Figure 1 shows the family tree of the family studied.
The proband is a 13-year-old boy (III1). Pregnancy and birth were unremarkable. Birth weight was 3.3 kg and length 53 cm (5th centile). The mother was 36 years old during the pregnancy. The proband started walking around 2 years old. Significant speech delay was noted by the parents at 3 years of age, but they did not consult for a specialized examination. The child came to medical attention again at the age of 6 due to his global developmental delay and suspected ASD. Indeed, he presented with autistic features such as abnormal behaviors, namely sensory and motor stereotypes (triggered in emotionally charged situations) and compulsive behavior. He has mild-moderate ID (according to the Weschler intelligence scale for children, third edition, WISC-III). In summary, these behavioral findings, along with the developmental delay and dysmorphic features suggest an ASD, according to the Autism Diagnostic Interview, a standardized investigator-based interview, and Autism Diagnostic Observation Schedule, a semi-structured, standardized assessment of social interaction, communication, play, and imaginative use of materials for individuals suspected of having an ASD.
The phenotypic manifestations included craniofacial dysmorphism with highly arched eyebrows, hypertelorism, strabismus, proptosis and downslanted palpebral fissure, thick alae nasi, short philtrum and large central incisors, everted upper lip, narrow mouth, prominent and large ears with uptilted lobules, and retrognathia. His height was 161 cm and weight 78 kg. He has no siblings.
No history of epilepsy was reported. The neurological examination was normal, and no structural abnormalities were observed on the MRI or the EEG. Hearing and sight functions as well as the skeletal X-rays were unremarkable. The urine and blood metabolic screening results were within the normal limits. There was no urogenital or limb malformation. He had no tremors, no picking, no joint stiffness, no feeding difficulties, and no kyphoscoliosis, according to the criteria described by Beunders et al. . He did not have any sleep disorders.
The mother of the proband is 49 years old (II2). Pregnancy was uneventful and birth weight was 2.9 kg (5th–10th centile). Her early development was normal, and she walked at the age of around 1 year. Her pubertal development was within the normal limits. The patient had a height of 156 cm (between third and tenth centile) and weighed 76 kg, with a head circumference of 52 cm. The psychological evaluation with the Wechsler Adult Intelligence Scale, third edition (WAIS-III) indicated that her verbal IQ falls within the borderline range (70 to 85). The evaluation of social cognition revealed disturbances in attributional style, theory of mind and emotional recognition. No psychiatric evaluation of a possible ASD was carried out in the absence of clinical signs. She leads an independent life and lives with her husband. No genetic or psychiatric information was available regarding the proband’s father, who exhibited no particular phenotype or behavior.
She presents with short stature, facial dysmorphism with highly arched and thick eyebrows, short philtrum and slightly posteriorly rotated ears. She has arched feet and shallow palmar creases (Fig. 2).
Since the age of 45, she developed delusional ideas with an erotomaniac component. She was convinced that a choirmaster loved her. She was consumed by the idea that every object or drawing she came across were signs that he had left for her as proof of his love. She had a severe interpretive and delusional experience.
The diagnosis of erotomania was made according to the clinical criteria set by the International Classification of Diseases, eleventh edition (ICD-11) (F22.0) and to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) (297.11). The latter allowed to specify the predominant type of delusional disorder.
There were no urogenital or limb malformations. She had no tremors, no picking, no joint stiffness, no feeding difficulties, according to the criteria described by Beunders et al. . There was no family history of substance-alcohol use. She wore a corset for kyphoscoliosis. She did not present with any sleep disorders or epileptic seizures. Brain MRI and blood screening were within the normal limits.
Aunt 1 is 50 years old (II3). Pregnancy and childbirth were unremarkable. Birth weight and birth length are not known. Her early development was unremarkable. The patient has a height of 160 cm (between third and tenth centile) and weighs 78 kg. The psychological evaluation using WAIS-III indicated an IQ within the normal range. The social cognition evaluation did not reveal any disturbances in social cognition but revealed high levels of social anxiety, severely impacting her daily life. She lives in her mother’s home and is not married. She has a job.
This patient presents dysmorphic features such as heart-shaped face, soft fine hair, highly arched eyebrow, a high broad forehead, a bilateral ptosis, large front teeth, kyphoscoliosis and mild micrognathia. No urogenital or limb malformations, nor tremors/picking/feed difficulties/sleep disorders were documented.
Concerning the psychiatric phenotype, Aunt 1 presented serious social anxiety, as has been evaluated during various specialized interviews by several psychiatrists but did not required any medication or supplementary psychiatric evaluations. The blood screening results and brain MRI were unremarkable.
Aunt 2 is 45 years old (II4). She was born at term and pregnancy and delivery were both unremarkable. Birth weight and length were not available. The patient has a height of 155 cm (between third and tenth centile) and weighs 61 kg. A lack of eye contact was noted at 6 months of age with global hypotonia and little social interaction. Mild motor and significant speech delay were evident during childhood.
She presents facial dysmorphism with ptosis, minor hand and feet anomalies. Low anterior hairline, narrow sloping forehead, prominent nasal bridge, broad nasal tip, low hanging columella, prominent eyes with bilateral ptosis, arched eyebrows, small mouth orifice, thin upper lip, high narrow palate, micrognathia and kyphoscoliosis were observed, corresponding to the characteristics of the AUTS2 syndrome. She has been followed for scoliosis since early adulthood. She presented feeding difficulties and severe sleep disorder.
She presented mild-to-moderate ID with behavioral problems such as self-harming and aggressivity without psychotic symptoms (verbal IQ < 35, WAIS-III). She had limited eye-contact with severe communication impairment (no verbal language with the use of gestures or grunts to communicate). Psychiatric medication associated Risperidone (2 mg/day), Fluoxetine (20 mg/day), Loxapine (150 mg/day).
Grandmother and grandfather
The grandmother is 76 years old (I2). We do not have any early information on pregnancy, birth and childhood, which it would appear were within the normal limits. There was notably no language delay. She went to school, worked all her life and apparently never presented any difficulties in her social interactions.
She does not have dysmorphic features. The patient has no abnormal cognitive features, no psychiatric diagnosis has ever been made. Blood screening showed no abnormalities.
As we can see in Fig. 1, her husband (I1) is dead and there is no information available about his birth, development, or cognitive abilities. We learn from the family that he presented qualitative deficiencies in his social interaction and communication.
The patient and the parents of the patient gave their written informed consent before participating in this study, and this study was approved by the ethical institutional review board of Le Vinatier hospital.
The karyotyping result for this patient was 46, XY. Array comparative genomic hybridization (CGH) did not show any unbalanced chromosomal rearrangement. The patient was investigated with a diagnostic gene panel of 450 genes whose mutations cause Mendelian neurodevelopmental disorders, including intellectual disability and autism spectrum disorder. Such a 450-gene panel for intellectual deficiency showed a heterozygous duplication of a single nucleotide, Chr7(GRCh37): g.70236569dup, ENST00000342771.4: c.1769dup in exon 11 of AUTS2, leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). No additional pathogenic or likely pathogenic variant was found in any of the other genes of the panel. The history, clinical and behavioral findings support the recurrent phenotypical features of “AUTS2 Syndrome”.
Sanger sequencing showed that the AUTS2 variant was found, in the heterozygous state, in the mother, aunt 1 and aunt 2 but was absent in the grandmother.
All neuropsychological evaluations were performed by trained neuropsychologists (EP and FH).
Table 1 summarizes the characteristics of the five members of the family carrying the AUTS2 variant.