The phenotype of recurrent 10q22q23 deletions and duplications.
The genomic architecture of the 10q22q23 region is characterised by two low-copy repeats (LCRs3 and 4), and deletions in this region appear to be rare. We report the clinical and molecular characterisation of eight novel deletions and six duplications within the 10q22.3q23.3 region. Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints. Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed. For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene. For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function. Duplications between LCRs3 and 4 are associated with variable phenotypic penetrance. Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip. In conclusion, duplications between LCRs3 and 4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development. However, the phenotypic spectrum is broad, and duplications have also been found in healthy family members of a proband. Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects.
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. B.vanBon@antrg.umcn.nl
Bregje W M
BW
van Bon
Jorune
J
Balciuniene
Gary
G
Fruhman
Sandesh Chakravarthy Sreenath
SC
Nagamani
Diane L
DL
Broome
Elizabeth
E
Cameron
Danielle
D
Martinet
Eliane
E
Roulet
Sebastien
S
Jacquemont
Jacques S
JS
Beckmann
Mira
M
Irons
Lorraine
L
Potocki
Brendan
B
Lee
Sau Wai
SW
Cheung
Ankita
A
Patel
Melissa
M
Bellini
Angelo
A
Selicorni
Roberto
R
Ciccone
Margherita
M
Silengo
Annalisa
A
Vetro
Nine V
NV
Knoers
Nicole
N
de Leeuw
Rolph
R
Pfundt
Barry
B
Wolf
Petr
P
Jira
Swaroop
S
Aradhya
Pawel
P
Stankiewicz
Han G
HG
Brunner
Orsetta
O
Zuffardi
Scott B
SB
Selleck
James R
JR
Lupski
Bert B A
BB
de Vries
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D057215:Body Dysmorphic Disorders / Q000235:genetics / Q000473:pathology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics; D002648:Child; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics; D008297:Male; D058627:Megalencephaly / Q000235:genetics / Q000473:pathology; D051379:Mice; D055628:Natural Cytotoxicity Triggering Receptor 3 / Q000235:genetics; D010641:Phenotype; D056916:Segmental Duplications, Genomic / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C409587:GRAP2 protein, human; C431710:NCR3 protein, human; D055628:Natural Cytotoxicity Triggering Receptor 3; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I
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