Dataset Information

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

ABSTRACT: 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 × 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.

SUBMITTER: Stessman HAF

PROVIDER: S-EPMC4890241 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

Stessman Holly A F HAF Willemsen Marjolein H MH Fenckova Michaela M Penn Osnat O Hoischen Alexander A Xiong Bo B Wang Tianyun T Hoekzema Kendra K Vives Laura L Vogel Ida I Brunner Han G HG van der Burgt Ineke I Ockeloen Charlotte W CW Schuurs-Hoeijmakers Janneke H JH Klein Wassink-Ruiter Jolien S JS Stumpel Connie C Stevens Servi J C SJC Vles Hans S HS Marcelis Carlo M CM van Bokhoven Hans H Cantagrel Vincent V Colleaux Laurence L Nicouleau Michael M Lyonnet Stanislas S Bernier Raphael A RA Gerdts Jennifer J Coe Bradley P BP Romano Corrado C Alberti Antonino A Grillo Lucia L Scuderi Carmela C Nordenskjöld Magnus M Kvarnung Malin M Guo Hui H Xia Kun K Piton Amélie A Gerard Bénédicte B Genevieve David D Delobel Bruno B Lehalle Daphne D Perrin Laurence L Prieur Fabienne F Thevenon Julien J Gecz Jozef J Shaw Marie M Pfundt Rolph R Keren Boris B Jacquette Aurelia A Schenck Annette A Eichler Evan E EE Kleefstra Tjitske T

American journal of human genetics 20160301 3

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 neu ...[more]

PMID: 26942287

Similar Datasets

Project description:BackgroundMaternal diabetes has been associated with a risk of neurodevelopmental disorders (NDDs) in offspring, though the common co-occurrence of autism spectrum disorders (ASD), attention-deficit/hyperactivity disorder (ADHD) and intellectual disability (ID) is rarely considered, nor is the potential for confounding by shared familial factors (e.g. genetics).MethodsThis population-based cohort study used data from Psychiatry Sweden, a linkage of Swedish national registers, to follow 2 369 680 individuals born from 1987 to 2010. We used population-averaged logit models to examine the association between exposure to maternal type 1 diabetes mellitus (T1DM), pre-gestational type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), and odds of NDDs in offspring. Subgroup analysis was then performed to investigate the timings of GDM diagnosis during pregnancy and its effect on the odds of NDDs in offspring. We compared these results to models considering paternal lifetime T1DM and T2DM as exposures.ResultsOverall, 45 678 individuals (1.93%) were diagnosed with ASD, 20 823 (0.88%) with ID and 102 018 (4.31%) with ADHD. All types of maternal diabetes were associated with odds of NDDs, with T2DM most strongly associated with any diagnosis of ASD (odds ratioadjusted 1.37, 95% confidence interval 1.03-1.84), ID (2.09, 1.53-2.87) and ADHD (1.43, 1.16-1.77). Considering common co-morbid groups, the associations were strongest between maternal diabetes and diagnostic combinations that included ID. Paternal T1DM and T2DM diagnoses were also associated with offspring NDDs, but these associations were weaker than those with maternal diabetes. Diagnosis of GDM between 27 and 30 weeks of gestation was generally associated with the greatest risk of NDDs in offspring, with the strongest associations for outcomes that included ID.ConclusionThe association of maternal diabetes with NDDs in offspring varies depending on the co-morbid presentation of the NDDs, with the greatest odds associated with outcomes that included ID. Results of paternal-comparison studies suggest that the above associations are likely to be partly confounded by shared familial factors, such as genetic liability.

Project description:ImportanceDepression is a frequently occurring mental disorder and may be common in adults with autism spectrum disorders (ASD), but there is a lack of longitudinal population-based studies examining this association. Whether any increased risk of depression in ASD has a shared familial basis and whether it differs by co-occurring intellectual disability is not well known.ObjectivesTo examine whether individuals with ASD are more likely to be diagnosed as having depression in adulthood than the general population and their nonautistic siblings and to investigate whether these risks differ by the presence or absence of intellectual disability.Design, setting, and participantsPopulation-based cohort study with a nested sibling comparison. The Stockholm Youth Cohort is a total population record linkage study that includes all children and young people (age range, 0-17 years) who were ever resident in Stockholm County, Sweden, between January 2001 and December 2011 (n?=?735?096). Data analysis was conducted between January 5 and November 30, 2017, in Stockholm County, Sweden.Main outcomes and measuresClinical diagnosis of depressive disorders was identified using the Stockholm County Adult Psychiatric Outpatient Register and the Swedish National Patient Register.ResultsParticipants were 223?842 individuals followed up to age 27 years by 2011, of whom 4073 had diagnosed ASD (mean [SD] age, 21.5 [2.7] years; 65.9% male; 2927 without intellectual disability and 1146 with intellectual disability) and 219?769 had no ASD (mean [SD] age, 22.1 [2.8] years; 50.9% male). By age 27 years, 19.8% (n?=?808) of individuals diagnosed having ASD had a diagnosis of depression compared with 6.0% (n?=?13?114) of the general population (adjusted relative risk [RR], 3.64; 95% CI, 3.41-3.88). The risk of a depression diagnosis was higher in ASD without intellectual disability (adjusted RR, 4.28; 95% CI, 4.00-4.58) than in ASD with intellectual disability (adjusted RR, 1.81; 95% CI, 1.51-2.17). Nonautistic full-siblings (adjusted RR, 1.37; 95% CI, 1.23-1.53) and half-siblings (adjusted RR, 1.42; 95% CI, 1.23-1.64) of individuals with ASD also had a higher risk of depression than the general population. Compared with their nonautistic full-siblings, individuals with ASD had more than a 2-fold risk of a depression diagnosis (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27) in young adulthood.Conclusions and relevanceAccording to this study's results, ASD, particularly ASD without intellectual disability, is associated with depression by young adulthood compared with the general population. It appears that this association is unlikely to be explained by shared familial liability. Future research to identify modifiable pathways between ASD and depression may assist in the development of preventive interventions.

Dataset Information

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

Publications

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets