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1.
Mol Autism ; 10: 33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31406558

RESUMO

Background: Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated. Methods: To improve access to services, an ambulatory team has been established since 1998, delivering on-site clinical genetics consultations and gradually upgrading services to 502 children and young adults with ASD in their standard environment across 26 day-care hospitals and specialized institutions within the Greater Paris region. The evaluation included a clinical genetics consultation, screening for fragile X syndrome, metabolic workup, chromosomal microarray analysis, and, in a proportion of patients, next-generation sequencing of genes reported in ASD and other neurodevelopmental disorders. Results: Fragile X syndrome and pathogenic copy number variants (CNVs) accounted for the disease in 10% of cases, including 4/312 (1.3%) with fragile X syndrome and 34/388 (8.8%) with pathogenic CNVs (19 de novo and 4 inherited). Importantly, adding high-throughput resequencing of reported intellectual disability/ASD genes to the screening procedure had a major impact on diagnostic yield in the 141 patients examined most recently. Pathogenic or likely pathogenic sequence variants in 27 disease genes were identified in 33/141 patients (23.4%; 23 were de novo and 10 inherited, including five X-linked and five recessive compound heterozygous variants). Diagnosed cases presented atypical and/or syndromic ASD with moderate to severe intellectual disability. The diagnostic yield of fragile X syndrome and array CGH testing combined with next-generation sequencing was significantly higher than fragile X syndrome and array CGH alone (p value 0.009). No inborn errors of metabolism were detected with the metabolic screening. Conclusion: Based on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability.

2.
Prenat Diagn ; 39(11): 1026-1034, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31299102

RESUMO

OBJECTIVE: Neural tube defects (NTDs) are one of the most common congenital anomalies caused by a complex interaction of many genetic and environmental factors. In about 10% of cases, NTDs are associated with genetic syndromes or chromosomal anomalies. Among these, SOX3 duplication has been reported in some isolated cases. The phenotype associated with this microduplication is variable and includes myelomeningocele (MMC) in both sexes as well as hypopituitarism and cognitive impairment in males. In order to determine the prevalence of this anomaly in fetuses with MMC, a retrospective cohort of fetuses with MMC was analyzed by quantitative PCR (qPCR) targeting SOX3 locus. METHODS: The detection of an SOX3 microduplication by chromosomal microarray analysis (CMA) in two female fetuses with MMC prompted us to analyze retrospectively by qPCR this gene in a cohort of 53 fetuses with MMC. RESULTS: In addition to our two initial cases, one fetus harboring an Xq27.1q28 duplication that encompasses the SOX3 gene was detected. CONCLUSION: Our data demonstrate that SOX3 duplication is a genomic imbalance involved in the pathogenesis of NTDs. In addition, our survey highlights the importance of CMA testing in fetuses with NTDs to enable genetic counseling upstream of any considerations of in utero fetal surgery.

3.
Prenat Diagn ; 39(10): 871-882, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31172545

RESUMO

OBJECTIVE/METHOD: 1p36 deletion syndrome is considered to be the most common deletion after 22q11.2 deletion. It is characterized by specific facial features, developmental delay, and organ defects. The primary objective of the present multicenter study was to survey all the cases of 1p36 deletion diagnosed prenatally by French cytogenetics laboratories using a chromosomal microarray. We then compared these new cases with the literature data. RESULTS: Ten new cases were reported. On average, the 1p36 deletion was diagnosed at 19 weeks of gestation. The size of the deletion ranged from 1.6 to 16 Mb. The 1p36 deletion was the only chromosomal abnormality in eight cases and was associated with a complex chromosome 1 rearrangement in the two remaining cases. The invasive diagnostic procedure had always been prompted by abnormal ultrasound findings: elevated nuchal translucency, structural brain abnormality, retrognathia, or a cardiac defect. Multiple anomalies were present in all cases. DISCUSSION: We conclude that 1p36 deletion is not associated with any specific prenatal signs. We suggest that a prenatal observation of ventriculomegaly, congenital heart defect, or facial dysmorphism should prompt the clinician to consider a diagnosis of 1p36 deletion syndrome.

4.
Clin Genet ; 96(3): 246-253, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31090057

RESUMO

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.

6.
Transl Psychiatry ; 9(1): 101, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30814487

RESUMO

Since the online publication of the above article, the authors have noted errors with the author list. The author names were listed as '(last name)(first name)' instead of '(first name)(last name)'.

7.
Prenat Diagn ; 39(6): 464-470, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30896039

RESUMO

OBJECTIVES: Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD. METHODS: In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015. RESULTS: A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1). CONCLUSION: The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions.

8.
JAMA Netw Open ; 2(3): e191062, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924894

RESUMO

Importance: Noninvasive prenatal testing (NIPT) using cell-free DNA in maternal blood is increasingly common compared with invasive testing (IT) in routine antenatal detection of Down syndrome (DS). Objective: To assess attitudes and decision making in pregnant women facing a risk of fetal DS greater than 1 in 250 as established by combined first trimester screening at 11 to 14 weeks of gestation. Design, Setting, and Participants: Survey study in which data were collected from pregnant women at high risk of fetal DS participating in a randomized clinical trial. Data were collected from April 8, 2014, to April 7, 2016, in 57 prenatal diagnosis centers in France. Data were analyzed in 2018. Interventions: Data on attitudes were collected prior to offering randomization between NIPT and IT, whereas data on decision making and test results were collected as part of the clinical trial. Main Outcome and Measures: The primary outcome related to attitudes. A hierarchical cluster analysis was conducted to identify clusters with contrasting attitudes. Logistic regression analyses were used to identify factors associated with attitudes. Results: All 2436 consecutive women to whom the study was proposed (mean [SD] age, 36.3 [5.0] years) answered the questionnaire: 515 (21.1%) expressed preference toward IT with complete karyotyping, whereas 1843 (75.7%) favored NIPT with almost certain but limited information. Hierarchical cluster analysis yielded 4 different clusters that mainly differed in attitudes toward risk taking and extent of information seeking. Factors likely associated with attitudes driven by risk aversion were mostly age and religious beliefs (adjusted odds ratio [aOR], 1.03; 95% CI, 1.00-1.05; P = .03 and aOR, 1.62; 95% CI, 1.29-2.04; P < .001, respectively), whereas higher nuchal translucency measurements by ultrasonography were associated with attitudes driven by ambiguity aversion (aOR, 1.67; 95% CI, 1.27-2.20; P < .001). For attitudes involving both risk and ambiguity aversion at different extents, lower education was associated with highly valuing all possibilities of getting information on pregnancy, whereas higher education was associated with highly valuing information on fetal DS as a primary concern (aOR, 0.54; 95% CI, 0.44-0.67; P < .001 and aOR, 1.44; 95% CI, 1.20-1.74; P < .001, respectively). In all, decision making was in line with attitudes. Conclusions and Relevance: Aversion to risk of fetal loss related to IT and aversion to ambiguity generated by incomplete information from NIPT played a major role in shaping attitudes and decision making. Informed decision making should require pregnant women at high risk of DS to receive extensive information on targeted abnormalities by both tests.


Assuntos
Síndrome de Down , Complicações na Gravidez , Diagnóstico Pré-Natal/psicologia , Adulto , Síndrome de Down/diagnóstico , Síndrome de Down/psicologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/psicologia , Risco , Inquéritos e Questionários
9.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

10.
Nucleic Acids Res ; 47(6): 2822-2839, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30698748

RESUMO

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.


Assuntos
Proteínas Cromossômicas não Histona/fisiologia , Metilação de DNA , Proteínas de Homeodomínio/genética , Repetições de Microssatélites/genética , Células Cultivadas , Reprogramação Celular/genética , Atresia das Cóanas/genética , Atresia das Cóanas/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Regulação da Expressão Gênica , Células HCT116 , Células HEK293 , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Microftalmia/genética , Microftalmia/metabolismo , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/metabolismo , Distrofia Muscular Facioescapuloumeral/patologia , Nariz/anormalidades
11.
Am J Med Genet A ; 176(9): 1981-1984, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30178921

RESUMO

The clinical presentation of distal duplications of the long arm of chromosome (chr) 16 is currently not well described. Only one case of microduplication of chr16q22.1 and another involving the chr16q22.1q23.1 region have been reported so far. Here, using array comparative genomic hybridization, we identified a second case of chr16q22.1q23.1 duplication in a Vietnamese boy, who shares significant clinical phenotype with the previously described case. Aside from developmental delay, intellectual disability and midface hypoplasia, our patient also displays a forked tongue, visual impairment and external ptosis. Our report further expands the clinical spectrum associated with duplication of this region.

12.
JAMA ; 320(6): 557-565, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30120476

RESUMO

Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated. Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening. Design, Setting, and Participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening. Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing. Main Outcomes and Measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing. Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%). Conclusions and Relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates. Trial Registration: ClinicalTrials.gov Identifier: NCT02127515.


Assuntos
Aborto Espontâneo/etiologia , Amniocentese/efeitos adversos , Ácidos Nucleicos Livres/sangue , Amostra da Vilosidade Coriônica/efeitos adversos , Síndrome de Down/diagnóstico , Testes Genéticos/métodos , Resultado da Gravidez/epidemiologia , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/prevenção & controle , Adulto , Transtornos Cromossômicos/diagnóstico , Feminino , Morte Fetal , Humanos , Nascimento Vivo , Gravidez , Segundo Trimestre da Gravidez , Fatores de Risco , Sensibilidade e Especificidade
13.
Eur J Hum Genet ; 26(6): 912-918, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29483668

RESUMO

Several hypotheses have been proposed to explain the phenotypic variability between parent and offspring carrying the same genomic imbalance, including unmasking of a recessive variant by a chromosomal deletion. Here, 19 patients with neurodevelopmental disorders harboring a rare deletion inherited from a healthy parent were investigated by whole-exome sequencing to search for SNV on the contralateral segment. This strategy allowed us to identify a candidate variant in two patients in the NUP214 and NCOR1 genes. This result demonstrates that the analysis of the genes included in non-deleted contralateral allele is a key point in the etiological investigation of patients harboring a deletion inherited from a parent. Finally, this strategy is also an interesting approach to identify new recessive intellectual disability genes.

14.
Prenat Diagn ; 37(11): 1169-1175, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28950416

RESUMO

OBJECTIVES: To analyze the efficiency of prenatal diagnosis of Pierre Robin sequence (PRS) regarding the final specific diagnosis and to determine whether infants have more severe respiratory disorders with than without prenatally suspected PRS. METHODS: Review of the outcome of all prenatal cases of suspected PRS managed in our prenatal diagnosis center during the last 15 years; analysis of the consistency between prenatal and postnatal diagnoses in 2 groups of women with and without a family history of PRS; comparison of the grades of disease severity for infants with and without prenatally suspected PRS. RESULTS: Fifty-nine files were studied. Prenatal and postnatal consistencies of a specific diagnosis of PRS were 100% for women with a family history of PRS and with prenatally suspected nonisolated PRS. It was 78.6% for those with prenatally suspected isolated PRS. We describe 13 terminations of pregnancy. The 41 children living beyond 18 months seem to have more functionally severe phenotypes than the 227 children without prenatally suspected PRS. CONCLUSION: Prenatal diagnosis of isolated PRS is a challenge as other features can be missed. Use of prenatal chromosomal microarray can improve the accuracy of diagnosis. In all cases, adequate neonatal care should be offered.


Assuntos
Síndrome de Pierre Robin/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Gravidez , Ultrassonografia Pré-Natal
15.
Birth Defects Res ; 109(19): 1586-1595, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28758373

RESUMO

BACKGROUND: Fetal cerebral ventricular dilatation (CVD) is a common abnormal prenatal finding that often predicts a poor prognosis. The etiology involves both genetic and nongenetic factors with diverse pathogenic mechanisms. We describe the neuropathological features of CVD in a large cohort of fetuses. The goals are to determine the physiopathological mechanisms and etiologies. METHODS: We retrospectively analyzed a series of 130 fetuses examined at the Necker University Hospital following termination of pregnancy between January 2000 and December 2014. Chiari II and Dandy-Walker malformations were excluded from our study population. Karyotype and/or array comparative genomic hybridization were performed in all cases. Targeted Sanger sequencing or next generation sequencing were carried out in 34 and 5 cases, respectively. RESULTS: We distinguished four groups of pathological entities: (1) midbrain/hindbrain patterning defects (54 cases, 42%), mainly related to aqueduct of Sylvius anomalies (atresia or stenosis); (2) cerebral cytoarchitectonic disorders (16 cases, 12%), essentially resulting from arachnoidal neuroglial ectopia; (3) hemorrhagic and perfusion failure (42 cases, 32%); and (4) nonspecific CVD (18 cases, 14%), without apparent obstruction, cortical malformation, or clastic injury. Although the pathogenic mechanisms of CVD were identified in 86% of cases, the causes, both acquired and genetic, were recognized in 21% of cases only. CONCLUSION: The neuropathological analysis is a powerful tool in the diagnosis of the fetal CVD pathogenic mechanisms and to identify homogeneous groups. The paucity of molecular diagnosis, notably in the major groups of midbrain/hindbrain patterning defects and hemorrhagic and perfusion failure, highlights the needs of future research to improve our current knowledge on CVD causes. Birth Defects Research 109:1586-1595, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Hidrocefalia/diagnóstico , Hidrocefalia/etiologia , Hidrocefalia/patologia , Agenesia do Corpo Caloso/patologia , Malformação de Arnold-Chiari/diagnóstico , Encéfalo/anormalidades , Aqueduto do Mesencéfalo/patologia , Ventrículos Cerebrais/diagnóstico por imagem , Hibridização Genômica Comparativa , Síndrome de Dandy-Walker/diagnóstico , Dilatação , Feminino , Feto/patologia , França , Humanos , Mesencéfalo/patologia , Malformações do Sistema Nervoso/patologia , Gravidez , Cuidado Pré-Natal , Estudos Retrospectivos , Rombencéfalo/patologia , Ultrassonografia Pré-Natal/métodos
16.
J Am Soc Nephrol ; 28(10): 2901-2914, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28566479

RESUMO

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five de novo heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (PBX1), a gene known to have a crucial role in kidney development. In contrast, the frequency of SOX17 and DSTYK variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that PBX1 is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Proto-Oncogênicas/genética , Anormalidades Urogenitais/genética , Estudos de Coortes , Análise Mutacional de DNA , Exoma , Feminino , Humanos , Masculino , Fator de Transcrição 1 de Leucemia de Células Pré-B
17.
Am J Med Genet A ; 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28488400

RESUMO

Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34-q36.3 in a 16-year-old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8-driven KS, in a child otherwise normally resistant to other infectious agents and without any other tumoral lesion, points to a very selective immunodeficiency. While defects in organogenesis have been described with such macrodeletions, this is the first report of immunodeficiency and cancer predisposition.

19.
Cytogenet Genome Res ; 151(3): 115-118, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28273668

RESUMO

Segmental aneusomies are usually associated with clinical consequences, but an increasing number of nonpathogenic cytogenetically visible as well as large cryptic chromosomal imbalances have been reported. Here, we report a 3.6-Mb Xq21.33 microduplication detected prenatally on a female fetus which was inherited from a phenotypically normal mother and grandfather. It is assumed that male patients harboring Xq or Xp duplication present with syndromic intellectual disability because of functional disomy of the corresponding genes. Female carriers are generally asymptomatic because of preferential inactivation of the abnormal X. In the present case, the 3.6-Mb-duplicated segment encompasses only 2 genes, DIAPH2 and RPL4A. Since the asymptomatic grandfather carries the duplication, we hypothesize that these genes are not dosage sensitive and/or involved in cognitive function. Our observation further illustrates that large copy number variants can be associated with a normal phenotype, especially where gene density is low. Reporting rare cases of large genomic imbalances without a phenotypic effect can be very helpful, especially for genetic counseling in the prenatal setting.


Assuntos
Duplicação Cromossômica/genética , Cromossomos Humanos X/genética , Transtornos dos Cromossomos Sexuais/diagnóstico , Adulto , Proteínas de Transporte/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteínas Ribossômicas/genética , Transtornos dos Cromossomos Sexuais/genética , Inativação do Cromossomo X
20.
Am J Hum Genet ; 100(2): 352-363, 2017 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132691

RESUMO

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Complexo de Endopeptidases do Proteassoma/genética , Adolescente , Animais , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Deleção de Genes , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Polimorfismo de Nucleotídeo Único , Peixe-Zebra/genética
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