title: Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes.
abstract: BACKGROUND
  Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes.
  
  
  METHODS
  Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3.
  
  
  RESULTS
  Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms.
  
  
  CONCLUSIONS
  The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.
authors.affiliation: Cytogenetics Department, VCGS Pathology, MCRI, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Damien L
authors.initials: DL
authors.lastname: Bruno
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Anderlid
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.forename: Conny
authors.initials: C
authors.lastname: van Ravenswaaij-Arts
authors.forename: Devika
authors.initials: D
authors.lastname: Ganesamoorthy
authors.forename: Johanna
authors.initials: J
authors.lastname: Lundin
authors.forename: Christa Lese
authors.initials: CL
authors.lastname: Martin
authors.forename: Jessica
authors.initials: J
authors.lastname: Douglas
authors.forename: Catherine
authors.initials: C
authors.lastname: Nowak
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Adam
authors.forename: R Frank
authors.initials: RF
authors.lastname: Kooy
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van der Aa
authors.forename: Edwin
authors.initials: E
authors.lastname: Reyniers
authors.forename: Geert
authors.initials: G
authors.lastname: Vandeweyer
authors.forename: Irene
authors.initials: I
authors.lastname: Stolte-Dijkstra
authors.forename: Trijnie
authors.initials: T
authors.lastname: Dijkhuizen
authors.forename: Alison
authors.initials: A
authors.lastname: Yeung
authors.forename: Martin
authors.initials: M
authors.lastname: Delatycki
authors.forename: Birgit
authors.initials: B
authors.lastname: Borgström
authors.forename: Lena
authors.initials: L
authors.lastname: Thelin
authors.forename: Carlos
authors.initials: C
authors.lastname: Cardoso
authors.forename: Bregje
authors.initials: B
authors.lastname: van Bon
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.forename: Anders
authors.initials: A
authors.lastname: Wallin
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.forename: Paul A
authors.initials: PA
authors.lastname: James
authors.forename: Howard R
authors.initials: HR
authors.lastname: Slater
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schoumans
mesh_terms: D000293:Adolescent; D001921:Brain / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics* / Q000473:pathology; D019465:Craniofacial Abnormalities / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D054082:Lissencephaly / Q000235:genetics* / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D056916:Segmental Duplications, Genomic