parents of teenagers. Conversely, girls, older children/adolescents, and urban youth were more likely to be wrongly perceived by parents as having an overweight issue. Only one in four children (27.8%) with available information received treatment for their perceived weight problem. Children with severe obesity were more likely to be treated (aRR 1.34; p < 0.0001), as were children of mothers with overweight/obesity (aRR 1.18; p = 0.002). Conclusions: Only one in four Chinese children perceived as overweight by their parents received treatment for their weight problem. Given that overweight/obesity in childhood tracks into adulthood and many parents did not intervene despite perceiving an overweight problem in their child, interventions for childhood obesity need to extend beyond parental perception of children's weight status.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Pais/psicologia , Obesidade Pediátrica/epidemiologia , Obesidade Pediátrica/psicologia , Adolescente , Peso Corporal/fisiologia , Criança , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Sobrepeso/epidemiologia , Sobrepeso/psicologia , Relações Pais-Filho , Fatores Socioeconômicos
20.
BMC Pediatr ; 19(1): 264, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31362719

RESUMO

BACKGROUND: The relationship between birth weight and blood pressure has not been well explored in Chinese children and adolescents. The aim of this study was to investigate the relationship between birth weight and childhood blood pressure in China. METHODS: A total of 15324 children and adolescents (7919 boys and 7405 girls) aged 7-17 years were stratified into six birth weight groups. Analysis of covariance and binary logistic regression were used to analyse the relationship between birth weight and blood pressure while controlling for potential confounding factors, including age, gestational age, season of birth and area of residence. RESULTS: The group with birth weights from 2500 to 2999 g had the lowest prevalence of hypertension (8.9%). Lower birth weight children (< 2000 g) had significantly higher systolic blood pressure (SBP) (106.00 ± 0.72, P = 0.017), and children with heavier birth weights also had higher SBP (3500-3999 g, 105.13 ± 0.17, P < .001; ≥ 4000 g, 105.96 ± 0.27, P < .001). No significant relationship was found between birth weight and diastolic blood pressure (DBP). The overall rate of hypertension was 10.8% (12.1% in boys and 9.4% in girls). The median weight group (2500-2999 g) had the lowest rate of hypertension (8.9%). Compared with children in the median weight group, children with lower birth weight had a higher prevalence of hypertension (< 2000 g, OR = 1.85, 95% CI = 1.25-2.74; 2000-2499 g, OR = 1.57, 95% CI = 1.15-2.13), and groups with higher birth weights also had higher risks of hypertension (3500-3999 g, OR = 1.22, 95% CI = 1.02-1.45; ≥ 4000 g, OR = 1.42, 95% CI = 1.16-1.74). CONCLUSIONS: Excluding the confounding effect of obesity, a U-shaped relationship between birth weight and risk of hypertension was found in children and adolescents in Chinese cities. Birth weight significantly influences SBP but has a minimal effect on DBP. Further basic research on foetal development and programming may shed light on this phenomenon.


Assuntos
Peso ao Nascer , Pressão Sanguínea , Hipertensão/epidemiologia , Adolescente , Índice de Massa Corporal , Criança , China/epidemiologia , Fatores de Confusão Epidemiológicos , Feminino , Idade Gestacional , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Modelos Logísticos , Masculino , Obesidade , Prevalência , Fatores de Risco
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