Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes.
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.
Bruno
Damien L
DL
Cytogenetics Department, VCGS Pathology, MCRI, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
Anderlid
Britt-Marie
BM
Lindstrand
Anna
A
van Ravenswaaij-Arts
Conny
C
Ganesamoorthy
Devika
D
Lundin
Johanna
J
Martin
Christa Lese
CL
Douglas
Jessica
J
Nowak
Catherine
C
Adam
Margaret P
MP
Kooy
R Frank
RF
Van der Aa
Nathalie
N
Reyniers
Edwin
E
Vandeweyer
Geert
G
Stolte-Dijkstra
Irene
I
Dijkhuizen
Trijnie
T
Yeung
Alison
A
Delatycki
Martin
M
Borgström
Birgit
B
Thelin
Lena
L
Cardoso
Carlos
C
van Bon
Bregje
B
Pfundt
Rolph
R
de Vries
Bert B A
BB
Wallin
Anders
A
Amor
David J
DJ
James
Paul A
PA
Slater
Howard R
HR
Schoumans
Jacqueline
J
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