Here, we presented clinical and molecular data on 15 new cases of individuals harboring a microduplication in the 2p25.3 region. We also reviewed the cases described in the literature and added a patient from the DECIPHER (23), from whom we obtained explicit consent for publication. Hence, we were able to describe a cohort of 43 people with a 2p25.3 microduplication involving MYT1L (Tables 1 and 2). These microduplications are rare, and only 27 cases had been reported previously (16). To the best of our knowledge, the present series is the largest yet reported.
The most frequently reported clinical features were psychomotor and speech delay (33%), mild-to-moderate ID (21%), ASD with or without ID (23%), schizophrenia (21%), and behavioral abnormalities (16%, including anxiety, attention-deficit/hyperactivity disorder, and aggressiveness). Our results are in line with previous observations of psychiatric and neurodevelopmental disorders as the main phenotype (4, 10, 16, 21, 24); however, the clinical feature most frequently reported in the literature (schizophrenia) was not observed in any of the 15 new cases (16). This discrepancy might be due to difference in the various studies’ inclusion criteria. Most of the previous studies focusing on schizophrenia (10, 14, 19–21), which explains why an association between microduplications involving MYT1L and schizophrenia (odds ratio: 15.7; p = 0.001) was identified in large case-control studies of patients of all ages. This association is reportedly stronger for childhood-onset schizophrenia than for adult-onset schizophrenia (odds ratio: 16.6; p = 0.01) (ref. 10).
Considering the 2p25.3 microduplications including MYT1L were inherited from a healthy parent in nine cases, one can hypothesized that the penetrance is variable. Furthermore, the highly heterogeneous phenotype is suggestive of variable expressivity. This might be due to differences in the breakpoints and duplication sizes, although these genetic features did not appear to be correlated with the clinical severity. For example, patients P17 and P14 (harboring duplications of 110 kb and 3.8 Mb, respectively) had much the same phenotype.
The microduplication size ranged from 62.4 kb to 3.8 Mb, and involved all or part of the critical MYT1L gene (4, 22). Haplo-insufficiency of MYT1L is not tolerated in humans (25), and the probability of loss of function intolerance score is 1. To date, disease-causing variants in MYT1L have been reported in 62 patients; the phenotype is more homogeneous but the clinical presentations resemble those seen in cases of microduplication syndrome (1). The most frequent clinical features are behavioral disorders (seen in 98% of cases), DD with language delay (95%), ID (70%), overweight or obesity (58%), and epilepsy (23%) (ref. 1). Furthermore, gene expression profiling of a MYT1L knockout cell line has shown that MYT1L haploinsufficiency can disrupt the expression of critical genes during brain development – suggesting that MYT1L regulates a network of genes involved in the etiology of neurodevelopmental disorders (25). Chen et al. (2021) generated a Myt1l haploinsufficiency mouse model that mimicked common clinical phenotypes associated with loss-of-function mutations in human MYT1L or 2p25.3 deletions, including obesity, white-matter thinning, microcephaly, hyperactivity, muscle weakness, and social alterations (3).
The phenotypic variability might be explained by a “two-hit” model. The second hit might be another copy number variation, a single-base-pair mutation disrupting a functionally related gene, or even an environmental factor that affects the phenotype. This second hit might be responsible for the development of more severe neurological phenotypes, such as ID/DD, ASD, and schizophrenia (26, 27).
Lastly, one can hypothesize that the phenotype is due to duplication of another gene. However, when considering the 43 patients described in our study and in the literature, defects in candidate genes that could be responsible for specific clinical findings in this syndrome were found in 26 cases only. Interestingly, 20 of the 43 duplications (particularly those associated with schizophrenia) affected MYT1L and PXDN. This prompts us to wonder whether PXDN is involved in schizophrenia susceptibility. PXDN encodes an extracellular, matrix-associated peroxidase thought to participate in peroxide-driven oxidations, phagocytosis, and immune defense. Many studies have shown that oxidative stress is part of the disease mechanism of schizophrenia (28). However, there are no literature data on the potential involvement of PXDN in schizophrenia or other neuropsychological features.
Regarding the mechanism underlying the duplication and given the absence of recurrent breakpoints or flanking segmental duplications, non-allelic homologous recombination can be ruled out (10). Hence, the involvement of other underlying mechanisms (such as non-homologous end joining, fork stalling and template switching, and microhomology-mediated break-induced replication) could be postulated.
Lastly, our findings reveal that MYT1L duplications are associated with variable, unpredictable phenotypic outcomes. Microduplications are often inherited from a phenotypically normal parent, making it difficult to establish a direct pathogenic effect. In this context, genetic counseling and a clinical prognosis are major challenges for clinicians. The enrichment of this microduplication in patients with neurodevelopmental disabilities and the more frequent occurrence of a second copy number variation in affected carriers suggest that 2p25.3 microduplications involving MYT1L can act as a susceptibility/risk locus for neurodevelopmental impairments.