TY - JOUR
T1 - Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders
AU - Stessman, Holly A. F.
AU - Willemsen, Marjolein H.
AU - Fenckova, Michaela
AU - Penn, Osnat
AU - Hoischen, Alexander
AU - Xiong, Bo
AU - Wang, Tianyun
AU - Hoekzema, Kendra
AU - Vives, Laura
AU - Voge, Ida
AU - Brunner, Han G.
AU - van der Burgt, Ineke
AU - Ockeloen, Charlotte W.
AU - Schuurs-Hoeijmakers, Janneke H.
AU - Wassink-Ruiter, Jolien S. Klein
AU - Stumpel, Connie
AU - Stevens, Servi J. C.
AU - Vles, Hans S.
AU - Marcelis, Carlo M.
AU - van Bokhoven, Hans
AU - Cantagre, Vincent
AU - Colleaux, Laurence
AU - Nicouleau, Michael
AU - Lyonnet, Stanislas
AU - Bernier, Raphael A.
AU - Gerdts, Jennifer
AU - Coe, Bradley P.
AU - Romano, Corrado
AU - Alberti, Antonino
AU - Grillo, Lucia
AU - Scuderi, Carmela
AU - Nordenskjold, Magnus
AU - Kvarnung, Malin
AU - Guo, Hui
AU - Xia, Kun
AU - Piton, Amelie
AU - Gerard, Benedicte
AU - Genevieve, David
AU - Delobel, Bruno
AU - Lehalle, Daphne
AU - Perrin, Laurence
AU - Prieur, Fabienne
AU - Thevenon, Julien
AU - Gecz, Jozef
AU - Shaw, Marie
AU - Pfundt, Rolph
AU - Keren, Boris
AU - Jacquette, Aurelia
AU - Schenck, Annette
AU - Eichler, Evan E.
AU - Kleefstra, Tjitske
PY - 2016/3/3
Y1 - 2016/3/3
N2 - Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 x 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.
AB - Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 x 10(-13); odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.
U2 - 10.1016/j.ajhg.2016.02.004
DO - 10.1016/j.ajhg.2016.02.004
M3 - Article
C2 - 26942287
SN - 0002-9297
VL - 98
SP - 541
EP - 552
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -