Clinical and molecular delineation of the 17q21.31 microdeletion syndrome

Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Journal of Medical Genetics (Impact Factor: 6.34). 11/2008; 45(11):710-20. DOI: 10.1136/jmg.2008.058701
Source: PubMed


The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.
We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.
We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)).
Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

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Available from: Ana CV Krepischi, Oct 03, 2015
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    • "and protection against stressinduced alcohol dependence (Nelson et al., 2010). The CRHR1 gene is located in this chromosomal region (Koolen et al., 2008) and the H2 haplotype has been noted to influence recombination at this site, modifying the risk of various neurological disorders such as mental retardation and progressive supranuclear palsy (Stefansson et al., 2005; Pastor et al., 2004). It was found that carriers of the H2 haplotype appeared to be protected from alcohol dependence in adulthood when exposed to early life adversity in the form childhood sexual abuse. "
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    01/2015; 1(1). DOI:10.1016/j.ynstr.2014.11.001
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    • "Most case of 17q21.31 deletions reported map to large clusters of flanking low copy repeats (LCRs), suggesting that the deletions are stimulated by non-allelic homologous recombination (NAHR) [26]. "
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    BMC Medical Genetics 07/2014; 15(1):79. DOI:10.1186/1471-2350-15-79 · 2.08 Impact Factor
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    • "The distal breakpoint in the 17q21.31 microdeletion syndrome cases has been determined to be more variable due to it being located in a polymorphic region adjacent to the critical deletion region [33]. Compared to the corresponding microdeletion syndrome , 17q21.31 "
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    ABSTRACT: Concurrent cryptic microdeletion and microduplication syndromes have recently started to reveal themselves with the advent of microarray technology. Analysis has shown that low-copy repeats (LCRs) have allowed chromosome regions throughout the genome to become hotspots for nonallelic homologous recombination to take place. Here, we report a case of a 7.5-year-old girl who manifests microcephaly, developmental delay, and mild dysmorphic features. Microarray analysis identified a microduplication in chromosome 17q21.31, which encompasses the CRHR1, MAPT, and KANSL1 genes, as well as a microdeletion in chromosome 7q31.33 that is localised within the GRM8 gene. To our knowledge this is one of only a few cases of 17q21.31 microduplication. The clinical phenotype of patients with this microduplication is milder than of those carrying the reciprocal microdeletions, and suggests that the lower incidence of the former compared to the latter may be due to underascertainment.
    02/2014; 2014:658570. DOI:10.1155/2014/658570
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