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1.
Prenat Diagn ; 44(5): 555-561, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38448008

RESUMO

OBJECTIVE: In singleton pregnancies, the use of cell-free DNA (cfDNA) analysis as a screening test for common fetal trisomies has spread worldwide though we still lack sufficient data for its use in triplet pregnancies. The objective of this study is to assess the performance of cfDNA testing in detecting fetal aneuploidies in triplet pregnancies as a first-tier test. METHOD: We performed a retrospective cohort study including data from pregnant women with a triplet pregnancy who underwent cfDNA testing between May 1, 2017, and January 15, 2020. cfDNA was obtained by massive parallel sequencing (VeriSeq NIPT solution; Illumina®). The objectives of the study were to assess the diagnostic performance of cfDNA testing for trisomy 21 (T21) (primary outcome), trisomy 18 (T18) and 13 (secondary outcomes). RESULTS: During the study period, cfDNA testing was performed in 255 women with triplet pregnancy, of which 165 (64.7%) had a neonatal outcome available. Three tests were positive for T21, one of which was confirmed by an antenatal karyotype, and the other was confirmed at birth. The third case did not undergo an invasive procedure and was not confirmed at birth (false positive). In one case, cfDNA testing was positive for T18 and was confirmed by an antenatal karyotype. There were no cases of trisomy 13 in the cohort. The no-call rate was 2.4% at first sampling. Fifty-eight (22.7%) women had embryo reduction, which in 40 (69%) of whom was performed after the cfDNA test result. CONCLUSION: cfDNA testing could be offered as primary screening for main fetal aneuploidies in triplet pregnancies after provision of appropriate patient information.


Assuntos
Ácidos Nucleicos Livres , Gravidez de Trigêmeos , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/análise , Adulto , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética , Síndrome da Trissomía do Cromossomo 18/sangue , Trissomia/diagnóstico , Trissomia/genética , Teste Pré-Natal não Invasivo/métodos , Teste Pré-Natal não Invasivo/estatística & dados numéricos , Teste Pré-Natal não Invasivo/normas , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/sangue , Síndrome da Trissomia do Cromossomo 13/genética , Estudos de Coortes , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Testes para Triagem do Soro Materno/métodos , Testes para Triagem do Soro Materno/estatística & dados numéricos , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/normas
2.
Am J Med Genet A ; 194(4): e63476, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37974505

RESUMO

Cat Eye Syndrome (CES) is a rare genetic disease caused by the presence of a small supernumerary marker chromosome derived from chromosome 22, which results in a partial tetrasomy of 22p-22q11.21. CES is classically defined by association of iris coloboma, anal atresia, and preauricular tags or pits, with high clinical and genetic heterogeneity. We conducted an international retrospective study of patients carrying genomic gain in the 22q11.21 chromosomal region upstream from LCR22-A identified using FISH, MLPA, and/or array-CGH. We report a cohort of 43 CES cases. We highlight that the clinical triad represents no more than 50% of cases. However, only 16% of CES patients presented with the three signs of the triad and 9% not present any of these three signs. We also highlight the importance of other impairments: cardiac anomalies are one of the major signs of CES (51% of cases), and high frequency of intellectual disability (47%). Ocular motility defects (45%), abdominal malformations (44%), ophthalmologic malformations (35%), and genitourinary tract defects (32%) are other frequent clinical features. We observed that sSMC is the most frequent chromosomal anomaly (91%) and we highlight the high prevalence of mosaic cases (40%) and the unexpectedly high prevalence of parental transmission of sSMC (23%). Most often, the transmitting parent has mild or absent features and carries the mosaic marker at a very low rate (<10%). These data allow us to better delineate the clinical phenotype associated with CES, which must be taken into account in the cytogenetic testing for this syndrome. These findings draw attention to the need for genetic counseling and the risk of recurrence.


Assuntos
Aneuploidia , Transtornos Cromossômicos , Cromossomos Humanos Par 22 , Anormalidades do Olho , Cardiopatias Congênitas , Humanos , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Cromossomos Humanos Par 22/genética , Cardiopatias Congênitas/genética
3.
Genes (Basel) ; 13(11)2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36360264

RESUMO

A vanishing twin (VT) occurs in up to 30% of early diagnosed twin pregnancies and is associated with an increased risk of fetal aneuploidy. Here, we describe our experience in a large VT population of 847 patients that underwent noninvasive prenatal testing (NIPT) for common fetal trisomies over a three-year period. All patients underwent an ultrasound examination prior to NIPT. Two comparison populations were included, namely, the singleton (n = 105,560) and the viable multiple gestation pregnancy samples (n = 9691) collected over the same period. All NIPT samples in the VT population received a result, of which 14 were high-risk for trisomy 21 (1.6%), nine for trisomy 18 (1.1%), and six for trisomy 13 (0.7%). Diagnostic testing confirmed the presence of trisomy 21 in 6/12 samples, giving a positive predictive value of 50%. One trisomy 18 case and no trisomy 13 cases were confirmed. The time between fetal demise and NIPT sampling did not appear to affect the number of true- or false-positive cases. In conclusion, NIPT is an effective screening method for trisomy 21 in the surviving fetus(es) in VT pregnancies. For trisomies 18 and 13, a positive NIPT should be interpreted carefully and ultrasound monitoring is preferrable over invasive diagnostic testing.


Assuntos
Síndrome de Down , Teste Pré-Natal não Invasivo , Gravidez , Feminino , Humanos , Trissomia/diagnóstico , Trissomia/genética , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética
4.
Front Genet ; 13: 926290, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36226188

RESUMO

A supernumerary marker chromosome (SMC) is a structurally abnormal chromosome that cannot be characterized by conventional banding cytogenetics. Marker chromosomes are present in 0.075% of prenatal cases. They are associated with variable phenotypes, ranging from normal to severely abnormal, and the prognosis is largely dependent on the results of further cytogenomic analysis. Here, we report the identification and characterization of a marker chromosome following prenatal screening in a 39-year-old pregnant patient. The patient had a normal first trimester ultrasound but was high-risk for fetal chromosome anomalies based on the results of maternal serum parameters. Chorionic villus sampling was performed, and analysis of chorionic villi revealed the presence of two identical marker chromosomes. In the interest of a rapid identification of the markers, we performed noninvasive prenatal testing (NIPT) together with chorionic villus sampling. A pericentromeric 29 Mb duplication of chromosome 20: dup (20) (p13q11.21) was identified and thereafter confirmed by targeted metaphasic FISH. Whole-genome sequencing-based NIPT was instrumental in rapid characterization of the SMCs and allowed us to obviate the need for multiple expensive and time-consuming FISH analyses.

5.
Front Genet ; 13: 975987, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105088

RESUMO

Cell-free (cf) DNA screening is a noninvasive prenatal screening approach that is typically used to screen for common fetal trisomies, with optional screening for sex chromosomal aneuploidies and fetal sex. Genome-wide cfDNA screening can screen for a wide variety of additional anomalies, including rare autosomal aneuploidies (RAAs) and copy number variants. Here, we describe a multi-cohort, global retrospective study that looked at the clinical outcomes of cases with a high-risk cfDNA screening result for a RAA. Our study cohort included a total of 109 cases from five different sites, with diagnostic outcome information available for 68% (74/109) of patients. Based on confirmatory diagnostic testing, we found a concordance rate of 20.3% for presence of a RAA (15/74) in our study population. Pregnancy outcome was also available for 77% (84/109) of cases in our cohort. Many of the patients experienced adverse pregnancy outcomes, including intrauterine fetal demise, fetal growth restriction, and preterm birth. These adverse outcomes were observed both in patients with fetal or placental confirmation of the presence of a RAA, as well as patients that did not undergo fetal and/or placental diagnostic testing. In addition, we have proposed some suggestions for pregnancy management and counseling considerations for situations where a RAA is noted on a cfDNA screen. In conclusion, our study has shown that genome-wide cfDNA screening for the presence of rare autosomal aneuploidies can be beneficial for both patients and their healthcare practitioners. This can provide a possible explanation for an adverse pregnancy outcome or result in a change in pregnancy management, such as increased monitoring for adverse outcomes.

6.
Taiwan J Obstet Gynecol ; 61(2): 382-384, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35361407

RESUMO

OBJECTIVE: Uniparental disomy (UPD) is one of the common causes of imprinting disorders, which can have an impact on gene expression according to the origin of the parental chromosome. Paternal UPD14 leads to Kagami-Ogata syndrome (KOS), which has a more severe phenotype than maternal UPD14, also called Temple syndrome. Small supernumerary marker chromosomes (SSMCs) are defined as structural chromosomal abnormalities that may be inherited or come from micronucleus-mediated chromothripsis. The association of UPD and SSMC is very rare but not fortuitous and several mechanisms can explain this phenomenon. CASE REPORT: We report the first prenatal case of paternal isodisomy for chromosome 14 associated with a de novo SSMC originating from chromosome 15 and revealed by KOS. The mechanism could be a chromothripsis mediated by trisomy rescue. CONCLUSION: Regarding this case, in relation to a de novo SSMC, it could be important to extend the research of UPD to other acrocentric chromosomes if ultrasound signs are evocative.


Assuntos
Cromossomos Humanos Par 15 , Dissomia Uniparental , Cromossomos , Cromossomos Humanos Par 14 , Feminino , Marcadores Genéticos , Humanos , Gravidez , Dissomia Uniparental/genética
7.
Am J Obstet Gynecol ; 225(6): 676.e1-676.e15, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34058167

RESUMO

BACKGROUND: Compared with standard karyotype, chromosomal microarray analysis improves the detection of genetic anomalies and is thus recommended in many prenatal indications. However, evidence is still lacking on the clinical utility of chromosomal microarray analysis in cases of isolated fetal growth restriction. OBJECTIVE: This study aimed to estimate the proportion of copy number variants detected by chromosomal microarray analysis and the incremental yield of chromosomal microarray analysis compared with karyotype in the detection of genetic abnormalities in fetuses with isolated fetal growth restriction. STUDY DESIGN: This retrospective study included all singleton fetuses diagnosed with fetal growth restriction and no structural ultrasound anomalies and referred to 13 French fetal medicine centers over 1 year in 2016. Fetal growth restriction was defined as an estimated fetal weight of

Assuntos
Retardo do Crescimento Fetal/genética , Análise em Microsséries , Diagnóstico Pré-Natal , Adulto , Feminino , França , Humanos , Gravidez , Estudos Retrospectivos
8.
J Clin Med ; 9(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32752152

RESUMO

Atypical fetal chromosomal anomalies are more frequent than previously recognized and can affect fetal development. We propose a screening strategy for a genome-wide non-invasive prenatal test (NIPT) to detect these atypical chromosomal anomalies (ACAs). Two sample cohorts were tested. Assay performances were determined using Cohort A, which consisted of 192 biobanked plasma samples-42 with ACAs, and 150 without. The rate of additional invasive diagnostic procedures was determined using Cohort B, which consisted of 3097 pregnant women referred for routine NIPT. Of the 192 samples in Cohort A, there were four initial test failures and six discordant calls; overall sensitivity was 88.1% (37/42; CI 75.00-94.81) and specificity was 99.3% (145/146; CI 96.22-99.88). In Cohort B, there were 90 first-pass failures (2.9%). The rate of positive results indicating an anomaly was 1.2% (36/3007) and 0.57% (17/3007) when limited to significant unbalanced chromosomal anomalies and trisomies 8, 9, 12, 14, 15, 16, and 22. These results show that genome-wide NIPT can screen for ACAs with an acceptable sensitivity and a small increase in invasive testing, particularly for women with increased risk following maternal serum screening and by limiting screening to structural anomalies and the most clinically meaningful trisomies.

9.
Fetal Diagn Ther ; 45(5): 302-311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29898450

RESUMO

OBJECTIVES: To evaluate the failure rate and performance of cell-free DNA (cfDNA) testing, mainly in terms of detection rates for trisomy 21, performed by 2 laboratories using different analytical methods. METHODS: cfDNA testing was performed on 2,870 pregnancies with the HarmonyTM Prenatal Test using the targeted digital analysis of selected regions (DANSR) method, and on 2,635 pregnancies with the "Cerba test" using the genome-wide massively parallel sequencing (GW-MPS) method, with available outcomes. Propensity score analysis was used to match patients between the 2 groups. A comparison of the detection rates for trisomy 21 between the 2 laboratories was made. RESULTS: In all, 2,811 patients in the Harmony group and 2,530 patients in the Cerba group had no trisomy 21, 18, or 13. Postmatched comparisons of the patient characteristics indicated a higher no-result rate in the Harmony group (1.30%) than in the Cerba group (0.75%; p = 0.039). All 41 cases of trisomy 21 in the Harmony group and 93 cases in the Cerba group were detected. CONCLUSIONS: Both methods of cfDNA testing showed low no-result rates and a comparable performance in detecting trisomy 21; yet GW-MPS had a slightly lower no-result rate than the DANSR method.


Assuntos
Ácidos Nucleicos Livres/sangue , Técnicas de Laboratório Clínico/normas , Testes para Triagem do Soro Materno/normas , Diagnóstico Pré-Natal/normas , Pontuação de Propensão , Adulto , Ácidos Nucleicos Livres/genética , Técnicas de Laboratório Clínico/métodos , Síndrome de Down/sangue , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Seguimentos , Humanos , Idade Materna , Testes para Triagem do Soro Materno/métodos , Gravidez , Diagnóstico Pré-Natal/métodos , Estudos Prospectivos , Síndrome da Trissomia do Cromossomo 13/sangue , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/sangue , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética
10.
J Transl Med ; 16(1): 335, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30509296

RESUMO

BACKGROUND: Recent studies have suggested a possible association between heparin treatment at the time of cell-free DNA (cfDNA) testing and a non-reportable result. However, these studies lack of proper methodology and had a low level of proof to firmly incriminate heparin. Our objective was to investigate further the relationship between heparin treatment and cfDNA test results. METHODS: Two complementary approaches were used for the demonstration. First, we conducted a retrospective analysis of a cohort of patients with a singleton pregnancy, screened for aneuploidies by using cfDNA, but with a non-reportable cfDNA result. We included patients between 2013 and 2016 including the patients from the DEPOSA study as controls. CfDNA testing was performed by massive parallel sequencing by using a whole-genome approach. A multiple logistic regression was used to account for the influence of the variables included. Second, we performed in vitro experiments on mimic samples containing increased concentrations of heparin. RESULTS: Of 9867 singleton pregnancies tested during the inclusion period, 58 (0.59%) had a non-reportable result and were compared to 295 control patients. Fifteen (25.9%) and 20 (6.8%) patients were treated with heparin in the group with a non-reportable cfDNA result and with a successful assay, respectively. In multivariable analysis, an increased calculated risk at the first-trimester combined screening (OR 28.8 CI 9.76-85.15, p < 0.001), maternal weight (OR 1.03, CI 1.01-1.06, p = 0.01), and the presence of an autoimmune disease (OR 10.38, CI 1.62-66.53, p = 0.01) were the only characteristics associated with a non-reportable result. In vitro experiments showed that heparin had no impact on fetal fraction measurement or the final result, no matter what the dose tested. CONCLUSIONS: Treatment by heparin had no impact on cfDNA screening test for aneuploidies, while the presence of an autoimmune disorder is an independent predictor of a non-reportable result.


Assuntos
Doenças Autoimunes/metabolismo , Ácidos Nucleicos Livres/análise , Heparina/farmacologia , Adulto , Sistema Livre de Células , Feminino , Humanos , Modelos Logísticos , Gravidez , Resultado da Gravidez
11.
Genet Med ; 20(11): 1346-1353, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29493578

RESUMO

PURPOSE: Cell-free DNA (cfDNA) as a primary screening test has been available for years but few studies have addressed this option in a prospective manner. The question is of interest after reports that maternal serum screening (MSS) is less accurate for pregnancies resulting from assisted reproduction technologies (ART) than for spontaneous pregnancies (SP). METHODS: A prospective interventional study was designed to address the performances of cfDNA compared with MSS in pregnancies with or without ART. Each patient was offered both MSS and cfDNA testing. The primary analysis cohort ultimately included 794 patients with a spontaneous pregnancy (SP) (n = 472) or pregnancy obtained after ART (n = 322). RESULTS: Overall, the false-positive rate and positive predictive value were 6.6% and 8.8% for MSS but 0% and 100% for cfDNA. MSS false-positive rate and positive predictive values were clearly poorer in the ART group (11.7% and 2.6%) than in the SP group (3.2% and 21.1%). The global rates of invasive procedures were 1.9% (15/794) with cfDNA but 8.4% (65/794) if MSS alone was proposed. CONCLUSION: cfDNA achieved better performance than MSS in both spontaneous and ART pregnancies, thus decreasing the number of invasive procedures. Our findings suggest that cfDNA should be considered for primary screening, especially in pregnancies obtained after ART.


Assuntos
Ácidos Nucleicos Livres/sangue , Síndrome de Down/sangue , Testes Genéticos , Diagnóstico Pré-Natal/métodos , Adulto , Ácidos Nucleicos Livres/genética , Síndrome de Down/genética , Síndrome de Down/patologia , Feminino , Feto , Humanos , Idade Materna , Gravidez , Primeiro Trimestre da Gravidez , Técnicas de Reprodução Assistida
12.
Prenat Diagn ; 38(2): 106-109, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29231978

RESUMO

OBJECTIVE: To assess the distribution of nuchal translucency (NT) measurements following a national policy without credentialing and its impact on first-trimester Down syndrome screening (DSS) detection rate. METHOD: All first-trimester DSS data recorded in France (2010-2014) were collected by the laboratories in charge via an Internet database (https://www.bionuqual.org/echo.php). There was no minimal requirement for image quality to allow sonographers to enter the screening process. A subgroup of DSS with complete DS follow-up corresponded to 1614 sonographers. Based on the distribution of maternal age, DS detection rate was calculated and split as a function of the distribution of NT multiple of the median (MoM). RESULTS: Four thousand nine hundred forty-three sonographers performed 2,337,372 NT measurements. Median NT expressed in MoM was 0.83. Screenings with complete follow-up consisted of 197,417 screenings, in which DSS detection rates were respectively 70.4%, 70.9%, 79.4%, 87.7%, and 79.5% for the following median NT MoM ranges: <0.7, 0.70 to 0.79, 0.80 to 0.89, 0.90 to 0.99, and >0.99 (trend χ = 12.21; P = .0158). CONCLUSION: In France, following a policy of quality assessment without standardized credentialing, the distribution of NT measurements did not fit the expected distribution. Down syndrome detection rate was 10% lower in screenings by sonographers with a median NT < 0.80 MoM.


Assuntos
Síndrome de Down/diagnóstico por imagem , Medição da Translucência Nucal/métodos , Adulto , Feminino , França , Humanos , Idade Materna , Medição da Translucência Nucal/estatística & dados numéricos , Gravidez , Primeiro Trimestre da Gravidez , Garantia da Qualidade dos Cuidados de Saúde
13.
Hum Mutat ; 37(7): 661-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26936114

RESUMO

Chromoanagenesis is the process by which a single catastrophic event creates complex rearrangements confined to a single or a few chromosomes. It is usually characterized by the presence of multiple deletions and/or duplications, as well as by copy neutral rearrangements. In contrast, an array CGH screen of patients with developmental anomalies revealed three patients in which a single chromosome carries from 8 to 11 large copy number gains confined to a single chromosome or chromosomal arm, but the absence of deletions. Subsequent fluorescence in situ hybiridization and massive parallel sequencing revealed the duplicons to be clustered together in distinct locations across the altered chromosomes. Breakpoint junction sequences showed both microhomology and non-templated insertions of up to 40 bp. Hence, these patients each demonstrate a single altered chromosome of clustered insertional duplications, no deletions, and breakpoint junction sequences showing microhomology and/or non-templated insertions. These observations are difficult to reconcile with current mechanistic descriptions of chromothripsis and chromoanasynthesis. Therefore, we hypothesize those rearrangements to be of a mechanistically different origin. In addition, we suggest that large untemplated insertional sequences observed at breakpoints are driven by a non-canonical non-homologous end joining mechanism.


Assuntos
Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Hibridização Genômica Comparativa , Feminino , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Masculino , Análise em Microsséries , Análise de Sequência de DNA
14.
Eur J Hum Genet ; 24(6): 844-51, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26508576

RESUMO

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.


Assuntos
Síndrome da Deleção 22q11/diagnóstico , Testes Genéticos/estatística & dados numéricos , Síndrome da Deleção 22q11/epidemiologia , Síndrome da Deleção 22q11/genética , Adolescente , Adulto , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Feminino , França , Testes Genéticos/métodos , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Masculino , Herança Paterna
15.
Obstet Gynecol ; 125(6): 1330-1337, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26000504

RESUMO

OBJECTIVE: To evaluate the utility of noninvasive prenatal testing using cell-free circulating fetal DNA for detection of the three main autosomal fetal trisomies in the setting of ultrasonographically identified fetal anomalies. METHODS: Nine hundred patients at risk for fetal aneuploidy with or without ultrasonography anomalies and who underwent invasive procedures were included in the study. Cell-free DNA analysis was performed by massive parallel sequencing during a multicenter, noninterventional, prospective study and the results were compared with a fetal karyotype. RESULTS: Among all 900 pregnancies, cell-free DNA identified 76 of 76 (100%) fetal Down syndrome, 22 of 25 (88%) trisomy 18, and 12 of 12 (100%) trisomy 13. In those with a normal ultrasonogram and normal cell-free DNA analysis, karyotype identified 2 of 483 (0.4%) additional aneuploidies other than trisomies 13, 18, and 21. In those with an abnormal ultrasonogram and a normal cell-free DNA analysis, there were 23 of 290 (7.9%) additional pathogenic karyotypes. These additional aneuploidies included sex chromosome abnormalities and triploidy. The rates of additional aneuploidies not identifiable by standard cell-free DNA screening in the two groups is significantly different at P<.01. CONCLUSION: In women with fetal abnormalities by ultrasonography, the rate of pathogenic chromosome abnormalities missed by cell-free DNA was 8%. Noninvasive prenatal testing should not be offered to women with fetal abnormalities because a negative result is falsely reassuring. LEVEL OF EVIDENCE: III.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos X , DNA/sangue , Síndrome de Down/genética , Aberrações dos Cromossomos Sexuais , Trissomia/genética , Adulto , Transtornos Cromossômicos/diagnóstico por imagem , Cromossomos Humanos Par 13/diagnóstico por imagem , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 18/diagnóstico por imagem , Cromossomos Humanos Par 18/genética , Síndrome de Down/diagnóstico por imagem , Reações Falso-Negativas , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariótipo , Gravidez , Estudos Prospectivos , Sensibilidade e Especificidade , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18 , Ultrassonografia Pré-Natal
16.
Am J Med Genet A ; 167(6): 1275-84, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25900228

RESUMO

Familial transmission of chromosome 6 duplications is rare. We report on the first observation of a maternally-inherited pure segmental 6q duplication split into two segments, 6q15q16.3 and 6q16.3q21, and associated with obesity. Obesity has previously been correlated to chromosome 6 q-arm deletion but has not yet been assessed in duplications. The aim of this study was to characterize the structure of these intrachromosomal insertional translocations by classic cytogenetic banding, array-CGH, FISH, M-banding and genotyping using microsatellites and SNP array analysis, in a mother and four offspring. The duplicated 6q segments, 9.75 Mb (dup 1) and 7.05 Mb (dup 2) in size in the mother, were inserted distally into two distinct chromosome 6q regions. They were transmitted to four offspring. A son and a daughter inherited the two unbalanced insertions and displayed, like the mother, an abnormal phenotype with facial dysmorphism, intellectual disability, and morbid obesity. Curiously, two daughters with a normal phenotype inherited only the smaller segment, 6q16.3q21. The abnormal phenotype was associated with the larger proximal 6q15q16.3 duplication. We hypothesize a mechanism for this exceptional phenomenon of recurrent reduction and transmission of the duplication during meiosis in a family. We expect the interpretation of our findings to be useful for genetic counseling and for understanding the mechanisms underlying these large segmental 6q duplications and their evolution.


Assuntos
Padrões de Herança , Deficiência Intelectual/genética , Mutagênese Insercional , Obesidade/genética , Trissomia , Adolescente , Adulto , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 6 , Hibridização Genômica Comparativa , Família , Feminino , Aconselhamento Genético , Heterogeneidade Genética , Humanos , Deficiência Intelectual/patologia , Masculino , Meiose , Repetições de Microssatélites , Pessoa de Meia-Idade , Obesidade/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo
17.
Eur J Med Genet ; 57(10): 567-70, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25128687

RESUMO

Structural alterations in chromosomes are a frequent cause of cancers and congenital diseases. Recently, the phenomenon of chromosome crisis, consisting of a set of tens to hundreds of clustered genomic rearrangements, localized in one or a few chromosomes, was described in cancer cells under the term chromothripsis. Better knowledge and recognition of this catastrophic chromosome event has brought to light two distinct entities, chromothripsis and chromoanasynthesis. The complexity of these rearrangements and the original descriptions in tumor cells initially led to the thought that it was an acquired anomaly. In fact, a few patients have been reported with constitutional chromothripsis or chromoanasynthesis. Using microarray we identified a very complex chromosomal rearrangement in a patient who had a cytogenetically visible rearrangement of chromosome 18. The rearrangement contained more than 15 breakpoints localized on a single chromosome. Our patient displayed intellectual disability, behavioral troubles and craniofacial dysmorphism. Interestingly, the succession of duplications and triplications identified in our patient was not clustered on a single chromosomal region but spread over the entire chromosome 18. In the light of this new spectrum of chromosomal rearrangements, this report outlines the main features of these catastrophic events and discusses the underlying mechanism of the complex chromosomal rearrangement identified in our patient, which is strongly evocative of a chromoanasynthesis.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 18 , Rearranjo Gênico , Pré-Escolar , Quebra Cromossômica , Anormalidades Craniofaciais/genética , Instabilidade Genômica , Humanos , Deficiência Intelectual/genética , Masculino , Síndrome
18.
Hum Genet ; 133(3): 367-77, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24178751

RESUMO

Oral-facial-digital syndrome type VI (OFD VI) is a recessive ciliopathy defined by two diagnostic criteria: molar tooth sign (MTS) and one or more of the following: (1) tongue hamartoma (s) and/or additional frenula and/or upper lip notch; (2) mesoaxial polydactyly of one or more hands or feet; (3) hypothalamic hamartoma. Because of the MTS, OFD VI belongs to the "Joubert syndrome related disorders". Its genetic aetiology remains largely unknown although mutations in the TMEM216 gene, responsible for Joubert (JBS2) and Meckel-Gruber (MKS2) syndromes, have been reported in two OFD VI patients. To explore the molecular cause(s) of OFD VI syndrome, we used an exome sequencing strategy in six unrelated families followed by Sanger sequencing. We identified a total of 14 novel mutations in the C5orf42 gene in 9/11 families with positive OFD VI diagnostic criteria including a severe fetal case with microphthalmia, cerebellar hypoplasia, corpus callosum agenesis, polydactyly and skeletal dysplasia. C5orf42 mutations have already been reported in Joubert syndrome confirming that OFD VI and JBS are allelic disorders, thus enhancing our knowledge of the complex, highly heterogeneous nature of ciliopathies.


Assuntos
Proteínas de Membrana/genética , Síndromes Orofaciodigitais/diagnóstico , Síndromes Orofaciodigitais/genética , Anormalidades Múltiplas , Adolescente , Adulto , Alelos , Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Cerebelo/anormalidades , Criança , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Exoma , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Hamartoma/diagnóstico , Hamartoma/genética , Humanos , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/genética , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Polidactilia/diagnóstico , Polidactilia/genética , Retina/anormalidades , Análise de Sequência de DNA , Adulto Jovem
19.
Am J Med Genet A ; 146A(1): 93-6, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18076123

RESUMO

Interstitial deletions of the long arm of chromosome 12 are rare rearrangements with only 15 cases reported in the literature. The phenotype may include facial dysmorphism, developmental delay, ectodermal abnormalities, cardiac and renal malformations depending on breakpoints' position. Here, we describe a third case of 12(q15-q21.2) deletion ascertained through CGH-array analyses and provide a 5-year follow-up. The patient presented with pre- and postnatal growth retardation, congenital heart defect, developmental delay, and facial dysmorphism changing with age, underlining the importance of long-term follow-up. We compared this new case with previous observations of 12q deletions in order to propose phenotype-karyotype correlations.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 12 , Anormalidades Craniofaciais/genética , Deficiência Intelectual/genética , Pré-Escolar , Bandeamento Cromossômico , DNA/genética , Feminino , Marcadores Genéticos , Humanos , Cariotipagem , Repetições de Microssatélites , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos
20.
Am J Med Genet A ; 134(4): 439-42, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15810003

RESUMO

Holt-Oram syndrome, the major "heart-hand" syndrome is defined by the association of radial defects or triphalangeal thumbs and septal heart defects. The transmission is autosomal dominant and the causative gene has been shown to be TBX5, located on 12q24.1, which encodes a transcription factor. Genetic heterogeneity has been suggested by several reports. We identified a 14(q23.3 approximately 24.2q31.1) deletion in a boy presenting severe bilateral asymmetrical radial aplasia, congenital heart defects, and developmental delay. This deletion, whose size could be estimated to be 9.6-13.7 Mb, was shown to be inherited via his mother's interchromosomal insertion. This is the second report of a chromosome 14 interstitial deletion associated with clinical features of Holt-Oram syndrome. These observations suggest the existence of a new "heart-hand" locus on chromosome 14q.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Deformidades Congênitas da Mão/patologia , Cardiopatias Congênitas/patologia , Anormalidades Múltiplas/patologia , Bandeamento Cromossômico , Evolução Fatal , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Cariotipagem , Masculino , Síndrome
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