Clinical and Molecular Delineation of the 17q21.31 Microdeletion Syndrome

Overview

Journal J Med Genet

Specialty Genetics

Date 2008 Jul 17

PMID 18628315

Citations 84

Authors

D A Koolen

A J Sharp

J A Hurst

H V Firth

S J L Knight

A Goldenberg

P Saugier-Veber

R Pfundt

L E L M Vissers

A Destree

B Grisart

L Rooms

N Van der Aa

M Field

A Hackett

K Bell

M J M Nowaczyk

G M S Mancini

P J Poddighe

C E Schwartz

E Rossi

M De Gregori

L L Antonacci-Fulton

M D McLellan 2nd

J M Garrett

M A Wiechert

T L Miner

S Crosby

R Ciccone

L Willatt

A Rauch

M Zenker

S Aradhya

M A Manning

T M Strom

J Wagenstaller

A C Krepischi-Santos

A M Vianna-Morgante

C Rosenberg

S M Price

H Stewart

C Shaw-Smith

H G Brunner

A O M Wilkie

J A Veltman

O Zuffardi

E E Eichler

B B A de Vries

Affiliations

Soon will be listed here.

Abstract

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(-5)).

Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Citing Articles

Epilepsy, EEG and chromosomal rearrangements.

Paprocka J, Coppola A, Cuccurullo C, Stawicka E, Striano P Epilepsia Open. 2024; 9(4):1192-1232.

PMID: 38837855 PMC: 11296106. DOI: 10.1002/epi4.12951.

Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases.

Pedicone C, Weitzman S, Renton A, Goate A Mol Neurodegener. 2024; 19(1):43.

PMID: 38812061 PMC: 11138017. DOI: 10.1186/s13024-024-00731-x.

KAT8 beyond Acetylation: A Survey of Its Epigenetic Regulation, Genetic Variability, and Implications for Human Health.

Yoo L, Mendoza D, Richard A, Stephens J Genes (Basel). 2024; 15(5).

PMID: 38790268 PMC: 11121512. DOI: 10.3390/genes15050639.

A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.

Awamleh Z, Choufani S, Wu W, Rots D, Dingemans A, Nadif Kasri N Eur J Hum Genet. 2024; 32(3):324-332.

PMID: 38282074 PMC: 10923882. DOI: 10.1038/s41431-024-01538-6.

Expanding the speech and language phenotype in Koolen-de Vries syndrome: late onset and periodic stuttering a novel feature.

St John M, Van Reyk O, Koolen D, de Vries B, Amor D, Morgan A Eur J Hum Genet. 2022; 31(5):531-540.

PMID: 36529818 PMC: 10172335. DOI: 10.1038/s41431-022-01230-7.

References

de Vries B, van den Ouweland A, Mohkamsing S, Duivenvoorden H, Mol E, Gelsema K . Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group. Am J Hum Genet. 1997; 61(3):660-7. PMC: 1715962. DOI: 10.1086/515496. View

Kirchhoff M, Bisgaard A, Duno M, Hansen F, Schwartz M . A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur J Med Genet. 2007; 50(4):256-63. DOI: 10.1016/j.ejmg.2007.05.001. View

Saugier-Veber P, Goldenberg A, Drouin-Garraud V, de La Rochebrochard C, Layet V, Drouot N . Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation. Eur J Hum Genet. 2006; 14(9):1009-17. DOI: 10.1038/sj.ejhg.5201661. View

Slager R, Newton T, Vlangos C, Finucane B, Elsea S . Mutations in RAI1 associated with Smith-Magenis syndrome. Nat Genet. 2003; 33(4):466-8. DOI: 10.1038/ng1126. View

Feuk L, Carson A, Scherer S . Structural variation in the human genome. Nat Rev Genet. 2006; 7(2):85-97. DOI: 10.1038/nrg1767. View

Roeleveld N, Zielhuis G, Gabreels F . The prevalence of mental retardation: a critical review of recent literature. Dev Med Child Neurol. 1997; 39(2):125-32. DOI: 10.1111/j.1469-8749.1997.tb07395.x. View

Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J . A common inversion under selection in Europeans. Nat Genet. 2005; 37(2):129-37. DOI: 10.1038/ng1508. View

Hutton M, Lendon C, Rizzu P, Baker M, Froelich S, Houlden H . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998; 393(6686):702-5. DOI: 10.1038/31508. View

Nickerson D, Tobe V, Taylor S . PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 1997; 25(14):2745-51. PMC: 146817. DOI: 10.1093/nar/25.14.2745. View

10.

Selzer R, Richmond T, Pofahl N, Green R, Eis P, Nair P . Analysis of chromosome breakpoints in neuroblastoma at sub-kilobase resolution using fine-tiling oligonucleotide array CGH. Genes Chromosomes Cancer. 2005; 44(3):305-19. DOI: 10.1002/gcc.20243. View

11.

Huang J, Wei W, Zhang J, Liu G, Bignell G, Stratton M . Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum Genomics. 2004; 1(4):287-99. PMC: 3525261. DOI: 10.1186/1479-7364-1-4-287. View

12.

Chen K, McLellan M, Ding L, Wendl M, Kasai Y, Wilson R . PolyScan: an automatic indel and SNP detection approach to the analysis of human resequencing data. Genome Res. 2007; 17(5):659-66. PMC: 1855178. DOI: 10.1101/gr.6151507. View

13.

Wagenstaller J, Spranger S, Lorenz-Depiereux B, Kazmierczak B, Nathrath M, Wahl D . Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Am J Hum Genet. 2007; 81(4):768-79. PMC: 2227926. DOI: 10.1086/521274. View

14.

Shaw-Smith C, Pittman A, Willatt L, Martin H, Rickman L, Gribble S . Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet. 2006; 38(9):1032-7. DOI: 10.1038/ng1858. View

15.

DSouza I, Poorkaj P, Hong M, Nochlin D, Lee V, Bird T . Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci U S A. 1999; 96(10):5598-603. PMC: 21906. DOI: 10.1073/pnas.96.10.5598. View

16.

Koolen D, Vissers L, Pfundt R, de Leeuw N, Knight S, Regan R . A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 2006; 38(9):999-1001. DOI: 10.1038/ng1853. View

17.

Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J . Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 1999; 8(4):711-5. DOI: 10.1093/hmg/8.4.711. View

18.

Schouten J, McElgunn C, Waaijer R, Zwijnenburg D, Diepvens F, Pals G . Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res. 2002; 30(12):e57. PMC: 117299. DOI: 10.1093/nar/gnf056. View

19.

Aradhya S, Manning M, Splendore A, Cherry A . Whole-genome array-CGH identifies novel contiguous gene deletions and duplications associated with developmental delay, mental retardation, and dysmorphic features. Am J Med Genet A. 2007; 143A(13):1431-41. DOI: 10.1002/ajmg.a.31773. View

20.

Myers A, Kaleem M, Marlowe L, Pittman A, Lees A, Fung H . The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Hum Mol Genet. 2005; 14(16):2399-404. DOI: 10.1093/hmg/ddi241. View