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

DA (David) Koolen, AJ Sharp, JA Hurst, HV Firth, SJL Knight, A Goldenberg, P Saugier-Veber, R Pfundt, LELM Vissers, A Destree, B Grisart, L Rooms, N Van der Aa, M Field, A Hackett, K Bell, MJM Nowaczyk, Grazia Verheijen - Mancini, PJ (Pino) Poddighe, CE SchwartzE Rossi, M De Gregori, LL Antonacci-Fulton, MD McLellan, JM Garrett, MA Wiechert, TL Miner, S Crosby, R Ciccone, L Willatt, Anita Rauch, M Zenker, S Aradhya, MA Manning, TM Strom, J Wagenstaller, AC Krepischi-Santos, AM Vianna-Morgante, C Rosenberg, SM Price, H Stewart, C Shaw-Smith, HG Brunner, AOM Wilkie, JA Veltman, O Zuffardi, EE Eichler, BBA de Vries

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181 Citations (Scopus)


Background: 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. Aim: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. Results: 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(25)). Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
Original languageUndefined/Unknown
Pages (from-to)710-720
Number of pages11
JournalJournal of Medical Genetics
Issue number11
Publication statusPublished - 2008

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