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ABSTRACT: Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree ofpre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26 we found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, attention-deficit-hyperactivity disorder, hearing loss and autism, have been found. We discuss clinical ramifications for cases with a loss of 15q26 detected by prenatal array-CGH.
European journal of medical genetics 04/2013; · 1.57 Impact Factor
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ABSTRACT: Complex chromosome rearrangements (CCRs) are rare genomic structural aberrations involving three or more breakpoints on two or more chromosomes. About one-third of all CCRs are familial. Transmittance of such a CCR results either in genomic imbalance due to abnormal segregation at meiosis I or is stably passed on to the next generation. Here we present a phenotypically normal mother with a CCR involving chromosomes 1, 3, and 5 that gave birth to a phenotypically abnormal son. The boy presented with hypotonia, mild facial dysmorphisms, and severe intellectual disability. Conventional karyotyping revealed the same apparently balanced CCR as in the mother. However, by use of array-comparative genome hybridization (array-CGH) and fluorescence in situ hybridization (FISH) we discovered that one of the derivative chromosomes in the patient contained a de novo rearrangement. It appears that during transmission of the CCR, an additional de novo deletion and duplication had arisen in one of the derivative chromosomes. We speculate that this was the result of the inverted duplication with a distal deletion mechanism. We also demonstrate the importance of high-resolution breakpoint analysis in CCRs and stress that genetic counseling of a familial CCR is not straightforward. To our knowledge, this would be the first description of this mechanism operating on a structurally abnormal chromosome. © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A 09/2012; 158A(11):2888-93. · 2.39 Impact Factor
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Wigard P Kloosterman,
Masoumeh Tavakoli-Yaraki,
Markus J van Roosmalen,
Ellen van Binsbergen,
Ivo Renkens,
Karen Duran,
Lucia Ballarati,
Sarah Vergult,
Daniela Giardino,
Kerstin Hansson, [......],
Arie van Haeringen,
Elly F Ippel,
Thomas Haaf,
Eberhard Passarge, Ron Hochstenbach,
Björn Menten,
Lidia Larizza,
Victor Guryev,
Martin Poot,
Edwin Cuppen
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ABSTRACT: Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyze the genomes of ten patients with congenital disease who were preselected to carry complex chromosomal rearrangements with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint junctions indicates that break repair involves nonhomologous or microhomology-mediated end joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred base pairs and several megabases. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template switching. Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements.
Cell reports. 06/2012; 1(6):648-55.
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Ron Hochstenbach,
Martin Poot,
Isaac J Nijman,
Ivo Renkens,
Karen J Duran,
Ruben Van't Slot,
Ellen van Binsbergen,
Bert van der Zwaag,
Maartje J Vogel,
Paulien A Terhal,
Hans Kristian Ploos van Amstel,
Wigard P Kloosterman,
Edwin Cuppen
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ABSTRACT: Array-based genome-wide segmental aneuploidy screening detects both de novo and inherited copy number variations (CNVs). In sporadic patients de novo CNVs are interpreted as potentially pathogenic. However, a deletion, transmitted from a healthy parent, may be pathogenic if it overlaps with a mutated second allele inherited from the other healthy parent. To detect such events, we performed multiplex enrichment and next-generation sequencing of the entire coding sequence of all genes within unique hemizygous deletion regions in 20 patients (1.53 Mb capture footprint). Out of the detected 703 non-synonymous single-nucleotide variants (SNVs), 8 represented variants being unmasked by a hemizygous deletion. Although evaluation of inheritance patterns, Grantham matrix scores, evolutionary conservation and bioinformatic predictions did not consistently indicate pathogenicity of these variants, no definitive conclusions can be drawn without functional validation. However, in one patient with severe mental retardation, lack of speech, microcephaly, cheilognathopalatoschisis and bilateral hearing loss, we discovered a second smaller deletion, inherited from the other healthy parent, resulting in loss of both alleles of the highly conserved heat shock factor binding protein 1 (HSBP1) gene. Conceivably, inherited deletions may unmask rare pathogenic variants that may exert a phenotypic impact through a recessive mode of gene action.
European journal of human genetics: EJHG 01/2012; 20(7):748-53. · 3.56 Impact Factor
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Emma van Daalen,
Chantal Kemner,
Nienke E Verbeek,
Bert van der Zwaag,
Trijnie Dijkhuizen,
Patrick Rump,
Renske Houben,
Ruben van 't Slot,
Maretha V de Jonge,
Wouter G Staal,
Frits A Beemer,
Jacob A S Vorstman,
J Peter H Burbach,
Hans Kristian Ploos van Amstel, Ron Hochstenbach,
Eva H Brilstra,
Martin Poot
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ABSTRACT: Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient's phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders.
Neurogenetics 08/2011; 12(4):315-23. · 3.35 Impact Factor
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ABSTRACT: We describe two patients with severe developmental delay, hypotonia and breathing abnormalities initially diagnosed with the autosomal recessive Joubert syndrome (JBS) who at a later stage appeared to carry chromosomal abnormalities. One case was due to a 4.8 Mb terminal 1q44 deletion, and the other due to a 15.5 Mb duplication of Xq27.2-qter containing the MECP2 gene. Critical evaluation of the clinical data showed that, retrospectively, the cases did not fulfil the diagnostic criteria for JBS, and that the diagnosis of JBS was incorrectly made. We discuss the diagnostic pitfalls and recommend adhering strictly to the JBS diagnostic criteria in the case of a negative molecular diagnosis. Critical assessment of the MRI findings by a specialized neuroradiologist is imperative. As chromosomal abnormalities may give rise to symptoms resembling JBS, we recommend array-based screening for segmental aneuploidies as an initial genetic test in all cases with a JBS-like phenotype.
Clinical dysmorphology 07/2011; 20(3):136-42. · 0.47 Impact Factor
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Wigard P Kloosterman,
Victor Guryev,
Mark van Roosmalen,
Karen J Duran,
Ewart de Bruijn,
Saskia C M Bakker,
Tom Letteboer,
Bernadette van Nesselrooij, Ron Hochstenbach,
Martin Poot,
Edwin Cuppen
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ABSTRACT: A variety of mutational mechanisms shape the dynamic architecture of human genomes and occasionally result in congenital defects and disease. Here, we used genome-wide long mate-pair sequencing to systematically screen for inherited and de novo structural variation in a trio including a child with severe congenital abnormalities. We identified 4321 inherited structural variants and 17 de novo rearrangements. We characterized the de novo structural changes to the base-pair level revealing a complex series of balanced inter- and intra-chromosomal rearrangements consisting of 12 breakpoints involving chromosomes 1, 4 and 10. Detailed inspection of breakpoint regions indicated that a series of simultaneous double-stranded DNA breaks caused local shattering of chromosomes. Fusion of the resulting chromosomal fragments involved non-homologous end joining, since junction points displayed limited or no homology and small insertions and deletions. The pattern of random joining of chromosomal fragments that we observe here strongly resembles the somatic rearrangement patterns--termed chromothripsis--that have recently been described in deranged cancer cells. We conclude that a similar mechanism may also drive the formation of de novo structural variation in the germline.
Human Molecular Genetics 02/2011; 20(10):1916-24. · 7.64 Impact Factor
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ABSTRACT: Constitutional developmental disorders are frequently caused by terminal chromosomal deletions. The mechanisms and/or architectural features that might underlie those chromosome breakages remain largely unexplored. Because telomeres are the vital DNA protein complexes stabilizing linear chromosomes against chromosome degradation, fusion, and incomplete replication, those terminal-deleted chromosomes acquired new telomeres either by telomere healing or by telomere capture. To unravel the mechanisms leading to chromosomal breakage and healing, we sequenced nine chromosome 4p terminal deletion boundaries. A computational analysis of the breakpoint flanking region, including 12 previously published pure terminal breakage sites, was performed in order to identify architectural features that might be involved in this process. All terminal 4p truncations were likely stabilized by telomerase-mediated telomere healing. In the majority of breakpoints multiple genetic elements have a potential to induce secondary structures and an enrichment in replication stalling site motifs were identified. These findings suggest DNA replication stalling-induced chromosome breakage during early development is the first mechanistic step leading toward terminal deletion syndromes.
Human Mutation 09/2010; 31(12):1343-51. · 5.69 Impact Factor
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ABSTRACT: One of the aims of clinical genetics is to identify gene mutations or genomic rearrangements that may underlie complex presentations of phenotypic features, such as multiple congenital malformations and mental retardation. During the decade after publication of the first article on array-based comparative genome hybridization, this technique has supplemented karyotyping as the prime genome-wide screening method in patients with idiopathic multiple congenital malformations and mental retardation. The use of this novel, discovery-based, approach has dramatically increased the detection rate of genomic imbalances. Array-based comparative genome hybridization detects copy number changes in the genome of patients and healthy subjects, some of which may represent phenotypically neutral copy number variations. This prompts the need for properly distinguishing between those copy number changes that may contribute to the clinical phenotype amid a pool of neutral copy number variations. We briefly review the characteristics of copy number changes in relation to their clinical relevance. Second, we discuss several published workflow schemes to identify copy number changes putatively contributing to the phenotype, and third, we propose a three-step procedure aiming to rapidly evaluate copy number changes on a case-by-case basis as to their potential contribution to the phenotype of patients with idiopathic multiple congenital malformations and mental retardation. This workflow is gene-centered and should aid in identification of disease-related candidate genes and in estimating the recurrence risk for the disorder in the family.
Genetics in medicine: official journal of the American College of Medical Genetics 08/2010; 12(8):478-85. · 3.92 Impact Factor
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Bert van der Zwaag,
Wouter G Staal, Ron Hochstenbach,
Martin Poot,
Henk A Spierenburg,
Maretha V de Jonge,
Nienke E Verbeek,
Ruben van 't Slot,
Michael A van Es,
Frank J Staal,
Christine M Freitag,
Jacobine E Buizer-Voskamp,
Marcel R Nelen,
Leonard H van den Berg,
Hans K Ploos van Amstel,
Herman van Engeland,
J Peter H Burbach
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ABSTRACT: High resolution genomic copy-number analysis has shown that inherited and de novo copy-number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR analysis revealed over 70% increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94% in patients vs. 0.42% controls, P = 0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2010; 153B(4):960-6. · 3.70 Impact Factor
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Almuth Caliebe,
Hester Y Kroes,
Jasper J van der Smagt,
José I Martin-Subero,
Holger Tönnies,
Ruben van 't Slot,
Rutger A J Nievelstein,
Hiltrud Muhle,
Ulrich Stephani,
Karsten Alfke,
Irina Stefanova,
Yorck Hellenbroich,
Gabriele Gillessen-Kaesbach, Ron Hochstenbach,
Reiner Siebert,
Martin Poot
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ABSTRACT: Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental delay, speech delay, hypotonia, hypo- or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration.
European journal of medical genetics 04/2010; 53(4):179-85. · 1.57 Impact Factor
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ABSTRACT: To determine the phenotypic significance of copy number changes (CNCs) in the human genome, we performed genome-wide segmental aneuploidy profiling by BAC-based array-CGH of 278 unrelated patients with multiple congenital abnormalities and mental retardation (MCAMR) and in 48 unaffected family members. In 20 patients, we found de novo CNCs composed of multiple consecutive probes. Of the 125 probes making up these probably pathogenic CNCs, 14 were also found as single CNCs in other patients and 5 in healthy individuals. Thus, these CNCs are not by themselves pathogenic. Almost one out of five patients and almost one out of six healthy individuals in our study cohort carried a gain or a loss for any one of the recently discovered microdeletion/microduplication loci, whereas seven patients and one healthy individual showed losses or gains for at least two different loci. The pathogenic burden resulting from these CNCs may be limited as they were found with similar frequencies among patients and healthy individuals (P=0.165; Fischer's exact test), and several individuals showed CNCs at multiple loci. CNCs occurring specifically in our study cohort were enriched for components of the glutamate receptor family (GRIA2, GRIA4, GRIK2 and GRIK4) and genes encoding proteins involved in guiding cell localization during development (ATP1A2, GIRK3, GRIA2, KCNJ3, KCNJ10, KCNK17 and KCNK5). This indicates that disease cohort-specific compilations of CNCs may aid in identifying loci, genes and biological processes that contribute to the phenotype of patients.
European journal of human genetics: EJHG 08/2009; 18(1):39-46. · 3.56 Impact Factor
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American Journal of Medical Genetics Part A 05/2009; 149A(5):1062-6. · 2.39 Impact Factor
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ABSTRACT: Anomalies of chromosome number and structure are considered to be the most frequent cause of unexplained, non-syndromic developmental delay and mental retardation (DD/MR). High-resolution, genome-wide, array-based segmental aneusomy profiling has emerged as a highly sensitive technique for detecting pathogenic genomic imbalances. A review of 29 array-based studies of DD/MR patients showed that a yield of at least approximately 19% pathogenic aberrations is attainable in unselected, consecutive DD/MR referrals if array platforms with 30-70 kb median probe spacing are used as an initial genetic testing method. This corresponds to roughly twice the rate of classical cytogenetics. This raises the question whether chromosome banding studies, combined with targeted approaches, such as fluorescence in situ hybridisation for the detection of microdeletions, still hold substantial relevance for the clinical investigation of these patients. To address this question, we reviewed the outcome of cytogenetic studies in all 36,325 DD/MR referrals in the Netherlands during the period 1996-2005, a period before the advent of array-based genome investigation. We estimate that in a minimum of 0.78% of all referrals a balanced chromosomal rearrangement would have remained undetected by array-based investigation. These include familial rearrangements (0.48% of all referrals), de novo reciprocal translocations and inversions (0.23% of all referrals), de novo Robertsonian translocations (0.04% of all referrals), and 69,XXX triploidy (0.03% of all referrals). We conclude that karyotyping, following an initial array-based investigation, would give only a limited increase in the number of pathogenic abnormalities, i.e. 0.23% of all referrals with a de novo, apparently balanced, reciprocal translocation or inversion (assuming that all of these are pathogenic), and 0.03% of all referrals with 69,XXX triploidy. We propose that, because of its high diagnostic yield, high-resolution array-based genome investigation should be the first investigation performed in cases of DD/MR, detecting >99% of all pathogenic abnormalities. Performing both array investigation and karyotyping may not be a feasible option when laboratories are faced with a need to limit the number of genetic tests available for each patient. However, laboratories that supplant karyotyping by array-based investigation should be aware that, as shown here, a chromosomal abnormality, with possible pathogenic consequences for the patient or the family, will escape detection in about 0.78% of all DD/MR referrals.
European journal of medical genetics 04/2009; 52(4):161-9. · 1.57 Impact Factor
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Bert van der Zwaag,
Lude Franke,
Martin Poot, Ron Hochstenbach,
Henk A Spierenburg,
Jacob A S Vorstman,
Emma van Daalen,
Maretha V de Jonge,
Nienke E Verbeek,
Eva H Brilstra, [......],
Hylke M Blauw,
Jan H Veldink,
Jacobine E Buizer-Voskamp,
Frits A Beemer,
Leonard H van den Berg,
Cisca Wijmenga,
Hans Kristian Ploos van Amstel,
Herman van Engeland,
J Peter H Burbach,
Wouter G Staal
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ABSTRACT: The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.
PLoS ONE 02/2009; 4(5):e5324. · 4.09 Impact Factor
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ABSTRACT: The Prader-Willi syndrome (PWS) is caused by a 5-6 Mbp de novo deletion on the paternal chromosome 15, maternal uniparental disomy 15 or an imprinting defect. All three lesions lead to the lack of expression of imprinted genes that are active on the paternal chromosome only: MKRN3, MAGEL2, NDN, C15orf2, SNURF-SNRPN and more than 70 C/D box snoRNA genes (SNORDs). The contribution to PWS of any of these genes is unknown, because no single gene mutation has been described so far. We report on two patients with PWS who have an atypical deletion on the paternal chromosome that does not include MKRN3, MAGEL2 and NDN. In one of these patients, NDN has a normal DNA methylation pattern and is expressed. In another patient, the paternal alleles of these genes are deleted as the result of an unbalanced translocation 45,X,der(X)t(X;15)(q28;q11.2). This patient is obese and mentally retarded, but does not have PWS. We conclude that a deficiency of MKRN3, MAGEL2 and NDN is not sufficient to cause PWS.
European journal of human genetics: EJHG 01/2009; 17(5):582-90. · 3.56 Impact Factor
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ABSTRACT: We report on a patient with developmental delay and several facial characteristics reminiscent of Wolf-Hirschhorn syndrome, who carries a terminal 4p16.3 deletion of minimally 1.691 Mb and maximally 1.698 Mb. This deletion contains the FGFRL1 gene, but does not include the WHSC1 gene. Given its expression pattern and its involvement in bone and cartilage formation during embryonic development, the FGFRL1 gene represents a plausible candidate gene for part of the facial characteristics of Wolf-Hirshhorn syndrome in 4p16.3 deletion patients.
European journal of human genetics: EJHG 11/2008; 17(1):129-32. · 3.56 Impact Factor
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Heather C Mefford,
Andrew J Sharp,
Carl Baker,
Andy Itsara,
Zhaoshi Jiang,
Karen Buysse,
Shuwen Huang,
Viv K Maloney,
John A Crolla,
Diana Baralle, [......],
Jonathan Sebat,
Corrado Romano,
Charles E Schwartz,
Joris A Veltman,
Bert B A de Vries,
Joris R Vermeesch,
John C K Barber,
Lionel Willatt,
May Tassabehji,
Evan E Eichler
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ABSTRACT: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.
We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons.
We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies.
We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.
New England Journal of Medicine 10/2008; 359(16):1685-99. · 53.30 Impact Factor
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ABSTRACT: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with a strong genetic etiology. Cytogenetic abnormalities have been detected in 5-10% of the patients with autism. In this study, we present the clinical, cytogenetic and array-comparative genomic hybridization (array-CGH) evaluation of a 13-year-old male with severe developmental delay, facial dysmorphic features, autism and self mutilation. The patient was found to carry a de novo duplication of chromosome region 8p21 of minimally 6.14 and maximally 6.58 Mb as ascertained by bacterial artificial chromosome (BAC)-based array-CGH. Hitherto, only a few patients with autism with cytogenetically visible duplications involving the chromosome 8p21 region have been described, but the extent of these duplications has not been determined at the molecular level. This represents the smallest rearrangement of chromosomal region 8p21 as yet found in a patient with autism. For 11 of the 36 genes with known functions located within this duplication clear transcription in the brain was found. Of those the STMN4 and DPYSL2 genes are the most likely candidate genes to be involved in neuronal development, and, if altered in gene-dosage, in the autistic phenotype of our patient.
Journal of Autism and Developmental Disorders 09/2008; 39(2):322-9. · 3.34 Impact Factor
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European journal of medical genetics 08/2008; 51(6):689-90. · 1.57 Impact Factor
