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. 2016 Mar 3;98(3):541-552.
doi: 10.1016/j.ajhg.2016.02.004.

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

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

Holly A F Stessman et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Protein Model of POGZ with Currently Identified Mutations Indicated All mutations (indicated by individual identifiers that correspond to Tables 1 and 2 and Tables S1, S3, and S4) have been annotated on the RefSeq transcript (GenBank: NM_015100.3) (POGZ). Events in red are LGD and blue are missense. Mutations listed on the top of the protein structure have not been previously identified or reported. Mutations listed on the bottom of the protein structure have been published previously. Protein domains are indicated on the structure. Abbreviations are as follows: ZNF, zinc finger; HTH, helix-turn-helix; CC, coiled coil; CHD, congenital heart defect; ASD, autism spectrum disorder; DDD, developmental delay; sib, sibling. Light-gray shaded portions indicate amino acids omitted by alternatively spliced POGZ transcripts (3, POGZ isoform; 2, POGZ isoform 2). ΨMutations for which inheritance is unknown. All other mutations are de novo.
Figure 2
Figure 2
Clinical Photographs of Individuals with De Novo LGD Mutations in POGZ Individuals harboring POGZ mutations show an overlap in facial features, including brachycephaly (not shown) and a broad forehead, a high nasal bridge, hypertelorism, and a thin upper lip in some. However, the facial phenotype is not very specific or recognizable. (A and B) Individual UMCN1 at the ages of 1 year (A) and 3 years (B). (C) Individual UMCN2 at the age of 9 years. (D and E) Individual UMCN3 at the ages of 4 years (D) and 8 years (E). (F and G) Individual UMCN4 at the ages of 4.5 years (F) and 5 years, 2 months (G). (H and I) Individual UMCN6 at the ages of 6 months (H) and 11 years (I). (J) Individual UMCN7 at the age of 4 years. (K and L) Individual UMCN8 as a child (K) and at the age of 26 years (L). (M) Individual UMCN9 at the age of 8 years. (N and O) Individual UMCN10 at the ages of 4 years (N) and 11 years (O). (P) Individual EE4 at the age of 12 years. (Q and R) Individual FR3 at the ages of 7 months (Q) and 6 years (R). (S) Individual FR4 at the age of 6 years. (T) Individual EE2 at the age of 14 years. (U) Individual EE6 at the age of 7 years. (V) Individual EE7 at the age of 7 years.
Figure 3
Figure 3
Expression of POGZ Is Highest in Cerebellum and Pituitary Tissues (A) Gene models of three RefSeq POGZ isoforms. Isoform 1, the longest isoform, is shown on top (GenBank: NM_015100.3), isoform 2 in the center (GenBank: NM_207171.2), and isoform 3 on the bottom (GenBank: NM_145796.3). Exons are shown as blocks and directionality as light-gray arrows. Exons in red contain a mutation identified in this study. Black stars indicate exons in which disruptive mutations were identified in control individuals. (B) Expression of POGZ shown by isoform (GenBank: NM_207171.2 on the left and GenBank: NM_145796.3 on the right), and subtissue from the GTEx database (v.6). Cerebellar tissues are shown in red and the pituitary gland is shown in blue. The red dashed line indicates reads per kilobase of transcript per million mapped reads (RPKM) of 25. (C) POGZ average expression of all brain subtissues across brain development (with RNA-seq RPKM values from the BrainSpan Atlas v.10; shown in red from 8 post-conception weeks to 40 years of age). Birth is indicated by a vertical gray dashed line, and the mean expression across all time points is indicated by a horizontal black dashed line.
Figure 4
Figure 4
Knockdown of the Drosophila POGZ Ortholog row Affects Non-Associative Learning in the Light-Off Jump Reflex Habituation Paradigm Jump responses were induced by repeated light-off pulses (100 trials) with a 1 s inter-trial interval. row knockdown flies (rowvdrc28196; genotype: w1118; 2xGMR-wIR/+; UAS-rowvdrc28196/elav-Gal4, UAS-Dicer-2) are plotted in red, and genetic background control flies (control; genotype: w1118; 2xGMR-wIR/+; elav-Gal4, UAS-Dicer-2/+) are plotted in dark gray. Linear regression model analysis revealed that flies with panneuronally-induced row knockdown habituated significantly slower (fold-change = 2.1;∗∗∗p < 0.001). (A) Average jump response (% of jumping flies) across 100 light-off trials. (B) Mean TTC of rowvdrc28196 (TTC = 21.57, n = 135) versus mean TTC of control flies (TTC = 10.2, n = 107). Error bars indicate SEM.

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