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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 917-920, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487544

RESUMO

Phelan-McDermid syndrome (PMS)(OMIM#606232) is a rare genetic disorder caused by a deletion of the distal long arm of chromosome 22q13 involving a variety of clinical features with considerably heterogeneous degrees of severity. This syndrome is characterized by global developmental delay, intellectual disability, hypotonia, absent or severely delayed speech, minor dysmorphic features and autism spectrum disorder. PMS is easy to be misdiagnosed due to the lack of specific clinical manifestations. SHANK3 has been identified as the critical candidate gene for the neurological features of this syndrome. However, some studies have shown that other genes located in the 22q13 region may have a role in the formation of symptoms in individuals with PMS. This article provides a review for recent progress made in research on PMS including etiology, clinical manifestation, diagnosis, and treatment, with a particular emphasis on clinical diagnosis and treatment.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22 , Humanos , Proteínas do Tecido Nervoso/genética
2.
Am J Hum Genet ; 108(8): 1409-1422, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34237280

RESUMO

Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics."


Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Mapeamento Cromossômico/métodos , Análise Citogenética/métodos , Variações do Número de Cópias de DNA , Genoma Humano , Análise em Microsséries/métodos , Transtornos Cromossômicos/genética , Humanos , Cariotipagem
3.
J Neurodev Disord ; 13(1): 26, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246244

RESUMO

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare genetic disorder compromising the 22q13 terminal region and affecting SHANK3, a gene crucial to the neurobehavioural phenotype and strongly linked to autism (ASD) and intellectual disability (ID). The condition is characterised by global developmental delay, ID, speech impairments, hypotonia and autistic behaviours, although its presentation and symptom severity vary widely. In this study, we provide a thorough description of the behavioural profile in PMS and explore differences related to deletion size and language ability. METHODS: We used standard clinical assessment instruments to measure altered behaviour, adaptive skills and autistic symptomatology in sixty participants with PMS (30 females, median age 8.5 years, SD=7.1). We recorded background information and other clinical manifestations and explored associations with deletion size. We performed descriptive and inferential analyses for group comparison. RESULTS: We found delayed gross and fine motor development, delayed and impaired language (~70% of participants non or minimally verbal), ID of different degrees and adaptive functioning ranging from severe to borderline impairment. Approximately 40% of participants experienced developmental regression, and half of those regained skills. Autistic symptoms were frequent and variable in severity, with a median ADOS-2 CSS score of 6 for every domain. Sensory processing anomalies, hyperactivity, attentional problems and medical comorbidities were commonplace. The degree of language and motor development appeared to be associated with deletion size. CONCLUSIONS: This study adds to previous research on the clinical descriptions of PMS and supports results suggesting wide variability of symptom severity and its association with deletion size. It makes the case for suitable psychotherapeutic and pharmacological approaches, for longitudinal studies to strengthen our understanding of possible clinical courses and for more precise genomic analysis.


Assuntos
Transtorno do Espectro Autista , Transtornos Cromossômicos , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Criança , Deleção Cromossômica , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 22 , Feminino , Humanos , Fenótipo
4.
Cytogenet Genome Res ; 161(3-4): 160-166, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34107486

RESUMO

Pure partial duplications of the long arm of chromosome 16 are rare and few cases are described with delineation by chromosomal microarray. Data about clinical abnormalities of pure partial 16q duplications are incomplete because many individuals die during the perinatal period. We describe the clinical features of a 47-month-old Brazilian girl with 16q21q24.1 duplication. To the best of our knowledge, she is the first person with this specific chromosome segment duplication, and we compare her phenotype with the only reported individual alive with intermediate-distal pure 16q duplication.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Brasil , Pré-Escolar , Bandeamento Cromossômico , Feminino , Humanos , Fenótipo
5.
Medicine (Baltimore) ; 100(24): e26307, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128868

RESUMO

INTRODUCTION: 22q13.3 deletion syndrome is a well-known syndrome characterized by typical clinical findings including neonatal hypotonia, absent or severely delayed speech, intellectual disability, and other various features, and detection of a heterozygous deletion of chromosome 22q13.3 with the involvement of at least part of SHANK3. It is reported that 10% to 29% of patients with 22q13.3 deletion syndrome present lymphedema. Protein-losing enteropathy (PLE) has never been reported in 22q13.3 deletion syndrome. PATIENT CONCERNS: The patient presented to our institution for refractory hypoalbuminemia and chronic lymphedema in both legs. DIAGNOSIS: The patient manifested intellectual disability, absent speech, tooth grinding, dysmorphic face, and abnormal hands and toenails. Copy-number variation sequencing confirmed the maternal deletion in 22q13.31-q13.33 (chr22:46285592-51244566, hg19). The patient was genetically diagnosed with 22q13.3 deletion syndrome. INTERVENTIONS: Low-fat diets and medium-chain triglycerides supplements were prescribed. The patient was recommended to wear compression garments and elevate legs. OUTCOMES: The symptom of diarrhea was resolved, but hypoalbuminemia persisted. Lower extremities lymphedema was gradually becoming severe. CONCLUSIONS: Primary lymphedema and PLE can occur simultaneously in a patient with 22q13.3 deletion syndrome. The 2 phenotypes could share the same genetic etiology of congenital lymphatic abnormalities. CELSR1 deletion may play a role in lymphatic dysplasia. The case also provides additional proof of the pathogenic effect of CELSR1 on hereditary lymphedema.


Assuntos
Caderinas/genética , Transtornos Cromossômicos/genética , Linfedema/genética , Enteropatias Perdedoras de Proteínas/genética , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Hipoalbuminemia/genética , Deficiência Intelectual/genética , Perna (Membro)/patologia , Adulto Jovem
6.
Medicine (Baltimore) ; 100(24): e26309, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128869

RESUMO

RATIONALE: The Schaaf-Yang syndrome (SYS) is an autosomal dominant multi-system genetic disease caused by melanoma antigen L2 (MAGEL2) gene mutations imprinted by mothers and expressed by fathers on the 15q11-15q13 chromosomes in the critical region of Prader-Willi. MAGEL2 is a single exon gene and one of the protein-coding genes of the Prader-Willi domain. MAGEL2 is a matrilineal imprinted gene (i.e., the maternal chromosome is methylated). It is only expressed by unmethylated paternal alleles, and the individual is affected only when the variation occurs on the paternal allele. PATIENT CONCERNS: We reported a patient with MAGEL2 gene new site mutation who had mild intellectual disability, social fear, small hands and feet, obesity issues, dyskinesia, growth retardation, language lag and sexual development disorder. DIAGNOSIS: Whole-exome sequencing showed a heterozygous variation in the MAGEL2 gene, NM_019066.4:c.1687C > T (p.Q563X) and diagnosed as Schaaf-Yang syndrome. INTERVENTIONS: Patient was advised to reduce weight, control blood lipids, blood glucose through appropriate strengthening of exercise and diet control in the future. At the same time, the family members were advised to provide mental training to the patient to strengthen the contact and communication with the outside world and improve the autistic symptoms. Because of the patient's bilateral cryptorchidism, it is recommended that the patient should be treated with bilateral cryptorchidism reduction fixation. OUTCOMES: After a follow-up of the patient for 2 months, the patient is still walking unsteadily and requires an auxiliary reference material to walk normally. There is no significant change in height compared to before, and the weight has dropped by about 2 kg in the past 2 months. The symptoms of autism have improved slightly. The patient is willing to communicate with outsiders; his intelligence has not improved significantly, and his academic performance in school is still at the middle and lower levels. LESSONS: The pathogenesis of SYS is complex, involving multiple pathways such as Leptin-POMC, MAGEL2-USP7-TRIM27 complex and oxytocin. Our study has also found that certain fatal phenotypes such as respiratory distress have a high incidence at individual sites, and early detection and timely intervention may prolong the life span of patients. Therefore, for patients in whom SYS is highly suspected, gene detection should be carried out as soon as possible.


Assuntos
Transtornos Cromossômicos/genética , Proteínas/genética , Adolescente , Humanos , Masculino , Mutação , Fenótipo , Sequenciamento Completo do Exoma
7.
Medicine (Baltimore) ; 100(20): e25999, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011095

RESUMO

ABSTRACT: Chromosomal microarray analysis (CMA) has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. The aim of this study was to compare the accuracy and value of CMA and karyotyping on diagnosis of chromosomal abnormalities in Fujian province of South China.In the study, 410 clinical samples were collected from pregnant women between March 2015 and December 2016, including 3 villus (0.73%, 3/410), 296 amniotic fluid (72.20%, 296/410), and 111 umbilical cord blood (27.07%, 111/410). All samples were screening for chromosomal abnormalities by both using CMA and karyotyping.The success rate of CMA and karyotyping was 100% (410/410) and 99.27% (407/410), respectively. Sixty-one (14.88%, 61/410) samples were presented with chromosomal abnormalities by using CMA, whereas 47 (11.55%, 47/407) samples were shown with chromosomal abnormalities by using karyotyping. Thirty-one (8.61%, 31/360) samples with normal karyotypes were found to exist chromosomal abnormalities by using CMA. Receiver operating characteristic analysis showed that the area under the curve of karyotyping on the diagnosis of chromosomal abnormalities was 0.90 (95% confidence interval: 0.87-0.93), the sensitivity and specificity was 87.56% and 91.22%, respectively. The area under the curve of CMA on the diagnosis of chromosomal abnormalities was 0.93 (95% confidence interval: 0.90-0.95), with 90.68% sensitivity and 94.40% specificity. Notably, the combination of CMA and karyotyping could improve the diagnosis of chromosomal abnormalities.CMA has a better diagnostic value for screening chromosomal abnormalities, especially for those pregnant women with normal karyotypes. This study has guiding value for prenatal diagnosis in Fujian province of South China.


Assuntos
Transtornos Cromossômicos/diagnóstico , Testes Genéticos/métodos , Cariotipagem/estatística & dados numéricos , Análise em Microsséries/estatística & dados numéricos , Diagnóstico Pré-Natal/métodos , Adulto , China , Transtornos Cromossômicos/genética , Cromossomos Humanos/genética , Feminino , Testes Genéticos/estatística & dados numéricos , Idade Gestacional , Humanos , Gravidez , Diagnóstico Pré-Natal/estatística & dados numéricos , Estudos Prospectivos , Curva ROC , Estudos Retrospectivos , Adulto Jovem
8.
Medicine (Baltimore) ; 100(18): e25777, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950970

RESUMO

RATIONALE: The chromosome 18p deletion syndrome is a syndrome with a deletion of all or a portion of the short arm of the chromosome 18. The phenotypes of the chromosome 18p deletion syndrome vary widely among individuals due to differences in size and breakpoints and the involved genes on the deletions. Given the varied and untypical clinical presentation of this syndrome, the prenatal diagnosis of the syndrome still presents as a challenge. PATIENT CONCERNS: We described 4 China cases with different chromosomal breakpoints. In case 1, a woman who with mild phenotypes gave birth to a severely deformed fetus. Three other cases were for prenatal diagnosis. Their phenotypes are the increased nuchal translucency (INT) and the noninvasive prenatal testing (NIPT) indicated deletions on the chromosome 18p and severe hydronephrosis respectively. DIAGNOSIS: The 4 cases were diagnosed with chromosome 18p deletion syndrome through karyotype analysis and array-based comparative genomic hybridization (array-CGH). INTERVENTIONS: Karyotype analysis and array-based comparative genomic hybridization were used to analyze the abnormal chromosome. OUTCOMES: Case 1 and case 2 revealed 11.51 and 12.39 Mb deletions in 18p11.32p11.21. Case 3 revealed 7.1 Mb deletions in 18p11.3218p11.23. Case 4 revealed 9.9 Mb deletions in 18p11.3218p11.22. LESSONS: In our report, we are the first to report that mother and progeny who have the same chromosomal breakpoint have different phenotypes, significantly. In addition, we found a new phenotype of chromosome 18p deletion syndrome in fetus, which can enrich the phenotypes of this syndrome in the prenatal diagnosis. Finally, we demonstrate that the individuals with different chromosomal breakpoints of 18p deletion syndrome have different phenotypes. On the other hand, the individuals with the same chromosomal breakpoints of 18p deletion syndrome may also have remarkably different phenotypes.


Assuntos
Cariótipo Anormal , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 18/genética , Feto/anormalidades , Hidronefrose/diagnóstico , Adulto , Deleção Cromossômica , Transtornos Cromossômicos/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Hidronefrose/genética , Cariotipagem , Teste Pré-Natal não Invasivo , Medição da Translucência Nucal , Gravidez , Índice de Gravidade de Doença
9.
Cytogenet Genome Res ; 161(3-4): 120-131, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33975305

RESUMO

In the present study, we retrospectively recruited 340 patients who underwent spontaneous abortions to investigate chromosomal abnormalities of the conception products in the first trimester. We also performed a relevant analysis of clinical factors. Of these patients, 165 had conception products with chromosomal abnormalities, including 135 aneuploidies, 11 triploidies, 10 complex abnormalities, and 9 segmental aneuploidies. The most common abnormal chromosomes were chromosome 16 in the embryo-transfer group and sex chromosomes in the natural-conception group. The most common abnormal chromosomes in all analyzed maternal age groups were sex chromosomes, 16, and 22. The chromosomal abnormality incidence was related to age and number of spontaneous abortions (both p < 0.05), but not to number of pregnancies, deliveries, induced abortions, or methods of conception (all p > 0.05). The rates of abnormality for chromosomes 12, 15, 20, and 22 increased with age, while the rates for chromosomes 6, 7, 13, and X decreased. In all age groups, aneuploidy was by far the most common abnormality; however, the low-incidence distributions of chromosomal abnormalities were entirely different. Overall, chromosomal aneuploidy was the primary cause of pregnancy loss in the first trimester, and low-frequency abnormalities differed across age subgroups. Chromosomal aberrations were found to be related to maternal age and spontaneous abortion, but not all chromosomal abnormalities increased with age.


Assuntos
Aborto Espontâneo/genética , Aneuploidia , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Análise Citogenética/métodos , Primeiro Trimestre da Gravidez/genética , Adulto , Feminino , Fertilização/genética , Humanos , Idade Materna , Monossomia , Gravidez , Estudos Retrospectivos , Triploidia , Trissomia , Adulto Jovem
10.
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
11.
Biomed Res Int ; 2021: 8893467, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34036105

RESUMO

Chromosomal abnormalities are the main genetic risk factor associated with reproductive and sexual development disorders (DSD). The goal of this study is to retrospectively evaluate the frequency of chromosomal aberrations in Moroccan subjects with problems of procreation or sexual ambiguity. A total of 1005 individuals, including 170 infertile couples, underwent cytogenetic analysis in the Cytogenetic Laboratory of the Pasteur Institute of Morocco. Heparinized blood samples were processed according to the standard karyotype method. A total (81.5%) of the patients studied had a normal karyotype, while the remaining (18.5%) patients had an abnormal karyotype. Female patients had more chromosomal abnormalities (52%) than male patients (48%). These chromosomal aberrations included 154 cases (83%) of sex chromosomal abnormalities, the most common being Turner's syndrome and Klinefelter's syndrome, and 31 cases (17%) had autosomal aberrations, especially chromosome 9 reversal (inv(9)(p12;q13)). The present data shows that among 170 couples, 10.6% had chromosomal abnormalities mainly involved in the occurrence of recurrent miscarriages. Genotype-phenotype correlations could not be made, and therefore, studies using more resolutive molecular biology techniques would be desirable.


Assuntos
Aberrações Cromossômicas , Predisposição Genética para Doença/genética , Desenvolvimento Sexual/genética , Transtornos Sexuais e da Identidade de Gênero/genética , Aborto Habitual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/genética , Citogenética , Feminino , Humanos , Lactente , Recém-Nascido , Infertilidade/genética , Cariótipo , Cariotipagem , Síndrome de Klinefelter/epidemiologia , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Marrocos , Estudos Retrospectivos , Transtornos Sexuais e da Identidade de Gênero/epidemiologia , Translocação Genética/genética , Síndrome de Turner/epidemiologia , Síndrome de Turner/genética , Adulto Jovem
12.
Genes (Basel) ; 12(5)2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922640

RESUMO

Chromosomal duplications are associated with a large group of human diseases that arise mainly from dosage imbalance of genes within the rearrangements. Phenotypes range widely but are often associated with global development delay, intellectual disability, autism spectrum disorders, and multiple congenital abnormalities. How different contiguous genes from a duplicated genomic region interact and dynamically affect the expression of each other remains unclear in most cases. Here, we report a genomic comparative delineation of genes located in duplicated chromosomal regions 8q24.13q24.3, 18p11.32p11.21, and Xq22.3q27.2 in three patients followed up at our genetics service who has the intellectual disability (ID) as a common phenotype. We integrated several genomic data levels by identification of gene content within the duplications, protein-protein interactions, and functional analysis on specific tissues. We found functional relationships among genes from three different duplicated chromosomal regions, reflecting interactions of protein-coding genes and their involvement in common cellular subnetworks. Furthermore, the sharing of common significant biological processes associated with ID has been demonstrated between proteins from the different chromosomal regions. Finally, we elaborated a shared model of pathways directly or indirectly related to the central nervous system (CNS), which could perturb cognitive function and lead to ID in the three duplication conditions.


Assuntos
Transtornos Cromossômicos/genética , Duplicação Cromossômica , Deficiência Intelectual/genética , Criança , Transtornos Cromossômicos/patologia , Feminino , Humanos , Deficiência Intelectual/patologia , Masculino , Neurogênese , Mapas de Interação de Proteínas
13.
Genes (Basel) ; 12(4)2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805390

RESUMO

In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90-95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies.


Assuntos
Transtornos Cromossômicos/diagnóstico , Testes Genéticos/métodos , Análise em Microsséries/métodos , Diagnóstico Pré-Natal/métodos , Transtornos Cromossômicos/genética , Feminino , Humanos , Gravidez
14.
Genes (Basel) ; 12(3)2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799648

RESUMO

Global medical associations (ACOG, ISUOG, ACMG) recommend diagnostic prenatal testing for the detection and prevention of genetic disorders. Historically, cytogenetic methods such as karyotype analysis, fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are utilized worldwide to diagnose common syndromes. However, the limitations of each of these methods, either performed in tandem or simultaneously, demonstrates the need of a revolutionary technology that can alleviate the need for multiple technologies. Optical genome mapping (OGM) is a novel method that fills this void by being able to detect all classes of structural variations (SVs), including copy number variations (CNVs). OGM is being adopted by laboratories as a tool for both postnatal constitutional genetic disorders and hematological malignancies. This commentary highlights the potential for OGM to become a standard of care in prenatal genetic testing based on its capability to comprehensively identify large balanced and unbalanced SVs (currently the strength of karyotyping and metaphase FISH), CNVs (by CMA), repeat contraction disorders (by Southern blotting) and multiple repeat expansion disorders (by PCR-based methods or Southern blotting). Next-generation sequencing (NGS) methods are excellent at detecting sequence variants, but they are unable to accurately resolve repeat regions of the genome, which limits their ability to detect all classes of SVs. Notably, multiple molecular methods are used to identify repeat expansion and contraction disorders in routine clinical laboratories around the world. With non-invasive prenatal testing (NIPT) becoming the standard of care screening assay for all global pregnancies, we anticipate that OGM can provide a high-resolution, cytogenomic assay to be employed following a positive NIPT screen or for high-risk pregnancies with an abnormal ultrasound. Accurate detection of all types of genetic disorders by OGM, such as liveborn aneuploidies, sex chromosome anomalies, microdeletion/microduplication syndromes, repeat expansion/contraction disorders is key to reducing the global burden of genetic disorders.


Assuntos
Aneuploidia , Transtornos Cromossômicos , Variações do Número de Cópias de DNA , Genômica , Optogenética , Diagnóstico Pré-Natal , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Feminino , Humanos , Gravidez
15.
Eur J Med Genet ; 64(7): 104225, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33872775

RESUMO

Ring X is a chromosomal anomaly mainly seen in females with turner syndrome and usually present in mosaic form with 45,X cells (45,X/46,X,r(X)) because of their mitotic instability. In males it is an extremely rare finding because large nullisomy for X chromosome material is likely not compatible with survival. Only two cases of male with ring chromosome X were previously reported. We report here a four-year-old male with ring chromosome X characterized using Karyotype, FISH and array CGH and presenting short stature, microcephaly and hypospadias. Molecular investigations showed 923 Kb terminal deletion on the pseudoautosomal region 1 (PAR1) including SHOX gene followed by a duplication of 2.4 Mb. The absence of functional nullisomy because of a second copy of deleted genes was present in chromosome Y PAR1 region may explain the compatibility with survival in our case of male with ring X. Short stature common with the two previously reported cases is likely related to SHOX gene deletion but also to the effect of "ring syndrome". However, hypospadias was not reported in the previous cases and can be due to the associated duplication outside PAR1 region including in particular PRKX gene coding for a protein involved in urogenital system morphogenesis.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos X/genética , Hipospadia/genética , Microcefalia/genética , Cromossomos em Anel , Pré-Escolar , Transtornos Cromossômicos/patologia , Deleção de Genes , Duplicação Gênica , Humanos , Hipospadia/patologia , Masculino , Microcefalia/patologia , Proteína de Homoeobox de Baixa Estatura/genética , Síndrome
16.
Zhonghua Yi Xue Za Zhi ; 101(15): 1088-1092, 2021 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-33878837

RESUMO

Objective: To investigate the general situation, detection range, testing reagents, and clinical performance of non-invasive prenatal testing (NIPT) for fetal chromosomal copy number variations (CNVs) in Chinese laboratories. Methods: The National Center for Clinical Laboratories of the National Health Commission designed a questionnaire for the detection of CNVs by NIPT, which included the investigation of whether the laboratory has carried out NIPT to detect CNVs and its testing scope, reagents/platforms, intended uses, screening populations and clinical performance. The questionnaires were distributed to 355 laboratories in 31 provinces, autonomous regions, and municipalities across the country on October, 2020. Further, the feedbacks were statistical analyzed. Results: Two hundred and twenty-eight laboratories had performed NIPT to detect CNVs, including 116 types of CNVs, and more than 95% of laboratories chose to detect the CNVs of 5p15 deletion, 22q11.2 deletion, 1p36 deletion, and 15q11.2 deletion. All testing reagents used were laboratory-developed tests and were based on massive parallel sequencing, the minimum amount of sequencing data was 3-15 M reads, the detection limit of fetal fraction was 3%-5%, and the minimum size of variants that can be detected was 1-5 Mb. The proportion of laboratories that apply CNVs testing for daily project, voluntary requirements of patients, and scientific research were 58.8% (134/228), 57.5% (131/228), and 20.6% (47/228), respectively. One hundred and thirty-four laboratories were fully or partially aware of the clinical performance of NIPT to detect microdeletion/microduplication syndromes, and the laboratories' declared sensitivity of NIPT for Cri du Chat syndrome, 22q11.2 deletion syndrome, 1p36 deletion syndrome, and Angelman syndrome were 50.0%-100%, 60.0%-100%, 50.0%-100%, and 33.3%-100%, and the positive predictive values were 9.0%-50.0%, 18.0%-100%, 20.0%-30.0%, and 20.0%. Conclusion: The detection of CNVs by NIPT in Chinese laboratories need to be standardized. Laboratories should detect CNVs with clear clinical significance in accordance with the guidelines, conduct performance validation of the reagents, then perform NIPT test and provide adequate interpretation after mastering the clinical performance sufficiently.


Assuntos
Transtornos Cromossômicos , Teste Pré-Natal não Invasivo , China , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Laboratórios , Gravidez , Diagnóstico Pré-Natal
17.
Hum Genet ; 140(7): 1047-1060, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33721060

RESUMO

Mutations in proteins involved in cell division and chromosome segregation, such as microtubule-regulating, centrosomal and kinetochore proteins, are associated with microcephaly and/or short stature. In particular, the kinetochore plays an essential role in mitosis and cell division by mediating connections between chromosomal DNA and spindle microtubules. To date, only a few genes encoding proteins of the kinetochore complex have been identified as causes of syndromes that include microcephaly. We report a male patient with a rare de novo missense variant in NUF2, after trio whole-exome sequencing analysis. The patient presented with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect. NUF2 encodes a subunit of the NDC80 complex in the outer kinetochore, important for correct microtubule binding and spindle assembly checkpoint. The mutated residue is buried at the calponin homology (CH) domain at the N-terminus of NUF2, which interacts with the N-terminus of NDC80. The variant caused the loss of hydrophobic interactions in the core of the CH domain of NUF2, thereby impairing the stability of NDC80-NUF2. Analysis using a patient-derived lymphoblastoid cell line revealed markedly reduced protein levels of both NUF2 and NDC80, aneuploidy, increased micronuclei formation and spindle abnormality. Our findings suggest that NUF2 may be the first member of the NDC80 complex to be associated with a human disorder.


Assuntos
Anormalidades Múltiplas/genética , Aneuploidia , Proteínas de Ciclo Celular/genética , Transtornos Cromossômicos/genética , Segregação de Cromossomos , Mutação de Sentido Incorreto , Anormalidades Múltiplas/patologia , Adolescente , Estatura/genética , Linhagem Celular , Transtornos Cromossômicos/patologia , Proteínas do Citoesqueleto/genética , Regulação para Baixo , Transtornos do Crescimento/genética , Humanos , Masculino , Microcefalia/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Fuso Acromático/patologia , Ubiquitina/metabolismo , Sequenciamento Completo do Genoma
18.
Taiwan J Obstet Gynecol ; 60(2): 318-323, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33678334

RESUMO

OBJECTIVE: The aim of this work was to characterize the genetic abnormalities and prenatal diagnosis indications in one fetus with Cri-du-Chat syndrome with codependent 10q24.2-q26.3 duplication in prenatal screening. MATERIALS AND METHODS: A 31-year-old woman had a second trimester serum screening that indicated the fetus was at low risk. During this pregnancy, the woman underwent amniocentesis at 18+4 weeks' gestation because of adverse fertility history and nuchal fold thickening. Cytogenetic analysis and next-generation sequencing analysis were simultaneously performed to provide genetic analysis of fetal amniotic fluid. According to abnormal results, parental chromosome karyotype of peripheral blood was performed to analysis. RESULTS: CNV-seq detected a 14.00 Mb deletion at 5p15.33-p15.2 and a 34.06 Mb duplication at 10q24.2-q26.3 in the fetus. Cytogenetic analysis of the fetus revealed a karyotype of 46, XY, der(5) t(5;10) (p15.2;q26.3). The karyotype of pregnant women was 46,XX,t(5;10) (p15.2;q24.2). The pregnancy was subsequently terminated after sufficient informed consent. CONCLUSION: This is the first study that reports prenatal diagnosis of a Cri-du-Chat syndrome with concomitant 10 q24.2-q26.3 duplication. Adverse pregnancy history has to be as an important indicator for prenatal diagnosis, and the genetic factors of abnormal pregnancy should be identified before next pregnancy. Nuchal fold thickening is closely related to fetal abnormalities. Combined with ultrasonography, the use of CNV-seq will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies.


Assuntos
Transtornos Cromossômicos/diagnóstico , Síndrome do Miado do Gato/diagnóstico , Trissomia/diagnóstico , Aborto Induzido , Adulto , Amniocentese , Transtornos Cromossômicos/embriologia , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 10/genética , Síndrome do Miado do Gato/embriologia , Síndrome do Miado do Gato/genética , Análise Citogenética , Feminino , Humanos , Cariotipagem , Gravidez , Segundo Trimestre da Gravidez/sangue , Trissomia/genética , Ultrassonografia Pré-Natal
19.
Taiwan J Obstet Gynecol ; 60(2): 350-354, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33678341

RESUMO

OBJECTIVE: The objective of this study was to report the first case of prenatal diagnosis of the fetal 20p13 microdeletion syndrome in the literature. CASE REPORT: The mother was 31 years old and had a first trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound at 23 weeks of gestation showed mild ventriculomegaly (10.2 mm) and absent septum pellucidum. She underwent amniocentesis because of the abnormal imaging results. Karyotype analysis revealed normal results. Chromosome microarray analysis (CMA) was then performed to provide genetic analysis of the fetus and parents. CMA detected 317.902 kb deletion of 20p13 in fetus. Finally, pregnancy was terminated at 32 weeks of gestation. CONCLUSION: This study is the first to report the prenatal diagnosis of a 20p13 microdeletion syndrome. Our results further confirmed that genes in this region, including SOX12, NRSN2 are essential for normal fetal growth and TBC1D20 for normal brain development.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal/métodos , Aborto Induzido , Adulto , Amniocentese , Deleção Cromossômica , Transtornos Cromossômicos/embriologia , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 20/genética , Feminino , Humanos , Cariotipagem , Gravidez
20.
Genetics ; 217(2)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33724415

RESUMO

Segmental duplications (SDs) are a class of long, repetitive DNA elements whose paralogs share a high level of sequence similarity with each other. SDs mediate chromosomal rearrangements that lead to structural variation in the general population as well as genomic disorders associated with multiple congenital anomalies, including the 7q11.23 (Williams-Beuren Syndrome, WBS), 15q13.3, and 16p12.2 microdeletion syndromes. Population-level characterization of SDs has generally been lacking because most techniques used for analyzing these complex regions are both labor and cost intensive. In this study, we have used a high-throughput technique to genotype complex structural variation with a single molecule, long-range optical mapping approach. We characterized SDs and identified novel structural variants (SVs) at 7q11.23, 15q13.3, and 16p12.2 using optical mapping data from 154 phenotypically normal individuals from 26 populations comprising five super-populations. We detected several novel SVs for each locus, some of which had significantly different prevalence between populations. Additionally, we localized the microdeletion breakpoints to specific paralogous duplicons located within complex SDs in two patients with WBS, one patient with 15q13.3, and one patient with 16p12.2 microdeletion syndromes. The population-level data presented here highlights the extreme diversity of large and complex SVs within SD-containing regions. The approach we outline will greatly facilitate the investigation of the role of inter-SD structural variation as a driver of chromosomal rearrangements and genomic disorders.


Assuntos
Transtornos Cromossômicos/genética , Anormalidades Craniofaciais/genética , Variação Estrutural do Genoma , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Duplicações Segmentares Genômicas , Convulsões/genética , Síndrome de Williams/genética , Pontos de Quebra do Cromossomo , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 16/genética , Deficiências do Desenvolvimento/genética , Humanos , Transtornos Mentais/genética
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