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1.
Prenat Diagn ; 41(10): 1351-1359, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34176145

RESUMEN

OBJECTIVE: To evaluate if non-invasive prenatal testing (NIPT) affects livebirth (LB) prevalence of Down syndrome (DS) in the Netherlands. METHOD: Data from clinical genetics laboratories and the Working Party on Prenatal Diagnosis and Therapy (2014-2018) and previous published data (1991-2013) were used to assess trends for DS LB prevalence and reduction percentage (the net decrease in DS LBs resulting from selective termination of pregnancies). Statistics Netherlands provided general population data. RESULTS: DS LB prevalence increased from 11.6/10,000 in 1991 to 15.9/10,000 in 2002 (regression coefficient 0.246 [95% CI: 0.105-0.388; p = 0.003]). After 2002, LB prevalence decreased to 11.3/10,000 in 2014 and further to 9.9/10,000 in 2018 (regression coefficient 0.234 (95% CI: -0.338 to -0.131; p < 0.001). The reduction percentage increased from 26% in 1991 to 55.2% in 2018 (regression coefficient 0.012 (95% CI: 0.010-0.013; p < 0.001)). There were no trend changes after introducing NIPT as second-tier (2014) and first-tier test (2017). CONCLUSIONS: Introducing NIPT did not change the decreasing trend in DS LB prevalence and increasing trend in reduction percentage. These trends may be caused by a broader development of more prenatal testing that had already started before introducing NIPT.


Asunto(s)
Síndrome de Down/diagnóstico por imagen , Pruebas Prenatales no Invasivas/normas , Adulto , Síndrome de Down/epidemiología , Femenino , Humanos , Nacimiento Vivo/epidemiología , Nacimiento Vivo/genética , Países Bajos/epidemiología , Pruebas Prenatales no Invasivas/métodos , Pruebas Prenatales no Invasivas/estadística & datos numéricos , Embarazo , Prevalencia , Sistema de Registros/estadística & datos numéricos
2.
Pediatr Blood Cancer ; 66(6): e27715, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30882989

RESUMEN

Mosaic genome-wide paternal uniparental disomy is an infrequently described disorder in which affected individuals have signs and symptoms that may resemble Beckwith-Wiedemann syndrome. In addition, they can develop multiple benign and malignant tumors throughout life. Routine molecular diagnostics may not detect the (characteristic) low level of mosaicism, and the diagnosis is likely to be missed. Genetic counseling and a life-long alertness for the development of tumors is indicated. We describe the long diagnostic process of a patient who already had a tumor at birth and developed multiple tumors in childhood and adulthood. Furthermore, we offer clues to recognize the entity.


Asunto(s)
Cromosomas Humanos/genética , Estudio de Asociación del Genoma Completo , Mosaicismo , Neoplasias/diagnóstico , Neoplasias/genética , Disomía Uniparental/diagnóstico , Disomía Uniparental/genética , Adulto , Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Femenino , Impresión Genómica , Genotipo , Humanos , Recién Nacido , Masculino , Neoplasias/clasificación , Polimorfismo de Nucleótido Simple , Pronóstico
4.
Mol Cytogenet ; 16(1): 26, 2023 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-37775759

RESUMEN

BACKGROUND: Balanced chromosome aberrations are reported in about 1:30 couples with recurrent pregnancy loss (RPL). Karyotyping of both parents is necessary to identify these aberrations. Genome-wide non-invasive prenatal testing (NIPT) in case of recurrent pregnancy loss could be a more efficient way to identify couples at increased risk for carrying a balanced chromosome rearrangement. The aim of this study was to evaluate whether the potential fetal imbalances caused by parental balanced aberrations detected in our center are large enough to be detectable by genome-wide non-invasive prenatal testing (NIPT). MATERIAL AND METHODS: From January 1970 until May 2020 our laboratory received 30,863 unique requests for karyotyping due to RPL. We have identified 16,045 couples and evaluated all abnormal cytogenetic results to assess the minimal size of the involved chromosomal segments in potential unbalanced products of the rearrangements. RESULTS: In the presented cohort we detected 277 aberrant balanced translocations/inversions in females and 185 in males amongst 16,045 couples with RPL, which can be translated to a risk of 1:35 (2.9%, 95% CI 2.6-3.2%). Our study showed that the vast majority (98.7%, 95% CI 97.1-99.5%) of these balanced aberrations will potentially cause a fetal imbalance > 10 Mb, which is detectable with genome-wide NIPT if it was performed during one of the miscarriages. CONCLUSIONS: Our study suggests that genome-wide NIPT is able to reveal most unbalanced products of balanced chromosomal rearrangements carried by couples with RPL and therefore can potentially identify balanced chromosomal aberration carriers. Moreover, our data suggest that these couples can be offered NIPT in case they decline invasive testing in future pregnancies.

5.
Am J Med Genet A ; 158A(10): 2412-20, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22893440

RESUMEN

Interstitial deletions of the chromosome 22q11.2 region are the most common microdeletions in humans. The TBX1 gene is considered to be the major candidate gene for the main features in 22q11.2 deletion syndrome, including congenital heart malformations, (para)thyroid hypoplasia, and craniofacial abnormalities. We report on eight patients with atypical deletions of chromosome 22q11.2. These deletions comprise the distal part of the common 22q11.2 deleted region but do not encompass the TBX1 gene. Ten similar patients with overlapping distal 22q11.2 deletions have been reported previously. The clinical features of these patients are described and compared to those found in the classic 22q11.2 deletion syndrome. We discuss the possible roles of a position effect or haploinsufficiency of distally located genes (e.g., CRKL) in the molecular pathogenesis of the 22q11.2 deletion syndrome.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/patología , Proteínas de Dominio T Box/genética , Adolescente , Adulto , Preescolar , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Síndrome de DiGeorge/genética , Femenino , Humanos , Recién Nacido , Masculino , Fenotipo , Embarazo
6.
J Clin Med ; 11(14)2022 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-35887798

RESUMEN

Prader−Willi syndrome (PWS) is a complex, rare genetic disorder caused by a loss of expression of paternally expressed genes on chromosome 15q11.2-q13. The most common underlying genotypes are paternal deletion (DEL) and maternal uniparental disomy (mUPD). DELs can be subdivided into type 1 (DEL-1) and (smaller) type 2 deletions (DEL-2). Most research has focused on behavioral, cognitive and psychological differences between the different genotypes. However, little is known about physical health problems in relation to genetic subtypes. In this cross-sectional study, we compare physical health problems and other clinical features among adults with PWS caused by DEL (N = 65, 12 DEL-1, 27 DEL-2) and mUPD (N = 65). A meta-analysis, including our own data, showed that BMI was 2.79 kg/m2 higher in adults with a DEL (p = 0.001). There were no significant differences between DEL-1 and DEL-2. Scoliosis was more prevalent among adults with a DEL (80% vs. 58%; p = 0.04). Psychotic episodes were more prevalent among adults with an mUPD (44% vs. 9%; p < 0.001). In conclusion, there were no significant differences in physical health outcomes between the genetic subtypes, apart from scoliosis and BMI. The differences in health problems, therefore, mainly apply to the psychological domain.

7.
Genes (Basel) ; 12(6)2021 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-34200226

RESUMEN

Prader-Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader-Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the 'Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations' (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype-phenotype relationship in PWS.


Asunto(s)
Proteínas Nucleares/genética , Síndrome de Prader-Willi/genética , Proteínas Nucleares snRNP/genética , Células Cultivadas , Femenino , Impresión Genómica , Células HEK293 , Homocigoto , Humanos , Persona de Mediana Edad , Mutación Missense , Proteínas Nucleares/metabolismo , Fenotipo , Síndrome de Prader-Willi/diagnóstico , Proteínas Nucleares snRNP/metabolismo
8.
Lancet Oncol ; 10(2): 125-34, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19138562

RESUMEN

BACKGROUND: Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. METHODS: We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. FINDINGS: Our classifier predicted ALL subtype with a median accuracy of 90.0% (IQR 88.3-91.7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87.9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR-ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR-ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59.5%, 95% CI 37.1-81.9) compared with patients with other precursor B-ALL (84.4%, 76.8-92.1%; p=0.012), a prognosis similar to that of patients with BCR-ABL1-positive ALL (51.9%, 23.1-80.6%). In the DCOG cohort, the prognosis of BCR-ABL1-like disease (57.1%, 31.2-83.1%) was worse than that of other precursor B-ALL (79.2%, 70.2-88.3%; p=0.026), and similar to that of BCR-ABL1-positive ALL (32.5%, 2.3-62.7%). 36 (82%) of the patients with BCR-ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0.0002). Compared with other precursor B-ALL cells, BCR-ABL1-like cells were 73 times more resistant to L-asparaginase (p=0.001) and 1.6 times more resistant to daunorubicin (p=0.017), but toxicity of prednisolone and vincristine did not differ. INTERPRETATION: New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. FUNDING: Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute, and American Lebanese Syrian Associated Charities.


Asunto(s)
Perfilación de la Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras/clasificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Niño , Preescolar , Análisis por Conglomerados , Hibridación Genómica Comparativa , Expresión Génica , Genes abl/genética , Humanos , Estimación de Kaplan-Meier , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Valor Predictivo de las Pruebas , Pronóstico , Resultado del Tratamiento
9.
Mol Genet Genomic Med ; 8(1): e1062, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31790156

RESUMEN

BACKGROUND: Two technological innovations in the last decade significantly influenced the diagnostic yield of prenatal cytogenetic testing: genomic microarray allowing high resolution analysis and noninvasive prenatal testing (NIPT) focusing on aneuploidy. To anticipate future trends in prenatal screening and diagnosis, we evaluated the number of invasive tests in our center and the number of aberrant cases diagnosed in the last decade. METHODS: We retrospectively analyzed fetal chromosomal aberrations diagnosed in 2009-2018 in 8,608 pregnancies without ultrasound anomalies. RESULTS: The introduction of NIPT as the first-tier test led to a substantial decrease in the number of invasive tests and a substantially increased diagnostic yield of aneuploidies in the first trimester. However, we have also noted a decreased detection of submicroscopic aberrations, since the number of invasive tests substantially decreased. We have observed that pregnant women were interested in broader scope of prenatal screening and diagnosis than detection of common trisomies. CONCLUSION: Since the frequency of syndromic disorders caused by microdeletions/microduplications is substantial and current routine NIPT and ultrasound investigations are not able to detect them, we suggest that a noninvasive test with resolution comparable to microarrays should be developed, which will also meet patient's needs.


Asunto(s)
Evaluación de Necesidades , Pruebas Prenatales no Invasivas/normas , Actitud , Aberraciones Cromosómicas , Femenino , Genoma , Humanos , Pruebas Prenatales no Invasivas/métodos , Embarazo , Mujeres Embarazadas/psicología , Sensibilidad y Especificidad
10.
Am J Med Genet A ; 149A(7): 1468-75, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19449434

RESUMEN

We present a family with multiple cytogenetic abnormalities, identified through a girl with several dysmorphic features and cardiac problems, suspected for Jacobsen syndrome. Cytogenetic analysis showed a 46,XX,del(11)(qter) karyotype, which was confirmed by fluorescence in situ hybridization (FISH). Cytogenetic investigation of the parents showed a chromosome aberration in both: the father had a t(11;12)(p13;q22) translocation and the mother was carrier of an ins(4;11)(p14;q24q25). FISH analysis with an 11q-subtelomeric probe from the second-generation telomere clone set and BACs from 11q24-q25 suggested a complex maternal rearrangement. However, subsequent array analysis showed a single interstitial deletion in the proband, derived from the maternal insertion. The aberrant karyotypes in both parents implicated an increased risk of unbalanced fetal chromosome composition, thus high risk for a child with multiple congenital abnormalities. Therefore, during the next pregnancy, the couple opted for prenatal diagnosis by means of amniocentesis. An interphase FISH strategy for uncultured amniotic fluid cells predicted two possible unbalanced fetal chromosome constitutions. Karyotyping of cultured amniotic cells confirmed one of the predicted unbalanced cytogenetic options, demonstrating the value of a fast interphase strategy for parents who both are carriers of a chromosomal abnormality. In addition, we present an overview of patients with Jacobsen syndrome and an interstitial 11q deletion reported thus far in literature.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 4 , Madres , Translocación Genética , Preescolar , Familia , Femenino , Humanos , Recién Nacido , Patrón de Herencia , Síndrome de Deleción Distal 11q de Jacobsen/diagnóstico , Síndrome de Deleción Distal 11q de Jacobsen/genética , Masculino
11.
Sci Rep ; 8(1): 15436, 2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30337552

RESUMEN

N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C > T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C > T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C > T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C > T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD.


Asunto(s)
N-Acetiltransferasa de Aminoácidos/genética , Elementos de Facilitación Genéticos , Variación Genética , Trastornos Innatos del Ciclo de la Urea/etiología , N-Acetiltransferasa de Aminoácidos/metabolismo , Secuencia de Bases , Niño , Preescolar , Femenino , Humanos , Hiperamonemia , Pronóstico , Trastornos Innatos del Ciclo de la Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/patología
12.
Eur J Med Genet ; 60(9): 445-450, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28602932

RESUMEN

Using SNP array and FISH analysis, a patient with moderate intellectual disability and obesity was found to harbour an atypical 1.6 Mb inverted duplication on 8p23.1, directly flanked by a distally located interstitial deletion of 2.3 Mb and a terminal segmental uniparental disomy. The duplicated and deleted regions lie exactly between the two segmental duplication regions. These segmental duplications on chromosome 8p23.1 are known to be involved in chromosomal rearrangements because of mutual homology and homology to other genomic regions. Genomic instability mediated by these segmental duplications is generally caused by non-allelic homologous recombination, resulting in deletions, reciprocal duplications, inversions and translocations. Additional analysis of the parental origin of the fragments of this atypical inverted duplication/interstitial deletion shows paternal contribution in the maternal derivate chromosome 8. Combined with the finding that the normal chromosome 8 carries an inversion in 8p23.1 we hypothesize that a double strand break in 8p23.1 of the maternal chromosome was postzygotically repaired with the paternal inverted copy resulting in a duplication, deletion and segmental uniparental disomy, with no particular mediation of the 8p23.1 segmental duplication regions in recombination.


Asunto(s)
Trastornos de los Cromosomas/genética , Discapacidad Intelectual/genética , Obesidad/genética , Niño , Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Duplicación Cromosómica , Cromosomas Humanos Par 8/genética , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Obesidad/diagnóstico , Síndrome , Telómero/genética
13.
Mol Cytogenet ; 9: 43, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27274769

RESUMEN

BACKGROUND: Chromosome 6q duplication syndrome is a chromosome abnormality associated with characteristic phenotypic features such as intellectual disability (ID), short stature, feeding difficulties, microcephaly, dysmorphic features (prominent forehead, downslanting palpebral fissures, flat nasal bridge, tented upper lip, micrognathia, short webbed neck) and joint contractures. Only a few cases of pure partial 6q trisomy have been published and the severity of the phenotype seems to depend on the breakpoint position. Unfortunately, most of these cases were identified using karyotyping or FISH, so breakpoints at the molecular level and thus gene content are not known. CASES PRESENTATION: We report the first two families with an interstitial 6q duplication identified by karyotyping where the gene content and breakpoints were characterized with microarray. In family 1, the 6q22.1q23.2 duplication was detected in a female patient with ID. In family 2, the 6q21q22.33 duplication was identified in a male fetus with multiple congenital malformations. In both families, the duplication seems to show phenotypic heterogeneity and in family 1 also incomplete penetrance suggesting the co-existence of an "additional hit" in affected patients. This "additional hit" was identified in the first family to be a microduplication in 16p11.2, a known susceptibility locus (SL) for neurodevelopmental disorders, that co-segregated with an abnormal phenotype in the affected family members. CONCLUSIONS: Our study shows that interstitial 6q21q23 duplication may represent a private variant that is benign, but may also contribute to developmental disorders of variable expressivity in a "multi-hit" model. Finding the "additional hit" within the family is therefore very important for genetic counseling and assessment of the CNV penetrance within the particular family.

14.
Haematologica ; 89(6): 671-8, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15194534

RESUMEN

BACKGROUND AND OBJECTIVES: The t(5;14)(q35;q32) is a novel cryptic translocation in pediatric T-cell acute lymphoblastic leukemia (T-ALL), involving HOX11L2 or CSX on 5q35. The 14q32 breakpoints are heterogeneous. Because the t(5;14)(q35;q32) is hard to detect using conventional karyotyping, it is easily missed in routine diagnostics. Here we describe the development and application of split signal fluorescence in situ hybridization (FISH) assays for both HOX11L2 and CSX, for detection of t(5;14) possibly present in T-ALL patients. DESIGN AND METHODS: We developed and validated two split signal FISH assays for metaphase and interphase detection of t(5;14) in T-ALL patients. We also investigated the involvement of IGH on 14q32. In addition, HOX11L2 and SIL-TAL1 expression was studied using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The FISH assays were validated on cell lines and T-ALL patients. We did not identify cases with a t(5;14)(q35;q32) involving CSX, but we did identify 5 cases of t(5;14) involving HOX11L2 out of 32 T-ALL cases studied; in each case the 14q32 breakpoint was found to be centromeric to the IGH region. All 5 positive cases showed HOX11L2 expression, as did 1 case without t(5;14)(q35;q32). Cases with t(5;14)(q35;q32) involving HOX11L2 did not show TAL1 abnormalities, whereas 5 HOX11L2 negative cases did. INTERPRETATION AND CONCLUSIONS: Using the newly developed and validated FISH probe sets, we identified 5 new cases of t(5;14) involving HOX11L2 both on metaphases and interphases. The incidence of the t(5;14)(q35;q32) involving CSX is probably low. RT-PCR results suggest that TAL1 and HOX11L2 expression, or TAL1 aberrations and the t(5;14)(q35;q32) involving HOX11L2 are mutually exclusive.


Asunto(s)
Hibridación Fluorescente in Situ/métodos , Leucemia-Linfoma de Células T del Adulto/genética , Translocación Genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 5 , Femenino , Proteína Homeótica Nkx-2.5 , Proteínas de Homeodominio/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Incidencia , Leucemia-Linfoma de Células T del Adulto/diagnóstico , Leucemia-Linfoma de Células T del Adulto/epidemiología , Masculino , Persona de Mediana Edad , Epidemiología Molecular , Proteínas Oncogénicas/genética , Factores de Transcripción/genética
15.
Nat Biotechnol ; 32(10): 1019-25, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25129690

RESUMEN

Despite developments in targeted gene sequencing and whole-genome analysis techniques, the robust detection of all genetic variation, including structural variants, in and around genes of interest and in an allele-specific manner remains a challenge. Here we present targeted locus amplification (TLA), a strategy to selectively amplify and sequence entire genes on the basis of the crosslinking of physically proximal sequences. We show that, unlike other targeted re-sequencing methods, TLA works without detailed prior locus information, as one or a few primer pairs are sufficient for sequencing tens to hundreds of kilobases of surrounding DNA. This enables robust detection of single nucleotide variants, structural variants and gene fusions in clinically relevant genes, including BRCA1 and BRCA2, and enables haplotyping. We show that TLA can also be used to uncover insertion sites and sequences of integrated transgenes and viruses. TLA therefore promises to be a useful method in genetic research and diagnostics when comprehensive or allele-specific genetic information is needed.


Asunto(s)
Genómica/métodos , Haplotipos/genética , Modelos Genéticos , Técnicas de Amplificación de Ácido Nucleico/métodos , Análisis de Secuencia de ADN/métodos , Fusión Génica/genética , Genes BRCA1 , Genes BRCA2 , Sitios Genéticos/genética , Humanos , Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética
16.
Eur J Med Genet ; 56(6): 331-5, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23542664

RESUMEN

A female patient, 20 years of age, is reported with a history characterized by developmental and psychomotor delay, and during grammar-school period increasing learning problems, ritualistic behaviours and social withdrawal. Subsequently, challenging and autistic-like behaviours became prominent. The patient showed mild facial dysmorphisms, long thin fingers with bilateral mild short V metacarpals, and hyperlaxity of the joints. Neuropsychiatric examination disclosed obsessive, ritualistic behaviours and vague ideas of reference. Neuropsychological assessment demonstrated mild intellectual disability, mental inflexibility and incongruent affect. MRI-scanning of the brain showed no relevant abnormalities. Genome wide SNP array analysis revealed a 1.2 Mb de novo interstitial microdeletion in 4q25 comprising 11 genes, that was considered to be causative for the developmental delay, perseverative cognitive phenotype and dysmorphisms. To the authors knowledge, this is the first report of a de novo 4q25 microdeletion that presents with a specific behavioural phenotype.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 4 , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Trastornos Mentales/diagnóstico , Trastornos Mentales/genética , Fenotipo , Encéfalo/patología , Hibridación Genómica Comparativa , Facies , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Imagen por Resonancia Magnética , Polimorfismo de Nucleótido Simple , Adulto Joven
17.
Eur J Med Genet ; 55(4): 265-8, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22406089

RESUMEN

In 1980, a case report on a boy with cleft palate, club feet, dysmorphic features, and developmental delay was published by Bijlsma as a possible distinct syndrome. This case is listed in the London Medical Databases version 1.0. We have reevaluated this patient at adult age. Using high resolution karyotyping and Affymetrix 250k SNP array analysis we identified an unbalanced three-way translocation with breakpoints at 17q22, 18q22.1, and 20p12.2 leading to deletion 18q and duplication 20p. Also, a 715 kb duplication in 1p34.2 and a 245 kb deletion at 1p21.1 were found. Mental retardation, cleft palate, and club feet have repeatedly been reported in deletion 18q patients and therefore we conclude that most of the patient's features can be explained by an 18q deletion.


Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Duplicación Cromosómica/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 20/genética , Adulto , Secuencia de Bases , Cromosomas Humanos Par 17/genética , Estudios de Seguimiento , Humanos , Cariotipificación , Masculino , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Translocación Genética
18.
Eur J Hum Genet ; 20(9): 986-9, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22395867

RESUMEN

Cat eye syndrome (CES) is caused by a gain of the proximal part of chromosome 22. Usually, a supernumerary marker chromosome is present, containing two extra copies of the chromosome 22q11.1q11.21 region. More sporadically, the gain is present intrachromosomally. The critical region for CES is currently estimated to be about 2.1 Mb and to contain at least 14 RefSeq genes. Gain of this region may cause ocular coloboma, preauricular, anorectal, urogenital and congenital heart malformations. We describe a family in which a 600 kb intrachromosomal triplication is present in at least three generations. The copy number alteration was detected using MLPA and further characterized with interphase and metaphase FISH and SNP-array. The amplified fragment is located in the distal part of the CES region. The family members show anal atresia and preauricular tags or pits, matching part of the phenotype of this syndrome. This finding suggests that amplification of the genes CECR2, SLC25A18 and ATP6V1E1, mapping within the critical region for CES, may be responsible for anorectal, renal and preauricular anomalies in patients with CES.


Asunto(s)
Anomalías Múltiples/genética , Sistema de Transporte de Aminoácidos X-AG/genética , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22/genética , Proteínas Mitocondriales/genética , Factores de Transcripción/genética , ATPasas de Translocación de Protón Vacuolares/genética , Adulto , Aneuploidia , Trastornos de los Cromosomas/complicaciones , Duplicación Cromosómica , Mapeo Cromosómico , Anomalías del Ojo , Familia , Femenino , Dosificación de Gen , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , Cariotipificación , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje
19.
Genes Chromosomes Cancer ; 45(5): 437-46, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16419055

RESUMEN

Chromosome rearrangements are found in many acute leukemias. As a result, genes at the breakpoints can be disrupted, forming fusion genes. One of the genes involved in several chromosome aberrations in hematological malignancies is NUP98 (11p15). As NUP98 is close to the 11p telomere, small translocations might easily be missed. Using a NUP98-specific split-signal fluorescence in situ hybridization (FISH) probe combination, we analyzed 84 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome with either normal karyotypes or 11p abnormalities to investigate whether there are unidentified 11p15 rearrangements. Neither NUP98 translocations nor deletions were identified in cases with normal karyotypes, indicating these aberrations may be very rare in this group. However, NUP98 deletions were observed in four cases with unbalanced 11p aberrations, indicating that the breakpoint is centromeric of NUP98. Rearrangements of NUP98 were identified in two patients, both showing 11p abnormalities in the diagnostic karyotype: a t(4;11)(q1?3;p15) with expression of the NUP98-RAP1GDS1 fusion product detected in a 60-year-old woman with AML-M0, and an add(11)(p15) with a der(21)t(11;21)(p15;p13) observed cytogenetically in a 1-year-old boy with AML-M7. JARID1A was identified as the fusion partner of NUP98 using 3' RACE, RT-PCR, and FISH. JARID1A, at 12p13, codes for retinoblastoma binding protein 2, a protein implicated in transcriptional regulation. This is the first report of JARID1A as a partner gene in leukemia.


Asunto(s)
Cromosomas Humanos Par 12 , Leucemia/genética , Proteínas de Complejo Poro Nuclear/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Cartilla de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular
20.
Genes Chromosomes Cancer ; 45(8): 731-9, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16646086

RESUMEN

The t(7;12)(q36;p13) is a recurrent translocation involving the ETV6/TEL gene (12p13) and a heterogeneous breakpoint at 7q36. A fusion transcript between HLXB9 and ETV6 in AML with t(7;12) is occasionally found. To study the incidence of t(7;12) in infant and childhood acute leukemia, we screened 320 cases <36 months using FISH. Additionally, 28 pediatric cases >36 months with cytogenetic breakpoints at 12p and 7q were investigated. We studied the presence of an HXLB9-ETV6 fusion transcript and quantified the expression of various genes located in the 7q36 breakpoint region. In total, six AML patients carried the t(7;12) of which five were infants and one child of 18 months. Only one out of 99 infant ALL patients harbored the t(7;12). No t(7;12) was found in older children with AML or ALL. AML patients carrying a t(7;12) had a poor outcome with a 3-year EFS of 0%. A fusion of HLXB9 to ETV6 was found in four AML cases with t(7;12). The 7q36 genes NOM1, LMBR1, RNF32, and SHH were equally expressed among t(7;12)-positive AML versus t(7;12)-negative AML, t(7;12)-negative ALL, or normal bone marrow. However, the HLXB9 expression was highly increased in t(7;12)-positive cases, including those with an HLXB9-ETV6 fusion. We conclude that the t(7;12) is almost exclusively present in infant AML and covers 30% of infant AML, while it is extremely rare in infant ALL and older children. The t(7;12) is associated with a poor outcome and an ectopic expression of HLXB9 is commonly involved in this genetic subtype of leukemia.


Asunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 7 , Proteínas de Homeodominio/genética , Leucemia Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Translocación Genética , Enfermedad Aguda , Preescolar , Rotura Cromosómica , Estudios de Cohortes , Femenino , Proteínas de Homeodominio/metabolismo , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Modelos Genéticos , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Factores de Transcripción/metabolismo , Proteína ETS de Variante de Translocación 6
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