Exonic Deletions in AUTS2 Cause a Syndromic Form of Intellectual Disability and Suggest a Critical Role for the C Terminus

Abstract

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…This phenotype is often associated with microcephaly in both zebrafish and humans. 37,39,40 To assess this possibility directly, we measured the head size at 4.5 dpf in control and LAT mRNA-injected embryos. Increasing amounts of LAT mRNA injected into zebrafish embryos (100 and 150 pg) yielded a significant reduction of the head size, measured both as distance between the eyes and the anterior-most part of the forebrain until the hindbrain of the fish (two-tailed t test p ¼ 2.96 3 10 À8 , and p ¼ 3.14 3 10 À5 , respectively; LAT-150 pg RNA-injected embryos compared to controls) ( Figures 1D and 1E).…”

A low‐grade astrocytoma in a sixteen‐year‐old boy with a 7q11.22 deletion

“…The phenotype can be subtle, and the severity of the syndrome is highly variable. Furthermore, the location and the type of deletion are important for the resulting phenotype, with a more severe phenotype with deletions in the C‐terminus 5. A recent study of Beunders et al.…”

“…Earlier studies with knockdown AUTS2 zebrafish shows a reduction in motor and sensory neurons in the spinal cord and developing neurons in regions that include the midbrain and cerebellum, which resulted in reduced movement and decreased response to touch 5, 7. Mouse studies show that there is expression of AUTS2 in developing neurons in the frontal cortex and cerebellum.…”

Chromosomal Microarrays: Understanding Genetics of Neurodevelopmental Disorders and Congenital Anomalies

“…95 Similar genotype-phenotype correlations are beginning to be explored and have been proposed for genes including NRXN1, 96,97 AUTS2, 98 MEF2C, 99 and CAMTA1. 100 These correlations are mainly based on clinical observations, but model organism data 98 and examination of transcriptional products from CNV carriers 100 provide some additional support.…”