Chromosomal Syndromes

Author: H. Brunner
Submitted: Sunday 12th of September 2010 08:51:50 AM
Submitted by: egf
Educational levels: expert, qc3



Aneuploid states cause recognizable clinical syndromes that are named after their discoverer (Down syndrome, Wolf-Hirschhorn syndrome etc), after their main clinical symptoms (velacardiofacial syndrome, cri-du-chat syndrome) or after their localization in the genome (1p36 deletion syndrome, 22q11 deletion syndrome). There are multiple classes of chromosomal aneuploidy syndromes. 1. Those involving an entire chromosome that is either extra, or missing. Examples are Down syndrome and Turner syndrome. The mechanism is mostly nondisjunction, although translocations occur in a minority. 2. Those that involve deletions and duplications of the chromosomal telomeres. Subtelomeric abnormalities often vary in size from case to case. Larger deletions may cause a more complex phenotype due to the involvement of additional genes. This is also called a contiguous gene syndrome. The availability of a large number of cases with deletions of different length allows for the creation of a phenotype map, that locates specific clinical features to small regions on the chromosome. In some instances, a single gene has been shown to account for the main features of a chromsomal deletion syndrome. A pertinent example is the 9q34 deletion syndrome that is present in patients with de novo mutations of the EuHMtase1 gene. Telomeric deletion and duplication syndromes may arise as the result of parental balanced translocations. These may be crypic (i.e. not detectable with conventional karyotype analysis) and then cause recurrence in the same sibship, or even unexpected recurrence in another pregnancy, elsewhere in the family. Subtelomeric deletions and duplications are a frequent cause of mental retardation, and account for approximately 6% of unexplained mental retardation with normal chromosomes by standard karyotyping. 3. Most interstitial deletions are unique, that is their breakpoint are not found in other patients. Here, phenotypic variability between patients and the rarity of any cytogenetic abnormality calls for a world-wide collection of such cases with careful descriptions of both genotype and phenotype. Online resources (such as ECARUCA / DECIPHER), as well as the Schinzel book and offline database are essential for clinical practice and may be used also for scientific analysis and the creation of phenotype maps. 4. A number of interstitial deletions and duplications are frequent and these tend to have similar chromsomal breakpoints. Detection of such microdeletion and microduplication syndromes generally requires molecular cytogenetic techniques such as FISH, MLPA, or genomic arrays, either as targeted arrays or as whole genome arrays. The reason that underlies their frequent occurrence is the presence of a specific chromosomal architecture involving repeat sequences flanking the site of the recurrent deletion or duplication. Since the genome is full of low-copy repeat sequences, new frequent microdeletion and microduplication syndromes are still being defined. The 17q21 deletion syndrome is one example. Refs: Feenstra I, Brunner HG, van Ravenswaaij CM. Cytogenetic genotype-phenotype studies: improving genotyping, phenotyping and data storage. Cytogenet Genome Res. 115: 231-239, 2006 Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, Genevieve D, Cormier-Daire V, van Esch H, Fryns JP, Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H. Loss-of-Function Mutations in Euchromatin Histone Methyl Transferase 1 (EHMT1) Cause the 9q34 Subtelomeric Deletion Syndrome. Am J Hum Genet. 79:370-377, 2006 De Vries BB, Winter R, Schinzel A, van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet. 2003 Jun;40(6):385-98. Lupski JR, Stankiewicz P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 2005 Dec;1(6):e49. Koolen DA, Vissers LELM, Pfundt R, de Leeuw N, Knight SJL, Regan R, Kooy FR, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, Geurts van Kessel A, Sistermans EA, Veltman JA, Brunner HG, de Vries BBA. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 38: 999-1001, 2006. Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D. A chromosomal deletion map of human malformations. Am J Hum Genet. 1998 Oct;63(4):1153-9. Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D. A chromosomal duplication map of malformations: regions of suspected haplo- and triplolethality--and tolerance of segmental aneuploidy--in humans. Am J Hum Genet. 1999 Jun;64(6):1702-8. Veltman JA, Jonkers Y, Nuijten I, Janssen I, van der Vliet W, Huys E, Vermeesch J, Van Buggenhout G, Fryns JP, Admiraal R, Terhal P, Lacombe D, van Kessel AG, Smeets D, Schoenmakers EF, van Ravenswaaij-Arts CM. Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH. Am J Hum Genet. 2003 Jun;72(6):1578-84. Databases linking cytogenetic abnormalities and phenotypes: * Off-line: Schinzel A (1994) Human cytogenetics database. Oxford University Press, Oxford Book: Catalogue of Unbalanced Chromosome Aberrations in Man 2nd edition. Albert Schinzel. Berlin: Walter de Gruyter, 2001. ISBN 3-11-011607-3. * On-line: Feenstra I, Fang J, Koolen DA, Siezen A, Evans C, Winter RM, Lees MM, Riegel M, de Vries BB, Van Ravenswaaij CM, Schinzel A. European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA); an online database for rare chromosome abnormalities. Eur J Med Genet. 2006 Jul-Aug;49(4):279-91. ECARUCA website: DECIPHER website:


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H. Brunner. Chromosomal Syndromes. EUROGENE portal. September 2010. online:

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