Whole Exome Sequencing Reveals a Novel AUTS2 In-Frame Deletion in a Boy with Global Developmental Delay, Absent Speech, Dysmorphic Features, and Cerebral Anomalies

Abstract

Neurodevelopmental disorders (NDDs) are a group of highly prevalent, clinically and genetically heterogeneous pediatric disorders comprising, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V), intellectual disability, developmental delay, autism spectrum disorders, and other neurological and cognitive disorders manifesting in the developmental age. To date, more than 1000 genes have been implicated in the etiopathogenesis of NNDs. Among them, AUTS2 (OMIM # 607270) encodes a protein involved in neural migration and neuritogenesis, and causes NNDs with different molecular mechanisms including copy number variations, single or multiple exonic deletion and single nucleotide variants. We describes a 9-year-old boy with global developmental delay, absent speech, minor craniofacial anomalies, hypoplasia of the cerebellar vermis and thinning of the corpus callosum, resulted carrier of the de novo AUTS2 c.1603_1626del deletion at whole exome sequencing (WES) predicted to cause the loss of eight amino acids [p.(His535_Thr542del)]. Notably, our patient is the first reported so far in medical literature carrying an in-frame deletion and the first in which absent language, hypoplasia of the cerebellar vermis and thinning of the corpus callosum has been observed thus useful to expand the molecular spectrum of AUTS2 pathogenic variants and to broaden our knowledge on the clinical phenotype associated.

Fetal Fractures in an Infant with Maternal Ehlers-Danlos Syndrome, CCDC134 Pathogenic Mutation and a Negative Genetic Test for Osteogenesis Imperfecta

“…Finally, AUTS2 encodes the autism susceptibility candidate 2 protein that is involved in neural migration and neurogenesis. It has been reported that mutations in this gene are associated with neurological and skeletal abnormalities [ 17 ], suggesting the possible link of this gene to skeletal development.…”

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

“…We calculated the frequency of the 32 items included in the ASSS in patients currently reported in the literature. For that, only 9 studies with a comprehensive description of the phenotype were considered: papers by Beunders et al, 2016 [ 5 ], which includes aggregated data from their two previous reports [ 4 , 6 ] as well as from other authors [ 10 , 14 , 15 , 16 , 17 , 27 , 28 , 29 ] and other seven studies [ 8 , 9 , 11 , 18 , 19 , 20 , 21 ]. The total number of patients reported by such studies was 61 but the number of patients evaluated for the 32 items was highly variable and ranged from 11 to 61 ( Table 1 ).…”

“…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].…”

“…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).…”