Erotomania and phenotypic continuum in a family frameshift variant of AUTS2: a case report and review

Genetic diagnosis in neurodevelopmental disorders has yielded a lot of new candidate genes for intellectual disability (ID) and autism spectrum disorders (ASDs) [1]. High-throughput sequencing of intellectual disability/ASD genes identified pathogenic or likely pathogenic variants in 23.5% of patients investigated in day-care hospitals and special schooling institutions [2]. A precise ASD and ID diagnosis is a key challenge as it makes it possible to define the mode of inheritance with a view to assessing the risk of recurrence, and potentially offering a prenatal diagnosis.

AUTS2 (autism susceptibility candidate gene 2) (OMIM: 615834) maps to 7q11.22, spanning 1.2 Mb of the genomic region (chr7:69,063,905-70,257,885; hg19). The AUTS2 gene (AUTS2–201, ENST00000342771.10) contains 19 exons coding for a 1259 amino acid protein, and its protein is highly conserved, with amino acid conservation ranging from 62% in zebrafish to 93% in mice and humans [3‐5]. AUST2 is involved in autosomal dominant intellectual disability. It is highly expressed in the neural tube and the embryonic, fetal and adult brain, indicating that it might play an important role during neuronal development [4, 6‐8], and more particularly in neuronal migration and neurogenesis [9]. Neuronal migration is one of the pivotal steps to form a functional brain, and disorganization of this process is believed to underlie the pathology of psychiatric disorders including schizophrenia, ASD and epilepsy. AUTS2 protein has dual functions: cytoplasmic AUTS2 regulates actin cytoskeleton to control neuronal migration and neurite extension, while nuclear AUTS2 controls transcription of various genes as a component of the polycomb complex 1 (PRC1) [10]. The set of ID, ASD, neurological abnormalities, and dysmorphic features with short stature, microcephaly and facial dysmorphism has been considered as a syndromic phenotype at the AUTS2 locus ([3, 6, 11‐14]. To date, the findings of numerous studies have provided functional evidence of a causal link between AUTS2 variations and early growth and neurodevelopment defects [15‐17]. AUTS2 syndrome emerges as a specific ID syndrome with dysmorphic features and a specific behavioral phenotype, and most notably with an ASD (MIM 607270).

In the last few years, CNVs involving the whole or parts of the AUTS2 gene have been reported in more than 100 unrelated patients [14]. Although the existing literature has established a relationship between various psychiatric disorders, including schizophrenia and ASD, and various AUTS2 single nucleotide variants, to our knowledge, only one mutation of two-base pair deletion has been identified in the literature in a male patient with syndromic ID, who has a moderate ID (IQ was tested at 45) with severe language delay and an autism spectrum disorder. This case further supports the finding that AUTS2 syndrome is a single gene disorder [11, 18].

Here we report, for the first time, AUTS2 locus family transmission of a pathogenic AUTS2 variant with variable cognitive, psychiatric and social outcomes. As previously documented, the presence of ASD was not constant within the family. This family case report further reinforces the hypothesis of a continuum between ASD and psychosis, including social cognitive disorders.

Here, we report on a psychotic erotomaniac phenotype in the proband’s mother [19, 20]. To our knowledge, this is the first study that suggests a genetic molecular basis for erotomania.

We provide full clinical description of these four patients including treatment outcomes, which may complement the current literature. A specific section on the genetic molecular aspects is provided after these case presentations.

Figure 1 shows the family tree of the family studied.

In the present report, c.1769dup of the AUTS2 gene results in a frameshift. This stop codon reading prevents interaction with a group of Polycomb proteins known to maintain gene expression patterns established during development by regulating the differentiation, proliferation, and maintenance of pluripotency. To our knowledge, this is the first report of this probable pathogenic variant. Thus, this paper presents the first whole family carrier of an AUTS2 mutation. The dysmorphic features, although of varying severity, were quite similar throughout the family and correspond to the usual phenotype for AUTS2-related syndrome, reported by Beunders et al. [3, 11, 18] and Zhang et al. [21]. In particular, craniofacial dysmorphism including hypertelorism, downslanted palpebral fissure, short philtrum and large central incisors, prominent and large ears, and retrognathia were found in the proband and aunt 2. However, the psychiatric characteristics varied throughout the family. This case seems important in the light of the current literature because it highlights the continuum between different psychiatric disorders, even though only one AUTS2 nucleotide variant has been reported.

The medical findings for the family were summarized and compared to the previously published literature on AUTS2 gene disruption (see Table 2).

Previous papers have found the cognitive and neurodevelopmental outcomes to be relatively constant between members of the same family. For example, Nagamani et al. [13] reported the case of two siblings with ASD, developmental delay, and dysmorphic features. Beunders et al. [3] reported cognitive phenotype in two parents/17 reported cases: one parent had learning difficulties and the other had a mild ID. Our report contradicts this finding. With the same variant (c.1769dup), we found considerable psychiatric phenotypic variation (without phenotypic gradient however) ranging from learning disorders, disabled social cognition, and ID to ASD. The proband and aunt 2 share an ASD. Aunt 2 presents an ID while her two sisters present with a milder phenotype with only social anxiety and social cognition deficits. As previously stated, this variability has been observed in other cases of familial deletions [29, 30], but has never been reported for the AUTS2 single nucleotide variant, probably because few family cases have been reported.

The early identification of social cognition or neurocognitive disorders may be difficult in some family members. If a genetic diagnosis is already established within the family, close monitoring of the development of other family members would be a legitimate proposition. This accurate, predictive characterization allows for the provision of clinical, socio-professional and medical care at the earliest possible stage. Of course, we are not suggesting proposing genetic explorations for every case of erotomania, but rather that genetic analyses could be offered based on the specific family in question and their environment.

More generally, the psychiatric literature has already reported a broad cognitive phenotype in relation to different pathogenic variants of AUTS2. Numerous association studies (Genome Wild Association Studies) have linked AUTS2 to autism [24, 25, 31], bipolar disorder [32], attention deficit-hyperactivity disorder [33], alcohol dependence [34], heroin dependence [35], epilepsy [36], dyslexia [37], and differences in information processing speed [38].

Schizoaffective disorder was reported by [39]. In 2014, Zhang et al. hypothesized that AUTS2 polymorphism might be associated with psychosis (rs6943555). Therefore, only a few studies have reported a mutation of AUTS2 with psychotic phenotypic expression. As far as we know, this is the first report of autistic and psychotic features underpinned by the same AUTS2 pathogenic nucleotidic variant, therefore assuming a continuum between ASD and persistent delusional disorders. Indeed, as we will detail below, erotomania is a form of persistent delusional disorders [40].

Erotomania is a rare condition. Its prevalence is estimated to be around 15 cases per 100,000 [41], with a sex ratio of 3 women to 1 man (3:1). According to the DSM-5 and the ICD-11, erotomania falls within the scope of persistent delusional disorders (without disorganization: “paranoid delirium with an erotic theme” and should then be distinguished from the diagnosis of schizophrenia) [19, 20]. The patient has the delusional belief that a person has fallen in love with him or her. This belief results from an intuitive mechanism at the beginning, then an interpretative mechanism [42]. It is described that subjects with erotomania usually have low self-esteem and often experience social isolation. They describe emotional excitement during the delusional phase. The social cognitive disorders reported in erotomania correspond mainly to a deficit of theory of mind and an affective style disorder [43].

To our knowledge, the only genetic study of erotomania reported in the international literature was a twin study by Farmer et al. showing less heritability for erotomania than schizophrenia [44]. This case report is the first reported case of erotomania underpinned by a mendelian event. This raises the question of the genetic workup in erotomania cases especially in cases with a family and/or a personal neurodevelopmental disorder.

Autism Spectrum Disorder (ASD) is characterized at the neuropsychological level by a deficit in social cognition. The concept of social cognition brings together theory of mind (being able to understand the cognitive and emotional states of others), the identification of emotions, attributional style (which can lead to interpretative biases), perception and social knowledge [45]. Two of the family members whose cases are reported here present with ASD, and two further members displayed social cognition disorders that do not fulfill the ASD diagnosis criteria.

In the literature, AUTS2 deficient mice displayed a decrease in exploratory behavior as well as lower anxiety-like behaviors in the absence of any motor dysfunction [46]. These findings highlight how critical AUTS2 is to the acquisition of neurocognitive function [47]. These cases not only reinforce the hypothesis of a social cognitive disorder in AUTS2, but more generally show that a cognitive disorder linked to a genetic mutation can lead to a range of psychiatric diagnoses. This reinforces the notion of a continuum between the psychiatric entities categorized in the DSM-5 [48], especially with regard to transdiagnostic models [49]. The precision provided by genetic analyses makes it possible to go beyond the diagnostic categories of statistical psychiatry [50].

This report sheds new light on AUTS2 syndrome. The clinical and functional prognosis of individuals with a psychiatric phenotype such as ASD, ID or any other cognitive impairment depends on the early causal identification of their disorder, which is a prerequisite for adapted care.

Cognitive performance and psychiatric disorders may be more variable than previously suggested within the same family. In particular, simple social cognitive disorders might be mistaken for a delusional syndrome and/or an ASD. Identifying a gene that might relate to social cognitive disorders could be beneficial for other family members with less visible disorders.

Moreover, we have shown that a genetic event could explain a case of erotomania. The fact that a genetic mutation has been found in the context of isolated erotomania for the first time shows that we could offer genetic analysis in the context of erotomania even if the symptom is isolated.

A comprehensive clinical characterization of AUTS2 syndrome, with representations of different genetic alterations and phenotypic severity, should involve biological studies, and take into account these new data, especially with regard to the wider variability of intellectual outcomes and psychiatric disorders.