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1.
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
2.
BMC Med Genomics ; 13(1): 181, 2020 Dec 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.

3.
Eur J Hum Genet ; 2020 Sep 03.
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.

4.
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.

5.
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
6.
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 , Grupo com Ancestrais do Continente Asiático/genética , 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
7.
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.

8.
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
9.
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
10.
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
11.
Sci Rep ; 9(1): 10726, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341179

RESUMO

Non-immune hydrops fetalis (NIHF) is a complex condition with a high mortality and morbidity rate. Here we report the etiology and outcome of 1004 fetuses with NIHF, in a large single Maternal and Children's hospital of Southern China, since the year of 2009 to 2016. Among these 1004 fetuses with NIHF, the etiology was identified prenatally in 722 of them (72%). The most common ones were hematologic diseases and chromosomal abnormalities. There were eight spontaneous abortions, 18 intrauterine fetal demise, 672 pregnancy terminations and 87 were lost to follow-up. 219 of the 1004 fetuses were live-born and the overall survival rate was 21.8% at this point. After birth 16 perinatal or early neonatal deaths were encountered and five lost to follow-up. Of the remaining 198 newborns, 153 thrived without apparent morbidity. The most significant factors associated with mortality were prematurity and low birthweight. In conclusion, we described the largest report of underlying causes and outcome of NIHF in Southern China. Etiologies were identified for 72% of 1004 fetuses with NIHF. And two poor prognostic factors for survival are preterm birth at less than 36.5 weeks and birthweight lower than 2575 g respectively.


Assuntos
Aberrações Cromossômicas/estatística & dados numéricos , Doenças Hematológicas/epidemiologia , Hidropisia Fetal/etiologia , Aborto Espontâneo/epidemiologia , Adulto , Peso ao Nascer , China , Feminino , Idade Gestacional , Doenças Hematológicas/complicações , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/epidemiologia , Lactente , Mortalidade Infantil , Masculino , Gravidez , Nascimento Prematuro/epidemiologia , Diagnóstico Pré-Natal/estatística & dados numéricos
12.
Hum Mutat ; 40(12): 2221-2229, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31286593

RESUMO

Hemoglobinopathies are the most common monogenic disorders worldwide. Substantial effort has been made to establish databases to record complete mutation spectra causing or modifying this group of diseases. We present a variant database which couples an online auxiliary diagnosis and at-risk assessment system for hemoglobinopathies (DASH). The database was integrated into the Leiden Open Variation Database (LOVD), in which we included all reported variants focusing on a Chinese population by literature peer review-curation and existing databases, such as HbVar and IthaGenes. In addition, comprehensive mutation data generated by high-throughput sequencing of 2,087 hemoglobinopathy patients and 20,222 general individuals from southern China were also incorporated into the database. These sequencing data enabled us to observe disease-causing and modifier variants responsible for hemoglobinopathies in bulk. Currently, 371 unique variants have been recorded; 265 of 371 were described as disease-causing variants, whereas 106 were defined as modifier variants, including 34 functional variants identified by a quantitative trait association study of this high-throughput sequencing data. Due to the availability of a comprehensive phenotype-genotype data set, DASH has been established to automatically provide accurate suggestions on diagnosis and genetic counseling of hemoglobinopathies. LOVD-DASH will inspire us to deal with clinical genotyping and molecular screening for other Mendelian disorders.


Assuntos
Bases de Dados Genéticas , Hemoglobinopatias/genética , Mutação , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Medição de Risco , Análise de Sequência de DNA
13.
J Med Genet ; 56(10): 685-692, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31186340

RESUMO

BACKGROUND: The 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilisation in patients with 46,XY disorders of sex development. This study aims to profile the regional distribution and phenotype-genotype characteristics of SRD5A2 in a large Chinese 5α-RD2 deficiency cohort through multi-centre analysis. METHODS: 190 subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled from eight medical centres in China. Their clinical manifestations and genetic variants were analysed. RESULTS: Hypospadias (isolated or combined with microphallus and/or cryptorchidism) was fairly common in the enrolled subjects (66.32%). 42 variants, including 13 novel variants, were identified in SRD5A2. Homozygous and compound heterozygous mutations presented in 38.42% and 61.58% of subjects, respectively, and predominated in exons 1, 4 and 5. The most prevalent variant was c.680G > A (52.37%), followed by c.16C > T, (10.79%), c.607G > A, (9.21%) and c.737G > A, (8.95%). However, their distributions were different: c.680G > A was more common in South China than in North China (62.62% vs 39.16%, p < 0.001), whereas the regional prevalence of c.16C > T was reversed (6.07% vs 16.87%, p = 0.001). Furthermore, c.680G > A prevailed in cases with normal meatus (68.75%) or distal hypospadias (66.28%), compared with those with proximal hypospadias (35.54%, p < 0.001). However, cases with proximal hypospadias showed a higher frequency of c.16C > T (20.48%) than those with normal meatus (3.13%) or distal hypospadias (3.49%, p < 0.001). CONCLUSIONS: This study profiled variable phenotypic presentation and wide mutational spectrum of SRD5A2, revealing its distinctive regional distribution in Chinese patients and further shaping the founder effect and genotype-phenotype correlation of SRD5A2.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/genética , Hipospadia/genética , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , China , Estudos de Coortes , Éxons/genética , Feminino , Efeito Fundador , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo
14.
Orphanet J Rare Dis ; 14(1): 144, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200758

RESUMO

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare syndromic short stature disorder caused by truncating variants in SRCAP. Few Chinese FHS patients had been reported so far and limited knowledge regarding the benefit of growth hormone treatment existed. METHODS: We ascertained 12 short stature patients with molecularly confirmed diagnosis of FHS by whole exome sequencing. We performed a comprehensive clinical evaluation for all patients and assessed the responsiveness of growth hormone treatment in a subset of the patients. RESULTS: Five distinct pathogenic/likely pathogenic variants were identified in 12 independent FHS patients including two previously reported variants (c.7303C > T/p.Arg2435Ter and c.7330C > T/p.Arg2444Ter) and three novel variants (c.7189G > T/p.Glu2397Ter, c.7245_7246delAT/p.Ser2416ArgfsTer26 and c.7466C > G/p.Ser2489Ter). The c.7303C > T/p.Arg2435Ter mutation appears more common in Chinese FHS patients. The clinical presentations of Chinese FHS patients are very similar to those of previously reported patients of different ethnicities. Yet we noticed micropenis and ear abnormalities in multiple patients, suggesting that these may be novel phenotypes of Floating-Harbor syndrome. Eight patients (one with GH deficiency, one with undetermined GH level, six without GH deficiency) underwent growth hormone treatment, 3 patients had good responses, one with modest and two with poor responses. CONCLUSION: We described novel genotypes and phenotypes in a Chinese FHS patient cohort. We showed that about half of FHS patients exhibited modest to good response to GH treatment regardless of their respective GH deficiency status. We didn't find any correlation between different mutations and response to GH treatment.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Comunicação Interventricular/genética , Mutação/genética , Adenosina Trifosfatases/genética , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , Nanismo Hipofisário/genética , Feminino , Genótipo , Humanos , Masculino , Fenótipo
15.
Front Pharmacol ; 10: 173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930770

RESUMO

Background: 5α-reductase type 2 deficiency (5αRD) is an autosomal recessive hereditary disease of the group of 46, XY disorders of sex development (DSD). Objective: To study the growth pattern in Chinese pediatric patients with 5αRD. Subjects: Data were obtained from 141 patients with 5αRD (age: 0-16 years old) who visited eight pediatric endocrine centers from January 2010 to December 2017. Methods: In this retrospective cohort study, height, weight, and other relevant data were collected from the multicenter hospital registration database. Baseline luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), and dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation test were measured by enzyme enhanced chemiluminescence assay. Bone age (BA) was assessed using the Greulich-Pyle (G-P) atlas. Growth curve was constructed based on λ-median-coefficient of variation method (LMS). Results: The height standard deviation scores (HtSDS) and weight standard deviation scores (WtSDS) in 5αRD children were in the normal range as compared to normal boys. Significantly higher HtSDS was observed in patients with 5αRD who were <1 year old (t = 3.658, 2.103, P = 0.002, 0.048, respectively), and higher WtSDS in those <6 months old (t = 2.756, P = 0.012). Then HtSDS and WtSDS decreased gradually and fluctuated near the median of the same age until 13 years. WtSDS in 5αRD children from northern China were significantly higher than those from the south (Z = -2.670, P = 0.008). The variation tendency of HtSDS in Chinese 5αRDs was consistent with the trend of stimulating T. HtSDS and stimulating T in the external masculinization score (EMS) <7 group were slightly higher than those in EMS ≥ 7 group without significant difference. Additionally, the ratio of BA over chronological age (BA/CA) was significantly <1 in children with 5αRD. Conclusion: Children with 5αRD had a special growth pattern that was affected by high levels of T, while DHT played a very small role in it. Their growth accelerated at age <1 year, followed by slowing growth and fluctuating height near normal median boys' height. The BA was delayed in 5αRD children. Androgen treatment, which may be considered anyway for male 5αRD patients with a micropenis, may also be beneficial for growth.

16.
Am J Med Genet C Semin Med Genet ; 181(2): 218-225, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30893510

RESUMO

CCCTC-binding factor (CTCF) is an important regulator for global genomic organization and gene expression. CTCF gene had been implicated in a novel disorder characterized by intellectual disability, feeding difficulty, developmental delay and microcephaly. So far, four patients have been reported with de novo CTCF mutations. We reported three additional Chinese patients with de novo variants in CTCF. The new evidence helped to establish the clinical validity between CTCF and the emerging disorder. We described the consistent phenotypes shared by all patients and revealed additional clinical features such as delayed or abnormal teeth development and a unique pattern of the eyebrow that may help to define a potential recognizable neurodevelopmental disorder. We also reported the first CTCF patient treated with recombinant human growth hormone. Follow-up and more case studies will further our understanding to the clinical presentations of this novel disorder and the prognosis of patients with this disorder.


Assuntos
Fator de Ligação a CCCTC/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Grupo com Ancestrais do Continente Asiático , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Sobrancelhas/patologia , Feminino , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Fenótipo , Anormalidades Dentárias
18.
Clin Chim Acta ; 489: 103-108, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30508507

RESUMO

BACKGROUND: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder. Although most patients present with isolated CH, some patients present with CH and extra-thyroidal congenital malformations (ECMs), for which less is known about the underlying genetics. The aim of this study was to investigate the genetic mechanisms in patients with CH and ECMs using chromosomal microarray (CMA) and whole exome sequencing (WES). METHODS: Peripheral venous blood samples were collected from 16 patients with CH and ECMs. Genomic DNA was extracted from peripheral blood leukocytes. CMA and WES were performed to detect copy number and single nucleotide variants. RESULTS: CMA identified clinically significant copy number variants in 7 patients consistent with their phenotypes. For 6 of them, the genotype and phenotype suggested a syndromic diagnosis, and the remaining patient carried a pathogenic microdeletion and microduplication including GLIS3. WES analysis identified 9 different variants in 7 additional patients. The variants included 2 known mutations (c.1096C>T (p.Arg366Trp) in KCNQ1 and c.848C>A (p.Pro283Gln) in NKX2-5) and 7 novel variants: one nonsense mutation (c.4330C>T (p.Arg1444*) in ASXL3), one frameshift mutation (c.1253_1259delACTCTGG (p.Asp418fs) in TG), three missense variants (c.1472C>T (p.Thr491Ile) in TG, c.4604A>G (p.Asp1535Gly) in TG, and c.2139G>T (p.Glu713Asp) in DUOX2, and two splice site variants (c.944-1G>C and c.3693 + 1G>T) in DUOX2. CONCLUSIONS: We report the first genetic study of CH patients with ECMs using CMA and WES. Overall, our detection rate for pathogenic and possibly pathogenic variants was 87.5% (14/16). We report 7 novel variants, expanding the mutational spectrum of TG, DUOX2, and ASXL3.


Assuntos
Cromossomos Humanos/genética , Hipotireoidismo Congênito/genética , Análise de Sequência com Séries de Oligonucleotídeos , Sequenciamento Completo do Exoma , Criança , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/etiologia , Humanos , Lactente , Mutação
19.
Eur J Hum Genet ; 27(2): 254-262, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30275481

RESUMO

Expanded carrier screening (ECS) has been demonstrated to increase the detection rate of carriers compared with traditional tests. The aim of this study was to assess the potential value of ECS for clinical application in Southern China, a region with high prevalence of thalassemia and with diverse ethnic groups, and to provide a reference for future implementations in areas with similar population characteristics. A total of 10,476 prenatal/preconception couples from 34 self-reported ethnic groups were simultaneously tested and analyzed anonymously for 11 Mendelian disorders using targeted next-generation sequencing. Overall, 27.49% of individuals without self-reported family history of disorders were found to be carriers of at least 1 of the 11 conditions, and the carrier frequency varied greatly between ethnic groups, ranging from 4.15% to 81.35%. Furthermore, 255 couples (2.43%) were identified as carrier couples at an elevated risk having an affected baby, sixty-five of which would not have been identified through the existing screening strategy, which only detects thalassemia. The modeled risk of fetuses being affected by any of the selected disorders was 531 per 100,000 (95% CI, 497-567 per 100,000). Our data demonstrate the feasibility of ECS, and provide evidence that ECS is a promising alternative to traditional one-condition screening strategies. The lessons learned from this experience should be applicable for other countries or regions with diverse ethnic groups.


Assuntos
Grupos Étnicos/genética , Triagem de Portadores Genéticos/métodos , Adulto , Feminino , Frequência do Gene , Genes Recessivos , Triagem de Portadores Genéticos/normas , Humanos , Masculino , Projetos Piloto , Tamanho da Amostra
20.
Mol Genet Metab Rep ; 16: 15-19, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29988809

RESUMO

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in EFTA, EFTB, or ETFDH. Many MADD patients are responsive to treatment with riboflavin, termed riboflavin-responsive MADD (RR-MADD). Here, we report three novel mutations and one previously reported mutation in ETFDH in four RR-MADD patients who presented at various ages, and characterize the corresponding changes in ETF-QO protein structure. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD, and may not only prevent patients from invasive testing, but also allow timely initiation of riboflavin treatment. The novel variants in ETFDH and the corresponding clinical features reported here enrich the allelic heterogeneity of RR-MADD and provide insight into genotype-phenotype relationships.

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