Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH).


:Disease-predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements that are challenging to detect and characterize using standard PCR-based mutation screening methods. Here, we describe a custom-made zoom-in microarray comparative genomic hybridization (CGH) platform of 60mer oligonucleotides. The 4 x 44 K array format provides high-resolution coverage (200-300 bp) of 400-700 kb genomic regions surrounding six cancer susceptibility genes. We evaluate its performance to accurately detect and precisely map earlier described or novel large germline deletions or duplications occurring in BRCA1 (n=11), BRCA2 (n=2), MSH2 (n=7), or MLH1 (n=9). Additionally, we demonstrate its applicability for uncovering complex somatic rearrangements, exemplified by zoom-in analysis of the PTEN and CDKN2A loci in breast cancer cells. The sizes of rearrangements ranged from several 100 kb, including large flanking regions, to <500-bp deletions, including parts of single exons that would be missed by standard multiplex ligation-dependent probe amplification (MLPA) methods. Zoom-in CGH arrays accurately defined the borders of rearrangements, allowing convenient design of primers for sequence determination of the breakpoints. The array platform can be streamlined for a particular application, e.g., focusing on breast cancer susceptibility genes, with increased capacity using multiformat design, and represents a valuable new tool and complement for genetic screening in clinical diagnostics.


Hum Mutat


Human mutation


Staaf J,Törngren T,Rambech E,Johansson U,Persson C,Sellberg G,Tellhed L,Nilbert M,Borg A




Has Abstract


2008-04-01 00:00:00












  • The human SHOX mutation database.

    abstract::The human SHOX database has recently been established to provide clinicians and scientists access to a central source of information about all known SHOX mutations associated with short stature phenotypes such as idiopathic short stature, Lèri-Weill dyschondrosteosis, Langer syndrome, and Turner syndrome. So far, the ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Niesler B,Fischer C,Rappold GA

    更新日期:2002-11-01 00:00:00

  • Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3.

    abstract::Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. I...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Itzkovitz B,Jiralerspong S,Nimmo G,Loscalzo M,Horovitz DD,Snowden A,Moser A,Steinberg S,Braverman N

    更新日期:2012-01-01 00:00:00

  • Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients.

    abstract::There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementat...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Thompson ER,Boyle SE,Johnson J,Ryland GL,Sawyer S,Choong DY,kConFab,Chenevix-Trench G,Trainer AH,Lindeman GJ,Mitchell G,James PA,Campbell IG

    更新日期:2012-01-01 00:00:00

  • The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis.

    abstract::We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon-Lefèvre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early-onset, severe periodontitis. Others have also reported CTSC mutations in patients with severe prepubertal pe...

    journal_title:Human mutation

    pub_type: 杂志文章,多中心研究


    authors: Hewitt C,McCormick D,Linden G,Turk D,Stern I,Wallace I,Southern L,Zhang L,Howard R,Bullon P,Wong M,Widmer R,Gaffar KA,Awawdeh L,Briggs J,Yaghmai R,Jabs EW,Hoeger P,Bleck O,Rüdiger SG,Petersilka G,Battino M,Bre

    更新日期:2004-03-01 00:00:00

  • NSD1 PHD domains bind methylated H3K4 and H3K9 using interactions disrupted by point mutations in human sotos syndrome.

    abstract::Sotos syndrome is a human developmental and cognitive disorder caused by happloinsufficiency of transcription factor NSD1. Similar phenotypes arise from NSD1 gene deletion or from point mutations in 9 of 13 NSD1 domains, including all 6 PHD domains, indicating that each NSD1 domain performs an essential role. To gain ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pasillas MP,Shah M,Kamps MP

    更新日期:2011-03-01 00:00:00

  • Screening of the PKD1 duplicated region reveals multiple single nucleotide polymorphisms and a de novo mutation in Hellenic polycystic kidney disease families.

    abstract::Mutations in the PKD1 gene account for approximately 85% of cases with autosomal dominant polycystic kidney disease (ADPKD1; MIM# 601313), which is considered one of the most frequent monogenic disorders, with a frequency of approximately 1:1000. The main symptom is the formation of fluid-filled cysts in the kidneys a...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Koptides M,Mean R,Demetriou K,Constantinides R,Pierides A,Harris PC,Deltas CC

    更新日期:2000-08-01 00:00:00

  • Functional characterization of splicing and ligand-binding domain variants in the LDL receptor.

    abstract::Familial hypercholesterolemia (FH) is an autosomal dominant disorder mostly caused by mutations in the LDLR gene. Although the detection of functional mutations in the LDLR gene provides an unequivocal diagnosis of the FH condition, there are many variants whose pathogenicity is still unknown. The aims of this study w...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Etxebarria A,Palacios L,Stef M,Tejedor D,Uribe KB,Oleaga A,Irigoyen L,Torres B,Ostolaza H,Martin C

    更新日期:2012-01-01 00:00:00

  • Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

    abstract::Cystic fibrosis, the most common lethal genetic disease in the white population, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Analysis of DNA from a pancreatic insufficient patient by chemical mismatch cleavage and subsequent DNA sequencing led to the identification of...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Strong TV,Smit LS,Nasr S,Wood DL,Cole JL,Iannuzzi MC,Stern RC,Collins FS

    更新日期:1992-01-01 00:00:00

  • Central mutation databases--a review.

    abstract::The Internet has been a key component in the coordination of the diverse group of scientists involved in the Human Genome Project. Nowhere has this contribution been more critical than in the maintenance and exchange of information about genetic variation and mutation. Whereas the majority of DNA sequence is generated...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Porter CJ,Talbot CC,Cuticchia AJ

    更新日期:2000-01-01 00:00:00

  • Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency.

    abstract::Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder of fatty acid oxidation caused by defective cellular carnitine transport. The disease is characterized by metabolic derangement simulating Reye's syndrome, hypoglcaemia, progressive cardiomyopathy and skeletal myopathy. Recently, it was sho...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Mayatepek E,Nezu J,Tamai I,Oku A,Katsura M,Shimane M,Tsuji A

    更新日期:2000-01-01 00:00:00

  • Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis.

    abstract::Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G > A (p.R122...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Teich N,Rosendahl J,Tóth M,Mössner J,Sahin-Tóth M

    更新日期:2006-08-01 00:00:00

  • Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described.

    abstract::X-linked Adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. It mainly involves the nervous system white matter, adrenal cortex and testes. Several distinct clinical phenotypes are known. The principal biochemical abnormality is the accumulation of saturated very-long-chain fatty acids (VLCFAs : > C...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lachtermacher MB,Seuánez HN,Moser AB,Moser HW,Smith KD

    更新日期:2000-01-01 00:00:00

  • A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).

    abstract::Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential en...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: McLaughlin HM,Sakaguchi R,Giblin W,NISC Comparative Sequencing Program.,Wilson TE,Biesecker L,Lupski JR,Talbot K,Vance JM,Züchner S,Lee YC,Kennerson M,Hou YM,Nicholson G,Antonellis A

    更新日期:2012-01-01 00:00:00

  • A novel splice site mutation of the EXT2 gene in a Finnish hereditary multiple exostoses family. Mutations in brief no. 197. Online.

    abstract::Hereditary multiple exostoses is a dominantly inherited disease characterized by multiple benign osteochondromas. The affected individuals have an increased risk of developing sarcoma. A large Finnish family with hereditary multiple exostosis was analyzed to find the disease-causing mutation. Blood samples were obtain...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Wolf M,Hemminki A,Kivioja A,Sistonen P,Kaitila I,Ervasti H,Kinnunen J,Karaharju E,Knuutila S

    更新日期:1998-01-01 00:00:00

  • Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome.

    abstract::Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Bacrot S,Doyard M,Huber C,Alibeu O,Feldhahn N,Lehalle D,Lacombe D,Marlin S,Nitschke P,Petit F,Vazquez MP,Munnich A,Cormier-Daire V

    更新日期:2015-02-01 00:00:00

  • Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.

    abstract::Uridine-diphosphoglucuronate glucuronosyltransferases (UGTs) are a family of enzymes that conjugate various endogenous and exogenous compounds with glucuronic acid and facilitate their excretion in the bile. Bilirubin-UGT(1) (UGT1A1) is the only isoform that significantly contributes to the conjugation of bilirubin. L...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Kadakol A,Ghosh SS,Sappal BS,Sharma G,Chowdhury JR,Chowdhury NR

    更新日期:2000-10-01 00:00:00

  • Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism.

    abstract::The beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta-cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutation...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Gloyn AL,Siddiqui J,Ellard S

    更新日期:2006-03-01 00:00:00

  • Pathogenic mitochondrial tRNA mutations--which mutations are inherited and why?

    abstract::Mitochondrial transfer RNA (mt-tRNA) mutations are the commonest mitochondrial (mtDNA) mutations to cause human disease. The majority of mt-tRNA mutations are heteroplasmic and while some exhibit maternal transmission within families, many others are only seen as sporadic mutations. Using the available clinical, bioch...

    journal_title:Human mutation

    pub_type: 杂志文章,meta分析


    authors: Elson JL,Swalwell H,Blakely EL,McFarland R,Taylor RW,Turnbull DM

    更新日期:2009-11-01 00:00:00

  • Copy number variation at the FCGR locus includes FCGR3A, FCGR2C and FCGR3B but not FCGR2A and FCGR2B.

    abstract::Human Fcgamma receptors (FcgammaRs) are glycoproteins that bind the Fc region of IgG. The genes encoding the low-affinity FcgammaRs are located on chromosome 1q23-24. Beside single nucleotide polymorphisms (SNPs), gene copy number variation (CNV) is now being recognized as an important indicator for inter-individual d...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Breunis WB,van Mirre E,Geissler J,Laddach N,Wolbink G,van der Schoot E,de Haas M,de Boer M,Roos D,Kuijpers TW

    更新日期:2009-05-01 00:00:00

  • Detection of more than 94% cystic fibrosis mutations in a sample of Belgian population and identification of four novel mutations.

    abstract::We have analysed 194 Belgian CF chromosomes using a variety of techniques: delta F508 was detected by polyacrylamide gel electrophoresis; dot blotting of PCR products was used to identify the mutations G542X, 1717-1 G-->A, and N1303K; molecular defects in exons 2, 3, 4, 5, 6b, 7, 11, 12, 13, 14a, 14b, 17b, 19, 20, and...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Mercier B,Lissens W,Audrézet MP,Bonduelle M,Liebaers I,Ferec C

    更新日期:1993-01-01 00:00:00

  • Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy.

    abstract::Influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, and high mortality in otherwise apparently healthy individuals. We have reported that a large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylc...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Yao D,Mizuguchi H,Yamaguchi M,Yamada H,Chida J,Shikata K,Kido H

    更新日期:2008-05-01 00:00:00

  • New point mutation (R243W) in the hormone binding domain of the c-erbA beta 1 gene in a family with generalized resistance to thyroid hormone.

    abstract::Two years after the first mutation on exon 7 in the carboxy-terminal part of the hinge domain (D) was reported (Behr and Loos 1992), we have identified the second mutation on exon 7 in patients with GRTH. Interestingly, our mutation it is not located in the two previously described "hot spot regions", but instead very...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pohlenz J,Schönberger W,Wemme H,Winterpacht A,Wirth S,Zabel B

    更新日期:1996-01-01 00:00:00

  • mirVAFC: A Web Server for Prioritizations of Pathogenic Sequence Variants from Exome Sequencing Data via Classifications.

    abstract::Exome sequencing has been widely used to identify the genetic variants underlying human genetic disorders for clinical diagnoses, but the identification of pathogenic sequence variants among the huge amounts of benign ones is complicated and challenging. Here, we describe a new Web server named mirVAFC for pathogenic ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Li Z,Liu Z,Jiang Y,Chen D,Ran X,Sun ZS,Wu J

    更新日期:2017-01-01 00:00:00

  • Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas.

    abstract::Schwannomatosis is characterized by the onset of multiple intracranial, spinal, or peripheral schwannomas, without involvement of the vestibular nerve, which is instead pathognomonic of neurofibromatosis type 2 (NF2). Recently, a schwannomatosis family with a germline mutation of the SMARCB1 gene on chromosome 22 has ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sestini R,Bacci C,Provenzano A,Genuardi M,Papi L

    更新日期:2008-02-01 00:00:00

  • Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis.

    abstract::The autosomal recessive lysosomal storage disorder, nephropathic cystinosis is characterized by impaired transport of free cystine out of lysosomes. The gene responsible for cystinosis, CTNS, consists of 12 exons and encodes a 55 kDa putative lysosomal membrane protein, called cystinosin. Up to now more than 55 differ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kiehntopf M,Schickel J,Gönne Bv,Koch HG,Superti-Furga A,Steinmann B,Deufel T,Harms E

    更新日期:2002-09-01 00:00:00

  • Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11).

    abstract::Both myosin 7A (MYO7A) and calmodulin (CaM) are required for transduction and adaptation processes in inner ear hair cells. We identified a novel heterozygous missense mutation (c.2557C>T; p.R853C) in a family with autosomal dominant non-syndromic hearing loss that changes an evolutionarily invariant residue of the fi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Bolz H,Bolz SS,Schade G,Kothe C,Mohrmann G,Hess M,Gal A

    更新日期:2004-09-01 00:00:00

  • Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations.

    abstract::Low-density lipoprotein receptor (LDLR) gene mutations cause familial hypercholesterol-emia (FH), one of the most common single gene disorders. The spectrum of LDLR mutations in Brazil is not known. The aim of this study was the characterization of LDLR mutations in 35 unrelated Brazilian patients with heterozygous FH...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Salazar LA,Hirata MH,Cavalli SA,Nakandakare ER,Forti N,Diament J,Giannini SD,Bertolami MC,Hirata RD

    更新日期:2002-04-01 00:00:00

  • A diagnostic genetic test for the physical mapping of germline rearrangements in the susceptibility breast cancer genes BRCA1 and BRCA2.

    abstract::The BRCA1 and BRCA2 genes are involved in breast and ovarian cancer susceptibility. About 2 to 4% of breast cancer patients with positive family history, negative for point mutations, can be expected to carry large rearrangements in one of these two genes. We developed a novel diagnostic genetic test for the physical ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Cheeseman K,Rouleau E,Vannier A,Thomas A,Briaux A,Lefol C,Walrafen P,Bensimon A,Lidereau R,Conseiller E,Ceppi M

    更新日期:2012-06-01 00:00:00

  • Mutation spectrum in patients with Rett syndrome in the German population: Evidence of hot spot regions.

    abstract::Mutations in the MECP2 (Methyl-CpG-binding protein) gene recently have been reported to cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disease. We investigated 125 sporadic cases of Rett syndrome by direct sequencing. Thirty different mutations were found in 97 patients with Rett syndrome. Seventee...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Laccone F,Huppke P,Hanefeld F,Meins M

    更新日期:2001-03-01 00:00:00

  • Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli.

    abstract::Deficiency of propionyl-CoA carboxylase (PCC) results in propionic acidemia, an autosomal recessive disorder characterized by ketoacidosis sufficiently severe to cause neonatal death. PCC is involved in the catabolism of branched-chain amino acids, odd-chain fatty acids, and cholesterol. The enzyme is a biotin-depende...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Chloupkova M,Maclean KN,Alkhateeb A,Kraus JP

    更新日期:2002-06-01 00:00:00