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.

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

“…Individual BAB2330 and four other carriers of heterozygous truncating variants in POGZ allowed the recent description of a new syndromic form of intellectual disability [57, 58]. We compared the phenotype of the remaining individuals (Additional file 1: Supplementary Text, Table 1, Additional file 2: Table S1) with those associated with the identified molecular diagnoses, including 47,XYY, Mowat-Wilson syndrome (MOWS; OMIM#235730), mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH; OMIM#300749), Kabuki syndrome-1 (KABUK1; OMIM#147920), glycine encephalopathy (GCE; OMIM#605899), X-linked syndromic mental retardation 13 (MRXS13; OMIM#300055), cardiofaciocutaneous syndrome (CFC4; OMIM #615280), and X-linked syndromic mental retardation Claes-Jensen type (MRXSC; OMIM#300534) (Additional file 2: Table S4).…”

Phenotypic spectrum associated with de novo mutations in QRICH1 gene

“…Habituation is a form of nonassociative learning that is highly relevant for both DD and ASD. 21 The QRICH1 protein is known to directly interact with 40 other proteins (http://thebiogrid.org/120219/table/homo-sapiens/qrich1. html), including amyloid precursor protein (APP) (familial Alzheimer disease) and ataxin 1 (ATXN1) (spinocerebellar ataxia 1), as well as Poly(U) Binding Splicing Factor 60 (PUF60).…”

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients

“…The following patients have been previously reported in articles: #3 and #4, #8, #13, #14, #23, #26, and #51 …”