Comparison With Prior Work on 16p13.11 Microduplication
New phenotypes associated with the dup16p13.11 CNV have been continuously discovered and reported since the syndrome first came to light in 2007 when Ullmann et al initially identified the 16p13.11 microduplication and believed it predisposed patients to ASD and intellectual disability [2]. Subsequently, further studies have indicated that the 16p13.11 microduplication is likely to be involved with a wide spectrum of neurodevelopmental disorders [1,24-27]. We hereby identified two neuropsychiatric disorders, anxiety and aggression, as supplementary evidence to the underrepresented cases in prior reports, and we underline a probable high occurrence of these two phenotypes in patients with dup16p13.11. As shown in Table 3, only two cases of anxiety have been previously reported; one by Ramalingam et al (1/8 patients) [1] in 2011 and another by Loureiro et al (1/4 patients) [19] in 2017. Although one case was inherited and the other occurred de novo, both aforementioned cases were associated with ASD or ADHD, which aligns with literature that anxiety is a common condition in patients with ADHD and ASD [28,29]. In our cases, however, just one individual with anxiety had co-occurring ASD, whereas the remaining three cases of anxiety appeared independently. Meanwhile, aggression was also noted in three family reports, and it has gone largely unreported since Hannes et al first described a case of aggression in a patient with dup16p13.11 in 2009 [5], and another case was reported in the study by Nagamani et al in 2011 [3]. Furthermore, a potential correlation between 16p13.11 microduplication and a range of immunological disorders, specifically autoimmune conditions, was uncovered in multiple individuals in our cohort.
Aggressive behavior is one of the most common reasons for mental health referrals in children and adolescents [30-32], and can co-occur with a broad array of psychiatric and neurological illnesses, including ASD, intellectual disability, ADHD, conduct disorder, oppositional defiant disorder, disruptive mood dysregulation disorder, schizophrenia, epilepsy, anxiety, depression, and sleep disorders [33,34]. While impulsive aggression may not indicate any specific disorder, it is an important marker of severity for many psychiatric diseases [35]. For example, aggression level may affect the decision to initiate or increase medication dosage in pediatric ADHD treatment [36]. Regardless of the controversy over whether to consider impulsive aggression as an independent categorical diagnosis like a disorder [37] or a measurable symptom secondary to some other diagnostic entity like fever or pain [32,38], it can greatly impact an individual’s development and health, or even lead to high economic and medical burden for families and communities [39-41]. This paper does not aim to address the dispute over the clinical perception of aggression by joining any side or to unduly correlate 16p13.11 microduplication with the aggression phenotype. Instead, we hope to draw more attention to the repeatedly mentioned and thus important phenotypes that are self-reported by the patient families and call for more focus on related research and therapeutics.
The potential connection between neuropsychiatric disorders and autoimmunity/immunological dysfunction has received growing interest over the past decades. For instance, a nationwide population-based prospective cohort study in Denmark used a longitudinal registry to find that autoimmune diseases and infection raised the risk for subsequent mood disorder [42]. Another well-covered example is the bidirectional relationship between psychosis and autoimmune disorders [43], specifically schizophrenia and celiac disease, between which positive correlations have been suggested through studies of epidemiology, genetics, and immunology [44,45]. Notably, the discovery of autoimmune encephalitis and the disruptive autoantibody mechanisms behind it provided more direct proof of etiological linkage [46-49]. Autoimmune encephalitis is an abrupt inflammatory brain disease characterized by a variety of neuropsychiatric symptoms, such as cognitive and behavioral alterations, seizures, anxiety, and sleep disturbances [50,51], and responds to immunotherapy treatment in many cases [52,53]. Among all the possible causative autoantibodies, one of the most discussed is the N-methyl-D-aspartate receptor (NMDAR) antibody. The NMDAR antibody targets a certain subunit of NMDAR, a synaptic and neuronal cell membrane protein, and has been revealed to play a role in the development and progression of schizophrenia [47,54-57] and ASD [58-61]. Given the long-lasting belief that ASD is largely genetic [62-66], our finding of several individuals with dup16p13.11 CNV who have immunity-related diseases and neuropsychiatric symptoms, especially a case with both ASD and autoimmune encephalopathy plus corresponding antibody positivity, supports the medical field’s current views and may influence future studies that seek to understand genetic origin.
It is worth noting that new associated phenotypes may emerge even for established genetic diseases as more scientific research is conducted and the demographic profiles of patient populations shift. For example, though the first case of Down syndrome was reported in the 19th century, it was not until the last two decades that individuals with Down syndrome were identified as having an increasing risk of early-onset Alzheimer disease as they age; many individuals with Down syndrome start to develop Alzheimer disease pathology in their 30s and approximately two-thirds have dementia by the age of 60 years [67,68]. Due to advancements in health care and social support, the life expectancy of the Down syndrome population has greatly improved, with the average age of death in developed countries now approaching 60 years [69]. A similar increase in knowledge has occurred regarding Turner syndrome, which was first described in the 1930s and is one of the most common genetic disorders [70,71]. Some patients with Turner syndrome who carried a mosaic 46, XY karyotype or an abnormal Y chromosome were recently found to have a higher risk of developing gonadoblastoma and other gonadal tumors owing to the widespread use and easy availability of polymerase chain reaction technology [7,72]. For genetic diseases with variable presentations and complex genotypes, such as Down syndrome and Turner syndrome, it may be too early to announce that all phenotypes have been exhaustively discovered and included.
We do not claim that Phenotypr is a substitute for clinician phenotyping, and it is unlikely that participants will be able to describe some of the highly technical aspects of their disorders in clinical terminology. Therefore, we do not consider the underreporting of some phenotypes in Phenotypr to be notable. In contrast, phenotypes that were repeatedly mentioned by participants but have not been well discussed in the literature are worthy of further investigation. It is possible that patients and families are not mentioning these phenotypes in clinic visits or that their existing concerns are not being fully understood.
Conclusions
In this study, we utilized the Phenotypr tool to collect self-phenotyping data from 19 16p13.11 microduplication syndrome cases, with the aim of identifying underrepresented phenotypes in the current scientific literature. A number of phenotypes were highlighted, including aggression, anxiety, and a range of immunological disorders. In addition to the typically recognized phenotypes, dup16p13.11 CNV showed a stronger predisposition to aggression and anxiety compared to previously reported cases, as both phenotypes were mentioned by multiple Phenotypr participant families (4/19, 21%). Moreover, we found that three out of four cases with anxiety did not have co-occurring ASD or ADHD, which differed from two other published cases [1,28]. An interesting case that involved ASD and autoimmune encephalopathy with corresponding antibody positivity was also identified using Phenotypr. These findings illustrate some important hypotheses. First, aggression and anxiety may be more common than previously understood in 16p13.11 microduplication cases. Second, anxiety may appear independently as a result of dup16p13.11 CNV instead of being accompanied with ASD or ADHD. Third, immune and autoimmune disorders might be phenotypes of 16p13.11 microduplication, and dup16p13.11 CNV might play a genetic role in the association between autoimmune encephalopathy and ASD. Fourth, in consideration of the incomplete penetrance and varied expression of this syndrome in a broad spectrum of neuropsychiatric disorders, patients and their clinicians should be aware of all possible phenotypes to ensure that treatment is as effective as possible. Fifth, HPO and layperson HPO profiles acquired through patient self-phenotyping can serve as a valuable data source for the exploration of underreported phenotypes in the scientific literature, especially for rare disorders with variable presentations.
Future work will apply Phenotypr to additional 16p13.11 microduplication cases and correlate phenotypic results to the size of the duplicated interval and the genes involved. We also look forward to adopting Phenotypr as a complementary data source in other genetic cohort studies of rare diseases.