Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes

Abstract

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Hoarding in children and adolescents with obsessive–compulsive disorder

“…Moreover, although collecting rituals are developmentally normative, with peak age of occurrence about 2 years of age (Evans et al, 1997), children with high levels of fear, shyness, and need for order and predictability may maintain and extend these rituals beyond the age when they are adaptive (Zohar & Felz, 2001). Alternatively, hoarding and autism may be neurodevelopmental consequences of deletions of the same, specific chromosomal regions, as suggested by recent findings (Lionel et al, 2014; McGrath et al, 2014). …”

Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

“…11 A recent large study revealed that heterozygous copy number variations affecting the 3′-terminal part of ASTN2 or both ASTN2 and TRIM32 are significantly enriched in males with neurodevelopmental and neurobehavioral disorders. 13 In this study, the patient with cognitive impairment has a homozygous deletion of ASTN2, whereas the other patient, heterozygous for the ASTN2 deletion, does not present any intellectual disability. This suggests a recessive effect of ASTN2 deletions, with a total loss of function associated with intellectual deficiency.…”

“…11 ASTN2 heterozygous deletions were reported at a high frequency in a number of neurodevelopmental and neurobehavioral conditions such as schizophrenia or autism spectrum disorders. 12,13 The diagnostic process of neuromuscular genetic diseases is tedious and expensive as at least 245 genes have been reported to date (http:// www.musclegenetable.fr), including 31 for LGMDs, some of which being very large. High-throughput techniques, that is, CGH (comparative genomic hybridization) array and massively parallel sequencing (MPS), enable searching simultaneously for copy number variations and single nucleotide variations in currently known genes and candidate genes.…”

A copy number variation map of the human genome

“…The chemokine (C-C motif ) ligand 3-like 1 (CCL3L1) gene is one of the most differentiated exonic CNVs 14 . There can also be sex-influenced modifiers 91 and CNVs that express phenotypes at different ages 92,93 , and many other complex phenomena, such as pleiotropy, could be involved 2 . These points highlight the breadth of phenotypic effects and that some of the currently excluded singleton variants may be included at a later time when additional samples are available.…”