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.
Highlights
Neurodevelopmental disorders are highly complex disorders characterized both by clinical and genetic heterogeneity and with a complex genetic architecture [1]
We describe the phenotype of five new patients with AUTS2 pathogenic variants, three of them harboring loss-of-function sequence variants, characterized by developmental delay, autistic features, and attention deficit hyperactivity disorder (ADHD)
We found that, except for one patient who was too young to be adequately assessed (RM-1935), all our patients had a diagnosis of attention deficit/hyperactivity disorder (ADHD) and or hyperactivity/inattention and displayed autistic features, and that 80% had a global developmental delay or mild intellectual disability
Summary
Neurodevelopmental disorders are highly complex disorders characterized both by clinical and genetic heterogeneity and with a complex genetic architecture [1]. #615834), characterized by a highly variable phenotype consisting of global developmental delay (GDD) and/or ID commonly associated with the combination of microcephaly, short stature, feeding difficulties, and hypotonia, as well as recognizable facial dysmorphic features [4,5,6]. The large interindividual, and even intrafamilial, variability observed in patients with AUTS2 pathogenic variants led Beunders and colleagues in 2013 to establish what they called an AUTS2 syndrome severity score (ASSS), and that has been systematically used in the literature to assess the severity and phenotype of patients with AUTS2 syndrome [6]. The ASSS is based on 32 features found with a frequency of over 10% in the first cohort of patients described with AUTS2 aberrations and includes items belonging to growth and feeding, neurodevelopment, neurologic disorders, dysmorphic features, skeletal abnormalities, and congenital anomalies [6]
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