De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects

Abstract

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C‐terminus part of the gene. This article reports a new patient with a syndromic neurodevelopmental disorder, who presents a deletion of 30 nucleotides in the exon 9 of the AUTS2 gene. Importantly, this deletion includes the transcription start site for the AUTS2 short transcript isoform, which has an important role in brain development. Gene expression analysis of AUTS2 full‐length and short isoforms revealed that the deletion found in this patient causes a remarkable reduction in the expression level, not only of the short isoform, but also of the full AUTS2 transcripts. This report adds more evidence for the role of mutated AUTS2 short transcripts in the development of a severe phenotype in the AUTS2 syndrome.

Attention Deficit Hyperactivity and Autism Spectrum Disorders as the Core Symptoms of AUTS2 Syndrome: Description of Five New Patients and Update of the Frequency of Manifestations and Genotype-Phenotype Correlation

“…More than 60 patients with AUTS2 syndrome have been described to date [4][5][6][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. These patients mostly carry de novo intragenic or exonic deletions, whereas loss-of-function small variants are not as frequently found in the literature [4,5,9,11,[19][20][21][22][23][24].…”

“…Even though the number and phenotype of patients with AUTS2 syndrome has increased since the first report, the genotype-phenotype correlation has not been updated since then, despite the overlap of ASSS values from patients with alterations of the 5 and 3 ends [4,6,8,9,16,20,21]. In order to confirm this genotype-phenotype correlation, we collected data on patients with ASSS values published in the literature and, along with our five patients, tested the association between the location of the variant (exons 1 to 8 versus 9 to 19) and such values.…”

“…A review of the literature retrieved seven studies reporting on 31 patients with AUTS2 syndrome with ASSS values and an AUTS2 pathogenic variant (Table 2; [4,6,8,9,16,20,21]). The 31 variants from the literature together with variants from the five patients, were grouped based on whether the location was N-terminal (exons 1 to 8; N = 26) or Cterminal (exons 9 to 19; N = 10).…”

“…Since the identification of the gene and the description of the phenotypic characteristics of AUTS2 syndrome [ 6 , 10 ], more than 60 patients with pathogenic variants have been reported in the literature [ 4 , 5 , 6 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Most variants reported to date are de novo intragenic deletions [ 4 , 5 , 6 ], involving one or more exons, while pathogenic sequence variants in AUTS2 only represent a small fraction of the AUTS2 mutational spectrum.…”

“…Most variants reported to date are de novo intragenic deletions [ 4 , 5 , 6 ], involving one or more exons, while pathogenic sequence variants in AUTS2 only represent a small fraction of the AUTS2 mutational spectrum. To date, only 13 sequence variants (nonsense single nucleotide variants, frameshift, and in-frame insertions and deletions) have been reported in the scientific literature [ 4 , 5 , 9 , 11 , 19 , 20 , 21 , 22 , 23 , 24 ], and 4 intragenic or exonic duplications [ 17 , 25 ], and thus the phenotype associated is less known. The ClinVar database currently has 96 variants in AUTS2 classified as pathogenic or likely pathogenic (accessed on 15 July 2021), of which 34 are sequence variants (missense, nonsense, inframe and frameshift deletions and duplications and/or acceptor/donor splice site variants) and 62 are deletions ( N = 53) or duplications ( N = 9).…”