Pathogenic Mechanisms and Clinical Consequences of Chromosomal Aberrations in Man


Structural genome variations (SVs) found in patients with ‘cytogenetic disorders’ are classified as deletions, duplications, translocations, inversions, insertion translocations and complex chromosome rearrangements. Some SVs are phenotypically neutral, but de novo SVs in isolated patients or SVs inherited from a diseased parent are generally considered pathogenic. A phenotypic effect results either from gene dosage‐dependent mechanisms, for example, haploinsufficiency, or mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and their interactions disturbed. This mechanism predominantly affects gene expression. Third, mixed mutational mechanisms in which an SV is combined with a different mutation on the other, homologous chromosome, have been documented. Inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. In addition, future studies with model systems such as inducible pluripotent stem cells from patients and transgenic organisms should substantiate current inferences regarding phenotypic effects of SVs.

Key Concepts

  • Structural genome variations (SVs) result either from one or two chromosome breaks; for example, terminal deletions, reciprocal translocations or from more than 2 breaks, that is, complex chromosome rearrangements.
  • The rate of detection and the apparent complexity of the detected SVs increase with improving resolution of detection techniques.
  • SVs may exert pathogenic effects by gene dosage alterations, disruption of genomic architecture and mixed mutational mechanisms.
  • Genes which encode proteins that engage in physical interactions with other proteins may cause phenotypic effects after gene dosage alterations.
  • Disruption of genomic architecture by SVs may provoke phenotypic effects by altering the transcription of genes in the vicinity of the chromosome break.
  • If a deletion on one chromosome is combined with a deletion or a single nucleotide variant in the same deleted segment on the other, homologous chromosome, a mixed mutational mechanism, such as ‘unmasking’, may arise.
  • In counselling families with at least one individual with an SV multiple, possibly pathogenic mechanisms have to be considered.

Keywords: structural genome variation; copy number variation; haploinsufficiency; disruption of transcription associated domains; mixed mutational mechanisms; unmasking of recessive alleles; karyotyping; array‐CGH; SNP‐array; mate‐pair sequencing

Figure 1. Schematic representation of the major types of SVs. Panel a: terminal deletions (one‐break‐events), interstitial deletions, tandem duplications, Robertsonian translocations, paracentric and pericentric inversions and reciprocal translocations (two‐break‐events); Panel b: complex rearrangements, involving more than 2 breaks. Coloured circles indicate deleted (red), duplicated (green) and relocated (yellow, magenta) loci; coloured bars indicate segments being relocated to a different chromosome.


Alkan C, Coe BP and Eichler EE (2011) Genome structural variation discovery and genotyping. Nature Reviews Genetics 12: 363–376.

Boveri T (1914) Zur Frage der Entstehung maligner Tumoren. Jena: Fischer.

Brand H, Pillalamarri V, Collins RL, et al. (2014) Cryptic and complex chromosomal aberrations in early‐onset neuropsychiatric disorders. The American Journal of Human Genetics 95: 454–461.

Bugge M, Bruun‐Petersen G, Brøndum‐Nielsen K, et al. (2000) Disease associated balanced chromosome rearrangements: a resource for large scale genotype‐phenotype delineation in man. Journal of Medical Genetics 37: 858–658.

Campbell CD and Eichler EE (2013) Properties and rates of germline mutations in humans. Trends in Genetics 9: 575–584.

Cooper GM, Coe BP, Girirajan S, et al. (2011) A copy number variation morbidity map of developmental delay. Nature Genetics 43: 838–846.

De Gregori M, Ciccone R, Magini P, et al. (2007) Cryptic deletions are a common finding in ‘balanced’ reciprocal and complex chromosome rearrangements: a study of 59 patients. Journal of Medical Genetics 44: 750–762.

Dixon JR, Selvaraj S, Yue F, et al. (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485: 376–380.

Firth HV, Richards SM, Bevan AP, et al. (2009) DECIPHER: database of chromosomal imbalance and phenotype in humans using ensemble resources. The American Journal of Human Genetics 84: 524–533.

Forabosco A, Percesepe A and Santucci S (2009) Incidence of non‐age‐dependent chromosomal abnormalities: a population‐based study on 88965 amniocenteses. European Journal of Human Genetics 17: 897–903.

Girirajan S and Eichler EE (2010) Phenotypic variability and genetic susceptibility to genomic disorders. Human Molecular Genetics 19: R176–187.

Hehir‐Kwa JY, Wieskamp N, Webber C, et al. (2010) Accurate distinction of pathogenic from benign CNVs in mental retardation. PLoS Computational Biology 6: e1000752.

Henrichsen CN, Vinckenbosch N, Zöllner S, et al. (2009) Segmental copy number variation shapes tissue transcriptomes. Nature Genetics 41: 424–429.

Hochstenbach R, van Binsbergen E, Engelen J, et al. (2009) Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. European Journal of Medical Genetics 52: 161–169.

Hochstenbach R, Buizer‐Voskamp JE, Vorstman JA and Ophoff RA (2011) Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research. Cytogenetic and Genome Research 135: 174–202.

Hochstenbach R, Poot M, Nijman IJ, et al. (2012) Discovery of variants unmasked by hemizygous deletions. European Journal of Human Genetics 20: 748–753.

Huang N, Lee I, Marcotte EM and Hurles ME (2010) Characterising and predicting haploinsufficiency in the human genome. PLoS Genetics 6: e1001154.

Itsara A, Wu H, Smith JD, et al. (2010) De novo rates and selection of large copy number variation. Genome Research 20: 1469–1481.

Jacobs PA, Browne C, Gregson N, Joyce C and White H (1992) Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. Journal of Medical Genetics 29: 103–108.

Kaminsky EB, Kaul V, Paschall J, et al. (2011) An evidence‐based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genetics in Medicine 13: 777–784.

Kearney HM, Thorland EC, Brown KK, et al. (2011) American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genetics in Medicine 13: 680–685.

Kloosterman WP, Tavakoli‐Yaraki M, van Roosmalen MJ, et al. (2012) Constitutional chromothripsis rearrangements involve clustered double‐stranded DNA breaks and nonhomologous repair mechanisms. Cell Reports 1: 648–655.

Klopocki E and Mundlos S (2011) Copy‐number variations, noncoding sequences, and human phenotypes. Annual Review of Genomics and Human Genetics 12: 53–72.

Lessel D, Saha B, Hisama F, et al. (2014) Atypical Aicardi‐Goutieres syndrome: is the WRN locus a modifier? American Journal of Medical Genetics Part A 164A: 2510–2513.

Liehr T, Ewers E, Kosyakova N, et al. (2009) Handling small supernumerary marker chromosomes in prenatal diagnostics. Expert Review of Molecular Diagnostics 9: 317–324.

Lupiáñez DG, Kraft K, Heinrich V, et al. (2015) Disruptions of topological chromatin domains cause pathogenic rewiring of gene‐enhancer interactions. Cell 161: 1012–1025.

Malvestiti F, De Toffol S, Grimi B, et al. (2014) De novo small supernumerary marker chromosomes detected on 143,000 consecutive prenatal diagnoses: chromosomal distribution, frequencies, and characterization combining molecular cytogenetics approaches. Prenatal Diagnosis 34: 460–468.

Mefford HC, Sharp AJ, Baker C, et al. (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. The New England Journal of Medicine 359: 1685–1699.

Miller DT, Adam MP, Aradhya S, et al. (2010) Consensus statement: chromosomal microarray is a first‐tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. The American Journal of Human Genetics 86: 749–764.

Nielsen J and Wohlert M (1991) Chromosome abnormalities found among 34,910 newborn children: results from a 13‐year incidence study in Arhus, Denmark. Human Genetics 87: 81–83.

Nora EP, Lajoie BR, Schulz EG, et al. (2012) Spatial partitioning of the regulatory landscape of the X‐inactivation centre. Nature 485: 381–385.

Nora EP, Dekker J and Heard E (2013) Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods?. Bioessays 35: 818–828.

Pellestor F, Anahory T, Lefort G, et al. (2011) Complex chromosomal rearrangements: origin and meiotic behavior. Hum Reprod Update 17: 476–494.

Peng HH, Chao AS, Wang TH, Chang YL and Chang SD (2006) Prenatally diagnosed balanced chromosome rearrangements: eight years' experience. The Journal of Reproductive Medicine 51: 699–703.

Poot M and Hochstenbach R (2010) A three‐step workflow procedure for the interpretation of array‐based comparative genome hybridization results in patients with idiopathic mental retardation and congenital anomalies. Genet Med 12: 478–485.

Poot M (2013) Towards identification of individual etiologies by resolving genomic and biological conundrums in patients with autism spectrum disorders. Molecular Syndromology 4: 213–226.

Poot M and Haaf T (2015) Mechanisms of origin, phenotypic effects and diagnostic implications of complex chromosome rearrangements. Molecular Syndromology 6: 109–133.

Poot M and Kas MJ (2013) Antisense may make sense of 1q44 deletions, seizures, and HNRNPU. American Journal of Medical Genetics Part A 161A: 910–912.

Poot M, van't Slot R, Leupert R, et al. (2009) Three de novo losses and one insertion within a pericentric inversion of chromosome 6 in a patient with complete absence of expressive speech and reduced pain perception. European Journal of Medical Genetics 52: 27–30.

Poot M, Beyer V, Schwaab I, et al. (2010) Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder. Neurogenetics 11: 81–89.

Poot M, van der Smagt JJ, Brilstra EH and Bourgeron T (2011) Disentangling the myriad genomics of complex disorders, specifically focusing on autism, epilepsy, and schizophrenia. Cytogenetic and Genome Research 135: 228–240.

Popp MW and Maquat LE (2013) Organizing principles of mammalian nonsense‐mediated mRNA decay. Annual Review of Genetics 47: 139–165.

Reymond A, Henrichsen CN, Harewood L and Merla G (2007) Side effects of genome structural changes. Current Opinion in Genetics & Development 17: 381–386.

Rippey C, Walsh T, Gulsuner S, et al. (2013) Formation of chimeric genes by copy‐number variation as a mutational mechanism in schizophrenia. The American Journal of Human Genetics 93: 697–710.

Robinson PN and Webber C (2014) Phenotype ontologies and cross‐species analysis for translational research. PLoS Genetics 10: e1004268.

Schlattl A, Anders S, Waszak SM, Huber W and Korbel JO (2011) Relating CNVs to transcriptome data at fine resolution: assessment of the effect of variant size, type, and overlap with functional regions. Genome Research 21: 2004–2013.

Schluth‐Bolard C, Delobel B, Sanlaville D, et al. (2009) Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: array CGH study of 47 unrelated cases. European Journal of Medical Genetics 52: 291–296.

Spielmann M and Klopocki E (2013) CNVs of noncoding cis‐regulatory elements in human disease. Current Opinion in Genetics & Development 23: 249–256.

Spielmann M and Mundlos S (2013) Structural variations, the regulatory landscape of the genome and their alteration in human disease. Bioessays 35: 533–543.

Stankiewicz P and Lupski JR (2010) Structural variation in the human genome and its role in disease. Annual Review of Medicine 61: 437–455.

Van Dyke DL, Weiss L, Roberson JR and Babu VR (1983) The frequency and mutation rate of balanced autosomal rearrangements in man estimated from prenatal genetic studies for advanced maternal age. American Journal of Human Genetics 35: 301–308.

Veitia RA and Birchler JA (2010) Dominance and gene dosage balance in health and disease: why levels matter!. Journal of Pathology 220: 174–185.

Wagner E and Lykke‐Andersen J (2002) mRNA surveillance: the perfect persist. Journal of Cell Science 115: 3033–3038.

Warburton D (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. The American Journal of Human Genetics 49: 995–1013.

Further Reading

Hart L and O'Driscoll M (2013) Causes and consequences of structural genomic alterations in the human genome. In: eLS. Chichester: John Wiley & Sons, Ltd. 10.1002/9780470015902.a0024976.

Hastings PJ, Lupski JR, Rosenberg SM and Ira G (2009) Mechanisms of change in gene copy number. Nature Reviews Genetics 10: 551–564.

Kloosterman WP and Hochstenbach R (2014) Deciphering the pathogenic consequences of chromosomal aberrations in human genetic disease. Molecular Cytogenetics 7: 100.

Liu P, Carvalho CM, Hastings PJ and Lupski JR (2012) Mechanisms for recurrent and complex human genomic rearrangements. Current Opinion in Genetics & Development 22: 211–220.

Sharp AJ, Cheng Z and Eichler EE (2006) Structural variation of the human genome. Annual Review of Genomics and Human Genetics 7: 407–442.

Tuna M (2015) Next‐generation sequencing in cancer: tools for fusion gene detection. In: eLS. Chichester: John Wiley & Sons Ltd. 10.1002/9780470015902.a0025848.

References for the Supplementary Tables

Auger J, Bonnet C, Valduga M, et al. (2013) De novo complex X chromosome rearrangement unmasking maternally inherited CSF2RA deletion in a girl with pulmonary alveolar proteinosis. American Journal of Medical Genetics Part A 161A: 2594–2599.

Backx L, Seuntjens E, Devriendt K, Vermeesch J and Van Esch H (2011) A balanced translocation t(6;14)(q25.3;q13.2) leading to reciprocal fusion transcripts in a patient with intellectual disability and agenesis of corpus callosum. Cytogenetic and Genome Research 132: 135–143.

Bedeschi MF, Colombo L, Mari F, et al. (2010) Unmasking of a recessive SCARF2 mutation by a 22q11.12 de novo deletion in a patient with Van den Ende‐Gupta syndrome. Molecular Syndromology 1: 239–245.

Bertelsen B, Melchior L, Jensen LR, et al. (2015) A t(3;9)(q25.1;q34.3) translocation leading to OLFM1 fusion transcripts in Gilles de la Tourette syndrome, OCD and ADHD. Psychiatry Research 225: 268–275.

Bisgaard AM, Kirchhoff M, Nielsen JE, et al. (2009) Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy. Clinical Genetics 75: 175–179.

Borsani G, Piovani G, Zoppi N, et al. (2008) Cytogenetic and molecular characterization of a de‐novo t(2p;7p) translocation involving TNS3 and EXOC6B genes in a boy with a complex syndromic phenotype. European Journal of Medical Genetics 51: 292–302.

Buysse K, Vergult S, Mussche S, et al. (2010) Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. American Journal of Medical Genetics Part A 152A: 2802–2804.

Di Gregorio E, Bianchi FT, Schiavi A, et al. (2013) A de novo X;8 translocation creates a PTK2‐THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia. Journal of Medical Genetics 50: 543–551.

Eykelenboom JE, Briggs GJ, Bradshaw NJ, et al. (2012) A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. Human Molecular Genetics 21: 3374–3386.

Flipsen‐ten Berg K, van Hasselt PM, Eleveld MJ, et al. (2007) Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf‐Hirschhorn syndrome. European Journal of Human Genetics 15: 1132–1138.

Fridman C, Hosomi N, Varela MC, et al. (2003) Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene. American Journal of Medical Genetics Part A 119A: 180–183.

Friedrich K, Lee L, Leistritz DF, et al. (2010) WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic‐specific alterations. Human Genetics 128: 103–111.

Ghai SJ, Shago M, Shroff M and Yoon G (2011) Cockayne syndrome caused by paternally inherited 5 Mb deletion of 10q11.2 and a frameshift mutation of ERCC6. European Journal of Medical Genetics 54: 272–276.

Gothelf D, Eliez S, Thompson T, et al. (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neuroscience 8: 1500–1502.

van Heesch S, Simonis M, van Roosmalen MJ, et al. (2014) Genomic and functional overlap between somatic and germline chromosomal rearrangements. Cell Reports 9: 2000–2010.

Holt R, Sykes NH, Conceição IC, et al. (2012) CNVs leading to fusion transcripts in individuals with autism spectrum disorder. European Journal of Human Genetics 20: 1141–1147.

Kabuki T, Kawai T, Kin Y, et al. (2003) A case of Williams syndrome with p47‐phox‐deficient chronic granulomatous disease. Nihon Rinshō Men'eki Gakkai Kaishi 26: 299–303.

Kuechler A, Hauffa BP, Köninger A, et al. (2010) An unbalanced translocation unmasks a recessive mutation in the follicle‐stimulating hormone receptor (FSHR) gene and causes FSH resistance. European Journal of Human Genetics 18: 656–661.

Kurotaki N, Shen JJ, Touyama M, et al. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genetics in Medicine 7: 479–483.

Lee ST, Nicholls RD, Bundey S, et al. (1994) Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader‐Willi syndrome plus albinism. The New England Journal of Medicine 330: 529–534.

Lesnik Oberstein SA, Kriek M, White SJ, et al. (2006) Peters plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase. The American Journal of Human Genetics 79: 562–566.

Liburd N, Ghosh M, Riazuddin S, et al. (2001) Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith‐Magenis syndrome. Human Genetics 109: 535–541.

Ludlow LB, Schick BP, Budarf ML, et al. (1996) Identification of a mutation in a GATA binding site of the platelet glycoprotein Ibbeta promoter resulting in the Bernard‐Soulier syndrome. Journal of Biological Chemistry 271: 22076–22080.

Malli T, Duba HC, Erdel M, et al. (2014) Disruption of the ARID1B and ADAMTS6 loci due to a t(5;6)(q12.3;q25.3) in a patient with developmental delay. American Journal of Medical Genetics Part A 164A: 3126–3131.

Mansouri MR, Carlsson B, Davey E, et al. (2006) Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation. Human Genetics 119: 162–168.

Masurel‐Paulet A, Andrieux J, Callier P, et al. (2010) Delineation of 15q13.3 microdeletions. Clinical Genetics 78: 149–161.

Newman S, Hermetz KE, Weckselblatt B and Rudd MK (2015) Next‐generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. The American Journal of Human Genetics 96: 208–220.

Nothwang HG, Kim HG, Aoki J, et al. (2001) Functional hemizygosity of PAFAH1B3 due to a PAFAH1B3‐CLK2 fusion gene in a female with mental retardation, ataxia and atrophy of the brain. Human Molecular Genetics 10: 797–806.

Pebrel‐Richard C, Debost‐Legrand A, Eymard‐Pierre E, et al. (2014) An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3. European Journal of Human Genetics 22: 369–373.

Riley D, Wiznitzer M, Schwartz S and Zinn AB (2001) A 13‐year‐old boy with cognitive impairment, retinoblastoma, and Wilson disease. Neurology 57: 141–143.

Rivera‐Brugués N, Albrecht B, Wieczorek D, et al. (2011) Cohen syndrome diagnosis using whole genome arrays. Journal of Medical Genetics 48: 136–140.

Rooryck C, Morice‐Picard F, Lasseaux E, et al. (2011) High resolution mapping of OCA2 intragenic rearrangements and identification of a founder effect associated with a deletion in Polish albino patients. Human Genetics 129: 199–208.

Vorstman JA, van Daalen E, Jalali GR, et al. (2011) A double hit implicates DIAPH3 as an autism risk gene. Molecular Psychiatry 16: 442–451.

Wakui K, Toyoda A, Kubota T, et al. (2002) Familial 14‐Mb deletion at 21q11.2‐q21.3 and variable phenotypic expression. Journal of Human Genetics 47: 511–516.

Yue Y, Grossmann B, Holder SE and Haaf T (2005) De novo t(7;10)(q33;q23) translocation and closely juxtaposed microdeletion in a patient with macrocephaly and developmental delay. Human Genetics 117: 1–8.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Poot, Martin, and Hochstenbach, Ron(Oct 2015) Pathogenic Mechanisms and Clinical Consequences of Chromosomal Aberrations in Man. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026379]