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1.
J Blood Med ; 12: 975-989, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803418

RESUMO

Objective: To better understanding and differentiation of traditional Chinese medicine (TCM) syndromes in severe aplastic anemia (SAA) patients undergoing hematopoietic stem cell transplantation (Allo-HSCT) and their correlation with iron metabolism, cAMP/cGMP, 17-OH-CS and thyroxine. Methods: Eighteen patients with SAA who underwent HSCT were enrolled. The syndrome was evaluated before conditioning and days after stem cell reinfusion (-10d, -1d, +7d, +30d, +60d, and +90d). The correlation of TCM syndrome (Yin, Yang, and stasis) to cyclic nucleotides, 17-OH-CS, thyroxine, and iron metabolism were analyzed and compared to data from normal subjects. Results: More "Yin deficiency" (n=11, 11/18) syndrome was observed before HSCT, and nearly 61% was complicated with "blood stasis". After conditioning, the proportion of "kidney Yin and Yang deficiency" increased to 61.6%. Fourteen days after HSCT, the syndrome developed into "Spleen-Kidney Yang Deficiency," and the stasis score decreased. On +90day, majority patients were diagnosed with "Kidney Yang Deficiency" (35.7%) or "Spleen-Kidney Yang Deficiency" (28.6%), and 88.9% were diagnosed without stasis. The correlation analysis showed that cGMP might represent "Deficient Yang" as well as low total triiodothyronine (T3) and free T3 (FT3). There was also a positive relation between labile plasma iron (LPI), hepcidin, soluble transferrin receptor (sTfR), and "Yin deficiency", and the last two factors, along with marrow nitric oxide synthase were also positively related to "Stasis" syndrome. Conclusion: During HSCT, the syndrome evolved from "kidney Yin and Yang deficiency" to "kidney Yang deficiency" or "spleen-kidney Yang deficiency", and the "stasis" along with "Yin deficiency" syndromes were quickly relieved within 90 days. The changes of cyclic nucleotides, 17-OH-CS, thyroxine, and iron metabolism indexes can be applied for better differentiation of TCM syndrome.

2.
Onco Targets Ther ; 14: 5027-5033, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34675547

RESUMO

Autoimmune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) can be observed in Waldenström macroglobulinemia (WM). The autoimmune disorders are primarily mediated by autoimmune monoclonal gammopathy, but drug-induced hemolysis should also be considered. Herein, we presented the case of a 63-year-old female WM patient complicated with ITP, who was admitted to our department with a complaint of abdominal pain. After first half of bortezomib/dexamethasone/rituximab (BRD) chemotherapy, her platelet level recovered, but subsequently decreased to extremely low level (around 1-2×109/L), and the patient suffered from platelet transfusion refractoriness. During the management of refractory thrombocytopenia, the patient developed severe hemolytic anemia, and further tests confirmed warm AIHA. FcγRIIα polymorphism test showed that the patient had FcγRIIα-131RH, which implied that the AIHA may not be WM-related. Given the effects of ibrutinib in controlling WM, secondary AITP and AIHA, ibrutinib single treatment was started, which quickly corrected the thrombocytopenia within five days, but not hemolysis. With a relatively safe platelet level, eltrombopag was stopped, and the hemolysis relieved three days after eltrombopag withdrawal. This is the first report on eltrombopag-induced AIHA in the management of WM-associated ITP.

3.
Front Genet ; 12: 717294, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659339

RESUMO

Background: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility. PPIB pathogenic variants cause a perinatal lethal form of OI type IX. A limited number of pathogenic variants have been reported so far worldwide. Methods: We identified a rare pedigree whose phenotype was highly consistent with OI-IX. Exome sequencing was performed to uncover the causal variants. The variant pathogenicity was classified following the ACMG/AMP guidelines. The founder effect and the age of the variant were assessed. Results: We identified a homozygous missense variant c.509G > A/p.G170D in PPIB in an affected fetus. This variant is a Chinese-specific allele and can now be classified as pathogenic. We estimated the allele frequency (AF) of this variant to be 0.0000427 in a Chinese cohort involving 128,781 individuals. All patients and carriers shared a common haplotype, indicative of a founder effect. The estimated age of variant was 65,160 years. We further identified pathogenic variants of PPIB in gnomAD and ClinVar databases, the conserved estimation of OI type IX incidence to be 1/1,000,000 in Chinese population. Conclusion: We reported a founder pathogenic variant in PPIB specific to the Chinese population. We further provided our initial estimation of OI-IX disease incidence in China.

4.
Front Genet ; 12: 743833, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691156

RESUMO

Background: Contactin 2, encoded by CNTN2 on chromosome 1q32.1, is a neural-specific glycoprotein and plays important roles in neurodevelopment. A deleterious homozygous variant in the CNTN2 gene was previously reported to cause autosomal recessive cortical myoclonic tremor and epilepsy. Since then, there has been no further report confirming the association of CNTN2 and epilepsy. Here, we reported one new case, who presented with epilepsy, carrying a novel homozygous frameshift variant in CNTN2. The clinical and genetic features of the patient were reviewed. Case presentation: The male patient presented with preschool age-of-onset neurodevelopmental impairment and focal seizures of temporal origin, and responded to valproate. A trio-whole exome sequencing revealed a novel homozygous frameshift variant in CNTN2 (c.2873_c.2874delCT, p.Thr958Thrfs). The patient's mother was a heterozygous carrier while his father was wild-type; they were both unaffected and non-consanguineous. Further study revealed that maternal uniparental disomy (1q32.1) unmasked the heterozygous variant of CNTN2 in the proband. Conclusions: This case enhanced the gene-disease relationship between CNTN2 and epilepsy, which will help to further understand this emerging disorder.

5.
Int J Dev Neurosci ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34708882

RESUMO

MN1 C-terminal truncation (MCTT) syndrome is a newly recognized neurodevelopmental disorder due to heterozygous gain-of-function C-terminal truncating mutations clustering in the last or penultimate exon of MN1 gene (MIM: 156100). Up to date, only 25 affected patients have been reported. Here, we report a 2-year-old Chinese girl with MCTT syndrome. The girl presented with the characteristic features of the syndrome, including global developmental delay (GDD), facial dysmorphism and hearing impairment. Notably, the patient did not have other frequently observed symptoms such as hypotonia, cranial or brain abnormalities, indicating variability of the phenotype of patients with MN1 C-terminal truncating mutations. Trio whole-exome sequencing revealed a novel de novo heterozygous nonsense variant in the extreme 3' region of penultimate exon of MN1 (NM_002430.3: c.3743G > A, p.Trp1248*). This rare truncating variant was classified as pathogenic due to its predicted gain-of-function effect, given that the gain-of-function MN1 truncating variants producing C-terminally truncated proteins have been confirmed to cause the recognizable syndrome. Additionally, a systematic review of previously reported MN1 variants including C-terminal truncating variants and N-terminal truncating variants shows that different location of MN1 truncating variants causes two distinct clinical subtypes. To our knowledge, this is the first reported case of MCTT syndrome caused by a novel MN1 C-terminal truncating variant in a Chinese population, which enriched the mutation spectrum of MN1 gene and further supporting the association of the novel MCTT syndrome with MN1 C-terminal truncating variants.

6.
Immunol Res ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34669176

RESUMO

Immune thrombocytopenia (ITP) was defined using the International Consensus Guidelines as a platelet count <100×109/L in the absence of other causes or disorders that may be associated with thrombocytopenia. For patients without response to first-line treatment or refractory, TPO receptor agonist (RA) is an ideal choice. This study was to evaluate the efficiency and safety of eltrombopag for multi-line failed Chinese patients with immune thrombocytopenia (ITP) and analyze the possible factors that may contribute to the differences based on personal characteristics. Thirty-five multi-line failed ITP patients who received eltrombopag treatment were enrolled retrospectively at the First Affiliated Hospital of Zhejiang Chinese Medical University from January 2018 to August 2020. The general information, peripheral hemogram changes, count of bone marrow megakaryocyte (MK), peripheral T cell subsets were recorded, the response, and adverse effects, was evaluated. Results showed that the overall, complete, and partial response rates were 54.3% (n=19), 48.6% (n=17), and 5.7% (n=2) respectively to eltrombopag in our center. The overall response rate of patients with decreased MK was 70%, which was unexpectedly higher than that of the patient with increased or normal MK count (52.9% and 40%, respectively). For patients with poorer eltrombopag response group, more NK cells were found in peripheral blood, and the patient with decreased MK have a higher level of T helper (Th) cells and regulatory T (Treg) cells. Nine eltrombopag-related adverse events were reported, and most commonly were upper respiratory tract infection (8.6%), elevated alanine transaminase (ALT, 5.7%), and venous thrombosis (5.7%). In conclusion, this study revealed that ITP patients with decreased megakaryocyte respond well to eltrombopag, and the abnormality of NK cells may play a role in patients with a poor eltrombopag response.

7.
Clin Chim Acta ; 523: 10-18, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34478686

RESUMO

BACKGROUND: Neurodevelopmental disorder with absent language and variable seizures (NEDALVS, OMIM # 618707) is a newly described autosomal dominant condition caused by heterozygous de novo mutation in WASF1 gene. WASF1 is a key component of the WAVE regulatory complex (WRC) required for actin polymerization. So far, only 3 distinct truncating variants clustering at the WCA domain, 3 missense variants localized to the meander region and a copy number variant (CNV) of WASF1 have been identified among 11 NEDALVS cases previously reported. CASE REPORT: We report a pediatric patient carrying novel de novo heterozygous missense variant (NM_003931.2: c.481T > C, p.Trp161Arg) in WASF1 gene. During the first hospitalization at age of 5.5 months, the patient was initially diagnosed with infantile spasms, developmental delay (DD) and microcephaly due to nodding-like epileptic spasms in clusters and hypsarrhythmia on video-electroencephalography, lacking head control and body rollover, and abnormal head circumference 39 cm (<-2SD). The genetic diagnosis with a causal WASF1 variant detected by trio exome sequencing indicated the rare NEDALVS. LITERATURE REVIEW: All the reported NEDALVS cases published in the PubMed English literature were reviewed to summarize the genetic and phenotypic spectrum of this novel disorder. CONCLUSION: We describe the third patient with a recurrently mutated amino acid site at p.Trp161 in WASF1, currently the 12th patient with NEDALVS. This hotspot missense variant and the truncating variants in WASF1 lead to similar phenotypic patterns with core features of severe DD/ID, and seizures, hypotonia, and microcephaly frequently observed. Our finding expands the WASF1 mutation spectrum and confirms the de novo hotspot missense variant at p.Trp161, further supporting the association of the novel NEDALVS with WASF1 gene and the actin regulatory pathway.

8.
J Genet Genomics ; 48(8): 727-736, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34334354

RESUMO

Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes. A nuclear gene HPDL (4-hydroxyphenylpyruvate dioxygenase-like), which encodes an intermembrane mitochondrial protein, has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes. Here, we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity, including developmental delay/intellectual disability, spasm, and hypertonia. Seven different pathogenic variants are identified, of which five are novel. Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function, which is also observed in HPDL-knockdown (KD) HeLa cells. In these HeLa cells, overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate. In addition, a decreased activity of the oxidative phosphorylation (OXPHOS) complex II is observed in patient-derived lymphocytes and HPDL-KD HeLa cells, further supporting an essential role of HPDL in the mitochondrial respiratory chain. Collectively, our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.

9.
Brain Dev ; 43(10): 1004-1012, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34120799

RESUMO

OBJECTIVE: To evaluate the clinical utility of next-generation sequencing (NGS) in unexplained pediatric epilepsy, and to identify the potential predictors associated with Mendelian genetic causes. METHODS: Two hundred and ten children with unexplained epilepsy, who underwent NGS test were included. We analyzed the demographic, clinical and genetic characteristics, and executed a Logistic regression analysis for identifying predictors for Mendelian genetic causes. Patients were classified as either with isolated epilepsy or syndromic epilepsy with concurrent neurodevelopmental phenotypes. RESULTS: The overall diagnostic yield was 29.0% (61/210). A total of 68 variants spanning 39 genes were identified in 58 patients (27.6%, 58/210) from exome sequencing based testing. Of the 68 variants, 33 were novel ones. Besides, STAR and CNTN2 were identified to be a candidate gene for epilepsy. Patients with syndromic epilepsy had a much higher diagnostic yield than that of isolated epilepsy (53/135, 39.3% vs. 8/75, 10.7%, p = 0.000). The odds ratio of detecting genetic cause was 3.939 (95% CI 1.369-11.332) for syndromic epilepsy without epileptic encephalopathy (EE), 5.814 (95% CI 2.208-15.306) for EE, 2.958 (95% CI 1.093-8.000) for patients with seizure onset <12 months, and 2.932 (95%CI 1.414-6.080) for female. Of the 210 patients, 78.4% of patients (145/185) had at least a 50% reduction in seizure frequency and 58.9% (109/185) reached seizure freedom. There was no difference between seizure prognosis and diagnostic outcomes. SIGNIFICANCE: NGS is effective for Mendelian genetic etiological diagnosis for unexplained pediatric epilepsy. Female patients with syndromic epilepsy with onset within the first year of life are most likely to yield a positive test result.

10.
Mol Genet Genomic Med ; 9(6): e1683, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33978323

RESUMO

BACKGROUND: Nemaline myopathy 8 is a severe autosomal recessive muscle disorder characterized by fetal akinesia or hypokinesia, contractures, fractures, respiratory failure and swallowing difficulties apparent at birth. METHODS: An affected dizygotic twin pair from a non-consanguineous Chinese family presented with severe asphyxia, lethargy and no response to stimuli. The dysmorphic features included prominent nasal bridge, telecanthus, excessive hip abduction, limb edema, absent palmar and sole creases, acromelia, bilateral clubfoot, appendicular hypertonia and cryptorchidism. Both infants died in the first week of life. Whole-exome sequencing was used to identify the causative gene. RESULTS: Whole-exome sequencing identified a recurrent missense variant c.1516A>C and a novel splice-acceptor variant c.1153-1G>C in KLHL40 gene in both siblings. We estimated the disease incidence in Southern Chinese population to be 2.47/100,000 based on the cumulative allele frequency of pathogenic and likely pathogenic variants in our internal database. CONCLUSION: Our study expanded the mutation spectrum of KLHL40 and the condition could have been underdiagnosed before. We identified a recurrent missense variant c.1516A>C and provided evidence further supporting the founder effect of this variant in Southern Chinese population. Given the severity of the condition and the relative high incidence, this not-so-rare disorder should be included in expanded carrier screening panel for Chinese population.

11.
Am J Med Genet C Semin Med Genet ; 187(2): 192-198, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33982873

RESUMO

Dwarfism has been depicted in various Chinese art forms including literature, sculpture, and painting. This article examines several representative Chinese works of art from different ages of Chinese history, in order to glimpse the living situations of people with dwarfism, their professions and social status, as well as the social attitude toward them in China. We highlight "" (Shan Hai Jing, translated as the Classic of Mountains and Seas), a remarkable collection of myths and illustrations which documented the existence of dwarf communities where the residents were capable of producing high-quality grains. Representations from sculptures and paintings frequently captured the images of individuals with dwarfism in royal courts, which showed their remarkable performance skills and social ability. There are also works of art associating dwarfism with rituals. In addition to portraying ordinary individuals with humble social status, there was one particular individual with dwarfism named Yan Zi () who was highly regarded as a figure of wisdom. Throughout the long Chinese history, dwarfism had been portrayed in art as either positive, neutral or derogatory, which reflected the fact that people with dwarfism, while short in stature, are usually intellectually normal, generally skillful, and often talented, in short, like the general population.


Assuntos
Nanismo , Medicina nas Artes , Pinturas , China , Humanos , Escultura
12.
J Matern Fetal Neonatal Med ; 34(16): 2710-2716, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33938369

RESUMO

OBJECTIVE: To evaluate the clinical application of expanded noninvasive prenatal screening (eNIPS) for genome-wide large copy number variation (CNV), i.e. chromosomal deletion/duplication >5 Mb, and aneuploidy; also to provide practical information for counseling eNIPS positive cases. METHOD: We recruited 34,620 women with singleton pregnancy for genome-wide cell-free plasma DNA sequencing. Screening positive cases were verified by karyotyping and/or SNP array. RESULT: A total of 461 (1.33%) positive cases were identified through our cfDNA screening including 209 cases of common trisomies (0.60%), 124 cases of sex chromosomal abnormalities (SCA) (0.36%), 71 cases of other autosomal anueploidies (OAA) (0.21%), and 57 CNVs larger than 5 Mb (0.16%). The predictive positive values (PPV) were 70.06% in general for common trisomies with as high as 91.67% for Trisomy21 (T21), 40.22% in general for SCAs with as high as 100% for Jacob Syndrome (XYY). The PPV for OAAs was 5.45%, and T7/T8/T16/T22 were the most frequent OAAs (n = 15, 9, 9, 8, respectively). The PPV for CNVs larger than 5 Mb was 51.22% (n = 57) with the CNV mostly detected on Chr5/Chr4/Chr2/Chr7 (n = 10, 8, 5, 5, respectively). CONCLUSION: The expanded NIPS had shown promising PPVs for CNVs (large than 5 Mb), SCAs and common trisomies, yet this method required higher efficacy in screening for OAAs. The post-test genetic counseling for expanded NIPS should be tailored to the types of positive cases and also address the origin of abnormal signals (fetal vs. maternal).


Assuntos
Transtornos Cromossômicos , Teste Pré-Natal não Invasivo , Aneuploidia , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Variações do Número de Cópias de DNA , Feminino , Aconselhamento Genético , Humanos , Gravidez , Diagnóstico Pré-Natal
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(5): 419-424, 2021 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-33974247

RESUMO

Chromosome microarray analysis (CMA) has become the first-tier testing for chromosomal abnormalities and copy number variations (CNV). This review described the clinical validation of CMA, the development and updating of technical standards and guidelines and their diagnostic impacts. The main focuses were on the development and updating of expert consensus, practice resources, and a series of technical standards and guidelines through systematic review of case series with CMA application in the literature. Expert consensus and practice resource supported the use of CMA as the first-tier testing for detecting chromosomal abnormalities and CNV in developmental and intellectual disabilities, multiple congenital anomalies and autism. The standards and guidelines have been applied to pre- and postnatal testing for constitutional CNV and tumor testing for acquired CNV. CMA has significantly improved the diagnostic yields but still needs to overcome its technical limitations and face challenges of new technologies. Guiding and governing CMA through expert consensus, practice resource, standards and guidelines in the United States has provided effective and safe diagnostic services to patients and their families, reliable diagnosis on related genetic diseases for clinical database and basic research, and references for clinical translation of new technologies.


Assuntos
Variações do Número de Cópias de DNA , Deficiência Intelectual , Criança , Aberrações Cromossômicas , Cromossomos , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/genética , Análise em Microsséries , Estados Unidos
14.
BMC Med Genomics ; 14(1): 95, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794876

RESUMO

BACKGROUND: ATP1A2 gene mutation has been indicated to cause alternating hemiplegia of childhood (AHC); however, limited evidence supports this relationship so far. CASE PRESENTATION: We reported two Chinese patients with de novo ATP1A2 variants (c.970G>A and c.889G>A). Both patients presented with episodes of alternating hemiplegia, seizures and mild developmental delay. Brain magnetic resonance imaging revealed abnormal signals in both patients. CONCLUSIONS: The new genetic evidence we reported here strengthened the gene-disease relationship, and the gene curation level between ATP1A2 and AHC became "Moderate" following the ClinGen Standard Operation Procedure. Consequently, the two variants can be reclassified as likely pathogenic.


Assuntos
Hemiplegia , Criança , China , Humanos , Masculino , Mutação
15.
Infect Drug Resist ; 14: 1311-1317, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854343

RESUMO

Monocytopenia and mycobacterial infection (MonoMAC) syndrome is a rare disease. Herein, we reported a 65-year-old Asian woman, previously diagnosed with myelodysplastic syndrome (MDS), suffering from recurrent pneumonia, intermittent fever, fatigue, and chest tightness lasting for five months. She was ultimately diagnosed with MonoMAC syndrome with Mycobacterium kansasii (M. kansasii) infection and GATA2 mutation through metagenomic generation sequencing (mNGS) of peripheral blood specimen, for which she was given anti-NTM therapy. Her situation significantly improved within 2 weeks of therapy. We discussed the clinical features, genetic characteristic, and prognosis of this disorder, aiming to further elucidate this rare syndrome. For MDS/AML patient with recurrent mixed infection and pancytopenia (especially with monocyte absence), MonoMAC syndrome should be highly suspected, and germline mutation and pathogen sequencing should be performed.

16.
Clin Chim Acta ; 519: 163-171, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33826954

RESUMO

BACKGROUND AND AIMS: Biallelic missense variants in PPA2 gene cause infantile sudden cardiac failure (SCFI; OMIM #617222) characterized by sudden cardiac failure, sudden cardiac death in infants. Here, we present an unusual survivor with one inherited plus one de novo variant in PPA2. Since next-generation sequencing (NGS) fails to resolve variant phasing, which require long-read sequencing to clarify the diagnosis. MATERIALS AND METHODS: Whole exome and Sanger sequencing were initially performed to identify the causative variants. PCR-based short tandem repeats (STRs) analysis and long-read single molecule real-time (SMRT) sequencing were further implemented for paternity testing and variant phasing. Pathogenicity evaluation of the biallelic variants in PPA2 was conducted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines based on VarSome. RESULTS: Whole exome and Sanger sequencing revealed two variants in PPA2, with one novel nonsense variant (c.524C > G; p.Ser175*) inherited from the mother and one de novo missense variant (c.379C > T; p.Arg127Cys). PCR-based STRs analysis verified the paternity. And long-read SMRT sequencing phased the two variants in trans and identified the paternal origin of the de novo variant. The genetic diagnosis clarified the genetic etiology of the proband and assisted in patient management and counseling. CONCLUSION: We identified a rare combination of one inherited plus one de novo variant of PPA2 in a patient with autosomal recessive SCFI, which expanded the mutation spectrum of PPA2 and demonstrated the power of target long-read sequencing to make up the diagnostic gap of prevailing NGS.


Assuntos
Exoma , Insuficiência Cardíaca , China , Códon sem Sentido , Humanos , Lactente , Linhagem , Sequenciamento Completo do Exoma
17.
Mol Genet Genomic Med ; 9(4): e1624, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33724704

RESUMO

BACKGROUND: Congenital hydrocephalus-3 with brain anomalies (HYC3, MIM 617967) is a rare form of congenital hydrocephalus characterized by severe hydrocephalus and cerebellar abnormalities, the onset of the disease occurs in utero even resulting in fetal death. A very limited spectrum of WDR81 pathogenic variants had been reported in three unrelated families with HYC3. This study aims at presenting novel compound heterozygous frameshift variants in WDR81 in a Chinese fetus. METHODS: Whole-exome sequencing (WES) was performed for a fetus with multiple congenital anomalies including sever hydrocephalus, cleft lip and palate, hydrops fetalis, hepatomegaly, and cerebellar hypoplasia. Sanger sequencing was performed to confirm the origin of the variants subsequently. Variants classification was based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Two novel heterozygous variants c.146_147insG (p.Thr52fs) and c.673delC (p.Leu225fs) in WDR81 were identified. Sanger sequencing revealed that the c.146_147insG mutation was maternal origin and the c.673delC mutation was paternal origin. Both variants were pathogenic according to the ACMG/AMP guidelines. CONCLUSION: The present study expands the mutation spectrum of WDR81 and help further define the genotype-phenotype correlations of HYC3. WDR81-related HYC3 were highly clinical heterogeneity. We suggested that fetal hydrocephalus with extracerebral manifestations may be suggestive of WDR81 deficiency and WES is effective for achieving a conclusive diagnosis for disorder.

18.
J Clin Endocrinol Metab ; 106(7): e2711-e2719, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33606014

RESUMO

CONTEXT: Aggrecan, encoded by the ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated. OBJECTIVE: We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone therapies. PATIENTS AND METHODS: Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by next-generation sequencing-based test. RESULT: We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort; it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, 5 of 11 ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SD score improvement. CONCLUSION: Our data suggest that ACAN mutation is 1 of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.


Assuntos
Agrecanas/genética , Grupo com Ancestrais do Continente Asiático/genética , Estatura/genética , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/genética , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Estudos de Coortes , Feminino , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento/uso terapêutico , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Fenótipo , Prevalência
19.
Anal Chim Acta ; 1143: 37-44, 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33384128

RESUMO

Phospholipase A2 (PLA2) may be a vital biomarker for the prediction and diagnosis of some diseases. Consequently, it is of great significance to quantitatively detect PLA2 in biologic samples. Herein, on the basis of the principle of luminescence resonance energy transfer (LRET) between upconversion nanoparticles (UCNPs) and SYBR Green I (SG), we proposed a technology for the highly sensitive detection of PLA2 amount. Therein, as an energy receptor, SG will be quantitatively loaded into liposomes firstly. Then, due to the hydrolysis of liposomes under the catalysis of PLA2, SG will be released and inserted into the double-stranded DNA (dsDNA) on the surface of UCNPs, which triggers the LRET because of the shortening of effective spatial distance between UCNPs and SG. Under exciting of NIR light, UCNPs emit luminescence at 476 nm, which makes SG emit fluorescence at 522 nm through LRET. Under optimal conditions, the emission intensity ratio (I522 nm/I476 nm) increased linearly with the PLA2 amount in the range of 20 U/L to 400 U/L, and the limit of detection (LOD) reached 15 U/L. Here, after comparing with the clinical standard method, it is found that the biosensor is expected to provide a convenient and sensitive assay for the detection of PLA2 in actual serum samples. Furthermore, such biosensor can also be used to test the inhibitor of PLA2.


Assuntos
Transferência Ressonante de Energia de Fluorescência , Nanopartículas , Benzotiazóis , Diaminas , Compostos Orgânicos , Fosfolipases , Quinolinas
20.
Genet Med ; 23(4): 669-678, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33402738

RESUMO

PURPOSE: To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders. METHODS: De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations. RESULTS: The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts. CONCLUSION: We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.


Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Criança , China/epidemiologia , Aberrações Cromossômicas , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética
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