Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances.
Behavioural differences have been described in patients with type I deletions (between breakpoints 1 and 3 (BP1-BP3)) or type II deletions (between breakpoints 2 and 3) of the 15q11.2 Prader-Willi/Angelman region. The larger type I deletions appear to coincide with more severe behavioural problems (autism, ADHD, obsessive-compulsive disorder). The non-imprinted chromosomal segment between breakpoints 1 and 2 involves four highly conserved genes, TUBGCP5, NIPA1, NIPA2, and CYFIP1; the latter three are widely expressed in the central nervous system, while TUBGCP5 is expressed in the subthalamic nuclei. These genes might explain the more severe behavioural problems seen in type I deletions. We describe nine cases with a microdeletion at 15q11.2 between BP1-BP2, thus having a haploinsufficiency for TUBGCP5, NIPA1, NIPA2, and CYFIP1 without Prader-Willi/Angelman syndrome. The clinical significance of a pure BP1-BP2 microdeletion has been debated, however, our patients shared several clinical features, including delayed motor and speech development, dysmorphisms and behavioural problems (ADHD, autism, obsessive-compulsive behaviour). Although the deletion often appeared to be inherited from a normal or mildly affected parent, it was de novo in two cases and we did not find it in 350 healthy unrelated controls. Our results suggest a pathogenic nature for the BP1-BP2 microdeletion and, although there obviously is an incomplete penetrance, they support the existence of a novel microdeletion syndrome in 15q11.2.
Doornbos
Marianne
M
Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, The Netherlands.
Sikkema-Raddatz
Birgit
B
Ruijvenkamp
Claudia A L
CA
Dijkhuizen
Trijnie
T
Bijlsma
Emilia K
EK
Gijsbers
Antoinet C J
AC
Hilhorst-Hofstee
Yvonne
Y
Hordijk
Roel
R
Verbruggen
Krijn T
KT
Kerstjens-Frederikse
W S Mieke
WS
van Essen
Ton
T
Kok
Klaas
K
van Silfhout
Anneke T
AT
Breuning
Martijn
M
van Ravenswaaij-Arts
Conny M A
CM