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1.
Nat Commun ; 11(1): 3987, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778678

RESUMO

Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Yet, the developmental consequences of specific aneuploidies remain unexplored. Here, we determine the extent of post-implantation development of human embryos bearing common aneuploidies using a recently established culture platform. We show that while trisomy 15 and trisomy 21 embryos develop similarly to euploid embryos, monosomy 21 embryos exhibit high rates of developmental arrest, and trisomy 16 embryos display a hypo-proliferation of the trophoblast, the tissue that forms the placenta. Using human trophoblast stem cells, we show that this phenotype can be mechanistically ascribed to increased levels of the cell adhesion protein E-CADHERIN, which lead to premature differentiation and cell cycle arrest. We identify three cases of mosaicism in embryos diagnosed as full aneuploid by pre-implantation genetic testing. Our results present the first detailed analysis of post-implantation development of aneuploid human embryos.


Assuntos
Aneuploidia , Implantação do Embrião/genética , Embrião de Mamíferos , Desenvolvimento Embrionário , Antígenos CD/genética , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Pontos de Checagem do Ciclo Celular , Linhagem da Célula , Segregação de Cromossomos , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 21 , Feminino , Genes erbB-1/genética , Testes Genéticos , Humanos , Monossomia , Mosaicismo , Gravidez , Células-Tronco , Trissomia
3.
Am J Hum Genet ; 106(6): 846-858, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32470372

RESUMO

The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.


Assuntos
Inversão Cromossômica/genética , Diabetes Mellitus/genética , Predisposição Genética para Doença , Hipertensão/genética , Obesidade/complicações , Obesidade/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Conjuntos de Dados como Assunto/normas , Diabetes Mellitus/patologia , Europa (Continente)/etnologia , Feminino , Perfilação da Expressão Gênica , Haplótipos , Humanos , Hipertensão/complicações , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Adulto Jovem
4.
Ann Biol Clin (Paris) ; 78(2): 187-190, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32319947

RESUMO

Acute myeloid leukemia (AML) with inv(16) is primarily associated with the eosinophilic LAM4 form belonging to the favorable prognosis group of AML. We report the case of an 18-year-old man with acute myeloid leukemia with unusual inversion of chromosome 16. Cytological, phenotypic and cytogenetic investigations showed a divergence from those in the literature. Indeed, the myelogram shows a medullary infiltration by elements blocked at the stage of myeloblates/promyelocytes, containing Auer rods grouped sometimes in fagots in blasts, promyelocytes and neutrophils. In view of this pathognomonic aspect, the diagnosis of AML type M3 is mentioned but quickly questioned by the results of immunophenotyping in favor of a maturing AML (M2). The karyotype and the FISH later objectify a recurrent anomaly "cytologically unexpected" inversion 16 (p13, q22) associated with trisomy 22.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 16 , Leucemia Mieloide Aguda/diagnóstico , Adolescente , Cromossomos Humanos Par 22/genética , Citodiagnóstico , Análise Citogenética , Humanos , Imunofenotipagem , Cariotipagem , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/genética , Masculino , Trissomia/diagnóstico , Trissomia/genética
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 135-138, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034738

RESUMO

OBJECTIVE: To assess the value of non-invasive prenatal screening (NIPS) for the detection of fetal chromosome 16 aneuploidy through multi-method verification and follow-up of pregnancy outcomes. METHODS: From January 2016 to December 2017, 7972 pregnant women with singleton pregnancies accepted the NIPS test after 10th gestational week with informed consent. Those with fetal chromosome 16 abnormality suggestive by the NIPS test were subjected to prenatal diagnosis including chromosomal karyotyping and chromosomal microarray analysis (CMA). RESULTS: Of the 7972 pregnant women tested by NIPS, 16 (0.2%) were predicted to have fetal chromosome 16 abnormality. The average age of the 16 pregnant women was 33.5 ± 5.24, and the average gestational week was 19.88±2.47. Chromosomal karyotyping verified that 3 fetuses had mosaicisms and 1 carried pericentric inversion of chromosome 9, which yielded a positive predictive value (PPV) of 18.8%. CMA has detected 7 fetuses with genomic abnormalities, which yielded a PPV of 43.8%. Eleven of the 16 women (68.8%) have given birth to healthy babies. CONCLUSION: For pregnant women with a high risk of chromosome 16 aneuploidy suggested by NIPS, the prognosis of fetus should be evaluated by multiple methods. Compared with conventional karyotyping analysis, molecular methods such as CMA are far superior.


Assuntos
Transtornos Cromossômicos , Cromossomos Humanos Par 16 , Teste Pré-Natal não Invasivo , Aneuploidia , Aberrações Cromossômicas , Feminino , Feto , Humanos , Gravidez , Diagnóstico Pré-Natal
6.
Ann Hematol ; 99(3): 487-500, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006151

RESUMO

Fusion partners of KMT2A affect disease phenotype and influence the current World Health Organization classification of hematologic neoplasms. The t(11;16)(q23;p13)/KMT2A-CREBBP is considered presumptive evidence of a myelodysplastic syndrome (MDS) and a MDS-related cytogenetic abnormality in the classification of acute myeloid leukemia (AML). Here, we report 18 cases of hematologic neoplasms with t(11;16). There were 8 males and 10 females with a median age of 51.9 years at time of detection of t(11;16). Of 17 patients with enough clinical information and pathological materials for review, 16 had a history of cytotoxic therapies for various malignancies including 12/15 patients who received topoisomerase II inhibitors, and 15 were classified as having therapy-related neoplasms. The median interval from the diagnosis of primary malignancy to the detection of t(11;16) was 23.2 months. Dysplasia, usually mild, was observed in 7/17 patients. Blasts demonstrated monocytic differentiation in 8/8 patients who developed AML at the time or following detection of t(11;16). t(11;16) was observed as the sole chromosomal abnormality in 10/18 patients. KMT2A rearrangement was confirmed in 11/11 patients. The median survival from the detection of t(11;16) was 15.4 months. In summary, t(11;16)(q23;p13) is rare and overwhelmingly associated with prior exposure of cytotoxic therapy. Instead of being considered presumptive evidence of myelodysplasia, we suggest that the detection of t(11;16) should automatically prompt a search for a history of malignancy and cytotoxic therapy so that proper risk stratification and clinical management are made accordingly. The dismal outcome of patients with t(11;16) is in keeping with that of therapy-related neoplasms.


Assuntos
Proteína de Ligação a CREB/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Bases de Dados Factuais , Neoplasias Hematológicas , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária , Proteínas de Fusão Oncogênica/genética , Inibidores da Topoisomerase II/administração & dosagem , Translocação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/mortalidade , Medição de Risco
7.
Genes (Basel) ; 10(12)2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817908

RESUMO

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10-7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Cromossomos Humanos Par 16/genética , Fenda Labial/genética , Fissura Palatina/genética , Animais , Bélgica , Cromossomos Humanos Par 10/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Knockout , Países Baixos , Fatores de Risco , Peixe-Zebra
9.
Am J Hum Genet ; 105(5): 947-958, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668704

RESUMO

Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2+/- and Bola2-/- animals. The Bola2-deficient mice and the mice carrying the deletion showed early evidence of iron deficiency, including a mild decrease in hemoglobin, lower plasma iron, microcytosis, and an increased red blood cell zinc-protoporphyrin-to-heme ratio. Our results indicate that BOLA2 participates in iron homeostasis in vivo, and its expansion has a potential adaptive role in protecting against iron deficiency.


Assuntos
Anemia/genética , Transtorno Autístico/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Homeostase/genética , Proteínas/genética , Animais , Deleção Cromossômica , Transtornos Cromossômicos/genética , Variações do Número de Cópias de DNA/genética , Feminino , Genótipo , Heterozigoto , Humanos , Ferro , Masculino , Fenótipo
10.
Nat Commun ; 10(1): 4897, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653860

RESUMO

Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification.


Assuntos
Estatura/genética , Índice de Massa Corporal , LDL-Colesterol/sangue , Herança Multifatorial , Obesidade/genética , Doenças Raras/genética , Apolipoproteínas B/genética , Transtorno Autístico/genética , LDL-Colesterol/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos X/genética , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Hipobetalipoproteinemias/genética , Deficiência Intelectual/genética , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/genética , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genética , Receptores de LDL/genética , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genética , Síndrome de Turner/genética , Cariótipo XYY/genética
11.
Science ; 366(6463)2019 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-31624180

RESUMO

Copy number variants (CNVs) are subject to stronger selective pressure than single-nucleotide variants, but their roles in archaic introgression and adaptation have not been systematically investigated. We show that stratified CNVs are significantly associated with signatures of positive selection in Melanesians and provide evidence for adaptive introgression of large CNVs at chromosomes 16p11.2 and 8p21.3 from Denisovans and Neanderthals, respectively. Using long-read sequence data, we reconstruct the structure and complex evolutionary history of these polymorphisms and show that both encode positively selected genes absent from most human populations. Our results collectively suggest that large CNVs originating in archaic hominins and introgressed into modern humans have played an important role in local population adaptation and represent an insufficiently studied source of large-scale genetic variation.


Assuntos
Introgressão Genética , Animais , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Evolução Molecular , Genoma Humano , Haplótipos , Hominidae/genética , Humanos , Melanesia , Modelos Genéticos , Homem de Neandertal/genética , Polimorfismo Genético , Seleção Genética , Sequenciamento Completo do Genoma
12.
Am J Hum Genet ; 105(3): 658-668, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31474320

RESUMO

Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600-700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy's complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (<1%) germline copy number variants (CNVs) in two independent, multi-ethnic cohorts totaling 5,585 children with neuroblastoma and 23,505 cancer-free control children. We identified a 550-kb deletion on chromosome 16p11.2 significantly enriched in neuroblastoma cases (0.39% of cases and 0.03% of controls; p = 3.34 × 10-9). Notably, this CNV corresponds to a known microdeletion syndrome that affects approximately one in 3,000 children and confers risk for diverse developmental phenotypes including autism spectrum disorder and other neurodevelopmental disorders. The CNV had a substantial impact on neuroblastoma risk, with an odds ratio of 13.9 (95% confidence interval = 5.8-33.4). The association remained significant when we restricted our analysis to individuals of European ancestry in order to mitigate potential confounding by population stratification (0.42% of cases and 0.03% of controls; p = 4.10 × 10-8). We used whole-genome sequencing (WGS) to validate the deletion in paired germline and tumor DNA from 12 cases. Finally, WGS of four parent-child trios revealed that the deletion primarily arose de novo without maternal or paternal bias. This finding expands the clinical phenotypes associated with 16p11.2 microdeletion syndrome to include cancer, and it suggests that disruption of the 16p11.2 region may dysregulate neurodevelopmental pathways that influence both neurological phenotypes and neuroblastoma.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16 , Predisposição Genética para Doença , Células Germinativas , Neuroblastoma/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino
13.
Arch Dermatol Res ; 311(10): 735-740, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31435740

RESUMO

Primary hyperhidrosis is a condition characterized by excessive sweating. The estimated prevalence is between 0.6 and 4.4%, and it can have economic, psychological, and social consequences for affected individuals. Family and genetic studies have suggested a genetic component in the inheritance of the disease. In this review, we summarize the current literature on genetic disposition to primary hyperhidrosis. We Identified 20 studies on Pubmed and Embase in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Probands reported a positive family history in 5.7-65% of cases, and the inheritance appeared to be either autosomal dominant or recessive. Individuals with palmoplantar phenotypes and a positive family history had a younger age of onset. Genetic linkage and genome-wide association studies have identified loci on chromosome 2, 14, and 16. However, the evidence is heterogeneous and limited. It seems that primary hyperhidrosis is polygenically inherited, and considering the impairment, further data to understand the genetic etiology of the disease are needed.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença , Hiperidrose/genética , Idade de Início , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Estudo de Associação Genômica Ampla , Humanos , Hiperidrose/epidemiologia , Anamnese , Prevalência
14.
Am J Hum Genet ; 105(2): 373-383, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353025

RESUMO

Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.


Assuntos
Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 9/genética , Doença da Artéria Coronariana/genética , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/genética , Deficiência Intelectual/genética , Fenômica , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Deleção Cromossômica , Cromossomos Humanos Par 16/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Fenótipo , Reino Unido
15.
Brain Dev ; 41(10): 888-893, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31353122

RESUMO

In partial monosomy of the distal part of chromosome 16q, abnormal facial features, intellectual disability (ID), and feeding dysfunction are often reported. However, seizures are not typical and the majority of them were seizure-free. Here we present the case of a 16q22.2-q23.1 interstitial deletion identified in a male patient with severe ID, facial anomalies including forehead protrusions and flat nose bridge, patent ductus arteriosus, bilateral vocal cord atresia treated by tracheotomy, and West syndrome, which were developed 10 months after birth. Although phenobarbital, sodium valproate (VPA), and zonisamide were not effective as monotherapies or combination therapies, the patient's epileptic seizures and electroencephalogram anomalies disappeared following combined therapy with lamotrigine and VPA. Although WW Domain Containing Oxidoreductase (WWOX), which is known as a cause of autosomal recessive epileptic encephalopathy, was included within the 6.8-Mb deleted region which identified by targeted panel sequencing and validated by chromosomal microarray analysis, no pathogenic variants were detected in the other allele of WWOX. Therefore, it is possible that other genes within or outside of the long deleted region or their interactions may cause West syndrome in this patient.


Assuntos
Cromossomos Humanos Par 16/genética , Espasmos Infantis/genética , Anticonvulsivantes/uso terapêutico , Epilepsia/genética , Humanos , Lactente , Deficiência Intelectual/genética , Lamotrigina/uso terapêutico , Masculino , Fenobarbital/uso terapêutico , Convulsões/tratamento farmacológico , Deleção de Sequência/genética , Ácido Valproico/uso terapêutico
16.
Tijdschr Psychiatr ; 61(6): 421-425, 2019.
Artigo em Holandês | MEDLINE | ID: mdl-31243752

RESUMO

Genetic factors play an important role in the development of psychotic disorders. With increasing evidence, several rare copy number variants (cnvs) have been identified as risk factors. We describe a patient who had two psychotic episodes during his adolescence. In this patient, a 16p11.2 duplication was detected. This duplication is a recurrent cnv associated with various somatic and psychiatric phenotypes including psychosis and schizophrenia. The potential clinical relevance of this finding is discussed.


Assuntos
Transtornos Psicóticos/genética , Adolescente , Cromossomos Humanos Par 16 , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Transtornos Psicóticos/diagnóstico , Adulto Jovem
17.
Nature ; 571(7763): 107-111, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217582

RESUMO

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.


Assuntos
Diarreia/congênito , Diarreia/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Intestinos/fisiologia , Deleção de Sequência/genética , Animais , Cromossomos Humanos Par 16/genética , Modelos Animais de Doenças , Feminino , Genes Reporter , Loci Gênicos/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linhagem , Fenótipo , Ativação Transcricional , Transcriptoma/genética , Transgenes/genética
18.
J Genet ; 98(2)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31204719

RESUMO

The 16p12.2 chromosome band contains three large segmental duplications: BP1, BP2 and BP3, providing a substrate for recombination and recurrent chromosomal rearrangements. The '16p12.2 microdeletion' is a recurrent deletion comprised between BP2 and BP3, associated with variable clinical findings. We identified a heterozygous 16p12.2 microdeletion spanning between BP1 and BP2 in a child evaluated for short stature and mild dyslexia. Unexpectedly, the mother carried the same deletion in the homozygous state and suffered from severe hearing loss. Detailed family history revealed consanguinity of the maternal grandparents. The 16p12.2 microdeletion is a rare condition and contains only three genes: METTL9, IGSF6 and OTOA of which the OTOA is considered responsible for DFNB22 hearing loss (MIM: 607039) under its homozygous condition. A number of OTOA mutations have been described, whereas very few cases of a 16p12.2 microdeletion similar to that observed in our family have been reported. In conclusion, we describe a rare 'distal 16p12.2microdeletion' widening the phenotypic spectrum associated with the recurrent 16p12.2 microdeletion and support the causative role of OTOA microdeletion in hearing impairment.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16 , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Adulto , Criança , Hibridização Genômica Comparativa , Facies , Feminino , Humanos , Masculino , Linhagem , Fenótipo
20.
Ned Tijdschr Geneeskd ; 1632019 03 21.
Artigo em Holandês | MEDLINE | ID: mdl-30945833

RESUMO

16p11.2 deletion syndrome is one of the most prevalent microdeletion syndromes in the world. Nevertheless, many doctors are not (yet) familiar with this syndrome. Prevalence has been estimated at approximately 3 in 10,000. The deletion can be identified in around 1 out of 100 people with autism. The syndrome is characterized by a wide range of phenotypic features including developmental delay, autism, obesity, increased head circumference, and epilepsy. Here we describe an 8-year-old female patient with developmental delay, autistic features and hyperphagia. After diagnosis of 16p11.2 deletion syndrome, her parents struggled due to limited information and support provision by healthcare staff. Since then, multidisciplinary healthcare has been introduced for this condition. In parallel, the patient's parents started an online support group for Dutch patients and parents. Given the diverse phenotype of 16p11.2 deletion syndrome, multidisciplinary collaboration is important. Establishing the diagnosis contributes to better treatment and understanding for parents and healthcare providers.


Assuntos
Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Testes Genéticos/métodos , Deficiência Intelectual/genética , Transtorno Autístico/diagnóstico , Criança , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 16/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Pais , Fenótipo
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