AUTS2 variant in a child diagnosed with autism spectrum disorder and intellectual disability disorder, a case report

Dear Editor, Intellectual disability and autism are neurodevelopmental disorders that often coexist and affect children from birth, causing impairment in their cognition and adaptive behavior. 1 About 1–3% of the population is affected, and it has been estimated that 30% of intellectual disability and autism are caused by genetic factors. 1 Forty-four pathogenic disruptions of AUTS2 have been described, such as six translocations, two inversions with one breakpoint in AUTS2, and 36 deletions. 2 Haploinsufficiency of AUTS2 is associated with syndromic neurodevelopmental disorders characterized by intellectual disability, autistic features, and microcephaly, known as intellectual developmental disorder (IDD), autosomal dominant 26 (AUTS2 variant). However, the clinical features of patients harboring AUTS2 sequence variants have not been extensively understood. 3 Here, we present a case of a child presenting with IDD and autism diagnosed as AUTS2 variant on genetic analysis. An 11-year-old female child presented with a history of language delay, poor eye contact, poor verbal and nonverbal communication, needing assistance in daily activities, poor academic performance, and adaptive functioning. Also, there was a lack of reciprocal social interaction, inadequate appreciation of social cues, impairment in social imitative play, and a lack of emotional response. There was rigidity and routine in play patterns and familiar habits from 3 years of age. Additionally, the mother had noticed several instances of choking, difficulty swallowing, and incontinence in the child. She occasionally showed temper tantrums while being assisted with her daily activities. There was a history of four paroxysmal episodes dating back to the age of 4, each characterized by a sudden loss of consciousness, followed by up rolling of eyes and facial twitching along with choking and urinary incontinence that lasted for about 1–2 minutes, after which she would appear confused and complain of a headache for another 5–10 minutes. A few episodes also occurred at night, but parents overlooked the semiology. The other twin of the patient was not found to have any psychopathology, and as the family were not willing, genetic testing was not done for the other twin. She was born of a third-degree consanguineous marriage with an antenatal history of anemia in the mother. The child was delivered preterm by a cesarean section and was noted to have a low birth weight (2 kg) and delayed cry at birth. The baby was in the intensive care unit (ICU) for 1 week for neonatal jaundice and feeding difficulty. The child had mild to moderate developmental delay in all domains, with the current developmental age being 5 to 6 years. On physical examination, the following features were found Table 1 and Figure 1. After a detailed evaluation of the child, diagnosis of moderate mental retardation, childhood autism, and epilepsy were considered according to the International Classification of Diseases, 10th edition (ICD-10). 4 Seguin form board test was done to assess IQ. The Childhood Autism Rating Scale 2nd edition revealed a 36 score, indicating moderate autism. Electroencephalogram (EEG) showed bilateral centrotemporal discharges with continuous spike waves in sleep record (CSWS), suggestive of atypical Rolandic epilepsy. The genetic evaluation was sought, singleton exome sequencing was performed, and a novel deletion variant, g. 70698620₇0698623del (c. 742₇42+3del) in exon 6–intron 6 junctions of AUTS2 (NC₀00007. 14), was identified in the heterozygous state. Segregation analysis and validation by Sanger sequencing revealed the de novo status of the variant known as AUTS2. Figure 1: The physical characters of the child. Arched eyebrows, Long palpebral fissures, Eversion of lateral 1/3rd of lower eyelid, Small mouth, High arched palate, Camptodactyly in 5th digits B/L, No fetal finger pads, Icthyosis, B/L pes planus, Exaggerated lumbar lordosis, UnderweightTable 1: Physical examination findings of the childOxcarbazepine was started and titrated up to 300 mg because of epilepsy. After a month, the urinary incontinence and difficulty swallowing improved along with epilepsy. Speech therapy was initiated and continued. No further seizure episodes were noted during the 6-month and 1-year follow-ups. The patient's mother's consent was taken for publication, and photographs were for reporting. Our multidisciplinary team consisted of a psychiatrist, a genetics specialist, and a pediatrician to evaluate this case. The main characteristics of the AUTS2 variant are intellectual deficits in 98% of patients, microcephaly in 65%, feeding difficulty in 62%, hyperactivity in 54%, and autistic features in 52%. 3 Around 7% were found to have epilepsy, but the type of epilepsy is not clear. 5 The most problematic feature of this variant is difficulty feeding, which usually resolves by 2 years and by a maximum of 8 years. 5 However, in our patient, this symptom persisted until the child was 11 years old. So, in neurodevelopmental disorders, a multidisciplinary approach would help in early detection, appropriate management of comorbid symptoms, and rehabilitative care of remaining disabilities of the patient. To our knowledge, this is the first case report of the AUTS2 variant from India. A close follow-up with a multidisciplinary team is mandatory to address the repeated infections and growth delay and reoccurrence of seizure. Financial support and sponsorship Funding was obtained for the current study from the DBT/Wellcome Trust India alliance for funding the study "Centre for rare disease diagnosis, research and Training" IA/CRC/20/1/600002. Conflicts of interest There are no conflicts of interest.