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

Abstract

Haploinsufficiency of AUTS2 has been associated with a syndromic form of neurodevelopmental delay characterized by intellectual disability, autistic features, and microcephaly, also known as AUTS2 syndrome. While the phenotype associated with large deletions and duplications of AUTS2 is well established, clinical features of patients harboring AUTS2 sequence variants have not been extensively described. In this study, we describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants. The phenotype of the patients was characterized by attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) or autistic features and mild global developmental delay (GDD) or intellectual disability (ID), all in 4/5 patients (80%), a frequency higher than previously reported for ADHD and autistic features. Microcephaly and short stature were found in 60% of the patients; and feeding difficulties, generalized hypotonia, and ptosis, were each found in 40%. We also provide the aggregated frequency of the 32 items included in the AUTS2 syndrome severity score (ASSS) in patients currently reported in the literature. The main characteristics of the syndrome are GDD/ID in 98% of patients, microcephaly in 65%, feeding difficulties in 62%, ADHD or hyperactivity in 54%, and autistic traits in 52%. Finally, using the location of 31 variants from the literature together with variants from the five patients, we found significantly higher ASSS values in patients with pathogenic variants affecting the 3′ end of the gene, confirming the genotype-phenotype correlation initially described.

AUTS2 Gene: Keys to Understanding the Pathogenesis of Neurodevelopmental Disorders

“…After the initial description by Beunders et al, a meta-analysis using the data of 31 patients with AUTS2 syndrome obtained from seven studies, in addition to five newly identified clinical cases, supported that the patients with ADHD and/or ASDs, who carry mutations at 3′ end of the AUTS2 locus showed higher ASSS values compared with individuals with AUTS2 aberrations at the 5′ end of the locus [ 35 ]. These findings imply that the ablation of C-terminal region of AUTS2 may contribute to the onset of AUTS2 syndrome.…”

Comparing a Novel Malformation Syndrome Caused by Pathogenic Variants in FBRSL1 to AUTS2 Syndrome

“…Depending on the location of AUTS2 point mutations/deletions the phenotype ranges from an isolated neurodevelopmental disorder (e.g., autism spectrum disorder, attention deficit hyperactivity disorder, learning disabilities and/or intellectual disability) to a syndromic disorder with microcephaly, short stature, feeding difficulties, heart defects, skeletal anomalies, contractures and dysmorphic features (Beunders et al, 2013;Beunders et al, 2016;Saeki et al, 2019;Sanchez-Jimeno et al,…”

“…The data for AUTS2 syndrome were adapted from Sanchez-Jimeno et al which is based on nine different studies (Sultana et al, 2002;Kalscheuer et al, 2007;Bakkaloglu et al, 2008;Huang et al, 2010;Girirajan et al, 2011;Jolley et al, 2013;Nagamani et al, 2013;Liu et al, 2015;Beunders et al, 2016). In addition, the data include a cohort of five patients published by Sanchez-Jimeno et al (Sanchez-Jimeno et al, 2021). The data for the FBRSL1 syndromic phenotype is based on the three patients published in Ufartes et al (Ufartes et al, 2020).…”

“…Frontiers 2021). To date, more than 60 patients with AUTS2 syndrome have been described in the literature and most of them carry an intragenic de novo deletion of AUTS2, whereas point mutations leading to the disease are rarely described (Sanchez-Jimeno et al, 2021). Due to a high inter-and intrafamilial variability an AUTS2 syndrome severity scoring system (ASSS) was established by Beunders and colleagues 2013.…”

“…In contrast, deletions of the C-terminus of AUTS2 are mostly associated with a severe AUTS2 syndrome phenotype combining neurodevelopmental features with malformations and dysmorphic features (Beunders et al, 2013). Therefore, it was suggested that the AUTS2 C-terminus plays a critical role in AUTS2 syndrome (Beunders et al, 2013;Beunders et al, 2016;Saeki et al, 2019;Sanchez-Jimeno et al, 2021). Interestingly, the situation seems to be different for the truncating FBRSL1 variants characterized in Ufartes et al (2020), which all localized to the N-terminus of the FBRLS1 gene.…”