Microdeletion Syndromes

Abstract

A microdeletion syndrome is the clinical consequence of a submicroscopic chromosome deletion leading to monosomy for a small chromosomal segment. The clinical pictures of well‐known microdeletion syndromes are relatively specific and the phenotypic characteristics were often recognised before the causal microdeletions were identified. In recent years, the widespread use of array comparative genomic hybridisation (array CGH) has lead to the discovery of numerous novel microdeletion and microduplication syndromes that were clinically delineated only after the chromosome aberration was ascertained by array. The newer microdeletion syndromes are more likely to be rare and to have milder, less specific clinical features, such as developmental delays and behavioural differences. Many of the phenotypes are still evolving. It is also becoming clear for some of the smaller deletions that the same microdeletions can be present in normal individuals and that they thus can be considered to be susceptibility factors for the development of neurocognitive differences.

Key Concepts:

  • There are numerous novel microdeletion and microduplication syndromes that have been identified and characterised after the use of array comparative genomic hybridisation (array CGH) became widespread.

  • Many microdeletion syndromes have a corresponding microduplication syndrome that is generally rarer and associated with a milder phenotype; the phenotypes of many of the newer microdeletion and microduplication syndromes are still evolving.

  • Low copy repeats (LCRs) predispose to chromosome deletions and duplications through nonallelic homologous recombination (NAHR), and many of the copy number variable regions that result in microdeletion or microduplication syndromes are situated between blocks of LCRs.

  • Most of the smaller microdeletions that were identified by array CGH have milder dysmorphic features that are less likely to be recognisable as a distinct phenotype; these microdeletions are also more likely to have been inherited from a normal or mildly affected parent.

  • Individuals with small microdeletions can still have a ‘chromosomal’ presentation that is developmental differences and intellectual disability, growth differences, behavioural problems, feeding difficulties, low muscle tone, seizures, dysmorphic features and a pattern of varying malformations.

Keywords: contiguous gene syndrome; haploinsufficiency; microdeletion; array CGH

Figure 1.

Fluorescence in situ hybridisation (FISH) results using Vysis DiGeorge Region Probe. The locus‐specific identifier (LSI) TUPLE1 probe (red) located in the DiGeorge syndrome critical region (22q11.2) and LSI ARSA control probe (green) mapped to 22q13.3. (a) FISH signal patterns of normal metaphase and interphase cells. (b) Deletion signal patterns. Absence of the red signal on one chromosome 22 (red arrow) indicates deletion of the TUPLE1 locus at 22q11.2. Courtesy of Dr Linda Jeng and Dr Zhongxia Qi.

Figure 2.

Microarray characterisation of a 16p11.2 deletion. (a) Microarray plot showing single‐copy loss of 14 oligonucleotide probes from the short arm of chromosome 16 at 16p11.2, approximately 570 kb in size (chr16: 29 528 220–30 098 040, hg18 coordinates). Image on the left shows the entire chromosome 16, and the image on the right shows a zoomed image of 16p11.2. (b) Normal chromosome 16 and 16p11.2 region images. Probes are ordered on the y‐axis according to physical mapping positions, with the most distal p‐arm probes to the top and the most distal q‐arm probes to the bottom. Values along the x‐axis represent log2 ratios of patient:control signal intensities. This array is an Aglient 2×105 K human whole genome microarray that was designed by the International Standard Cytogenomic Array (ISCA). Results are visualised using BlueFuse Multi (BlueGnome, Cambridge, United Kingdom). Courtesy of Dr Linda Jeng and Dr Zhongxia Qi.

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Web Links:

Exostoses (multiple) 1 (EXT1); Locus ID: 2131. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2131

Exostoses (multiple) 1 (EXT1); MIM number: 133700. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?133700

Miller–Dieker syndrome chromosome region (MDCR); Locus ID: 4186. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4186

Miller–Dieker syndrome chromosome region (MDCR); MIM number: 247200. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?247200

Trichorhinophalangeal syndrome I (TRPS1); Locus ID: 7227. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt. cgi?l=7227

Trichorhinophalangeal syndrome I (TRPS1); MIM number: 604386. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?604386

Ubiquitin protein ligase E3A (human papilloma virus E6‐associated protein, Angelman syndrome) (UBE3A); Locus ID: 7337. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7337

Ubiquitin protein ligase E3A (human papilloma virus E6‐associated protein, Angelman syndrome) (UBE3A); MIM number: 601623. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?601623

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Slavotinek, Anne(Jan 2012) Microdeletion Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005549.pub2]