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

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.

European commission[LSHG-CT-2006-037627]

European Commission

Netherlands Organisation for Health Research and Development[ZonMW 907-00-058]

Netherlands Organisation for Health Research and Development

Netherlands Organisation for Health Research and Development[ZonMW 917-86-319]

Netherlands Organisation for Health Research and Development

Netherlands Organisation for Health Research and Development[ZonMW 920-03-338]

Netherlands Organisation for Health Research and Development

Netherlands Organisation for Health Research and Development

Netherlands Organisation for Health Research and Development[ZonMW 912-04-047]

Hersenstichting Nederland

Hersenstichting Nederland

South Carolina Department of Disabilities and Special Needs (CES)

South Carolina Department of Disabilities and Special Needs (CES)

National Institutes of Health (NIH)[HD043569]

U.S. National Institutes of Health (NIH)