A Novel Variant in the MYT1L Gene Shared by Three Individuals with Neuropsychiatric and Neurodevelopmental Manifestations in a Family

Familial aggregation may help identify rare and private mutations that underlie disease. Many such genes are increasingly being identified, especially those linked to neurodevelopmental disorders and neuropsychiatric syndromes, uncovering both de novo and inherited mutations. ¹ Nonetheless, the mechanisms by which the several variants in these genes contribute to illness development, the diverse clinical presentations, and genotype–phenotype correlations need further exploration. One such gene is the pro-neuronal myelin transcription factor 1-like (MYT1L) gene.

Pathogenic mutations in MYT1L are associated with a neurodevelopmental condition known as MYT1L syndrome, mostly marked by intellectual impairment, behavioral anomalies, and obesity.^2–6 These mutations have been documented across the gene, encompassing nonsense, frameshift, and missense mutations, as well as infrequent instances of copy-number variants involving gene deletion, all linked to neurodevelopmental disorders. ² Duplications in the MYT1L gene have been linked to an elevated risk of schizophrenia. ⁷ In this report, we present a family of three affected individuals (father and two daughters) displaying a range of neuropsychiatric manifestations, and for whom exome sequencing revealed a novel variant in the MYT1L gene.

Case Reports

We used the CARE (Case Report) reporting guideline to draft this manuscript ⁸ (Supplementary File). Three members of a family, from Western India, presented to the psychiatry outpatient department of a tertiary medical college with a range of clinical manifestations (Figure 1).

Figure 1.

Pedigree Chart of the Family of the Affected Individuals.

Case 1

Mr A, a 50-year-old male with well-adjusted premorbid functioning, father of four children, has been married to a distant relative within his community. He presented with multiple episodes of increased activity, aggressive behavior, overvalued ideas, and persecutory beliefs, with interspersed hypomanic spells over 10 years with inter-episodic remission. Over the course of illness, he was treated with various antipsychotics, including olanzapine, amisulpride, and risperidone. Subsequently, he developed extrapyramidal symptoms in the form of bilateral hand tremors and fluctuating symptoms, including akathisia, rigidity, bradykinesia, and tardive dyskinesia. He had three distinct episodes (in 2015, 2017, and 2019) characterized by an acute onset of confusion, high-grade fever, severe generalized stiffness, dysphagia, bowel and bladder incontinence, and hallucinations, leading to marked functional impairment. Each episode lasted between 1 and 4 months before getting better. As per available records, during the 2017 episode, while receiving Clozapine 150 mg/day, he additionally developed ataxia, purple purpuric patches, and one episode of generalized tonic–clonic seizure. The family history of psychiatric illness included two daughters (details discussed below), a paternal uncle, and a paternal aunt, both diagnosed with schizophrenia spectrum disorder. Further, there was a history of diabetes mellitus and hypertension in his parents. On current physical examination, there were features of parkinsonism (pill rolling, resting tremors, stooped posture, masked facies, slowed movements, reduced arm swing) and tardive dyskinesia. Cognitive testing using the Addenbrooke’s Cognitive Examination revealed a score of 62/100 (below normal). ⁹ A diagnosis of bipolar type I disorder, currently in full remission ¹⁰ with neuroleptic sensitivity was kept. The patient has been clinically stable on quetiapine 300 mg/day and sodium valproate 1,600 mg/day, with no further episodes reported on follow-up.

Case 2

Ms B was a 22-year-old female, born out of a third-degree consanguineous marriage (mothers of both parents were sisters), with a history of trachea-esophageal fistula for which she was operated on at around 1.5 months of age. She presented with features since childhood of poor scholastic performance, requiring assistance in activities and instrumental activities of daily living, minimal social interaction, and poor eye-to-eye contact. However, no formal intelligence test was administered at that time. In 2019, she developed features of labile mood and aggression. On being treated with antipsychotics (amisulpride and haloperidol) at another hospital before presenting to us, she developed high-grade fever, rigidity, dystonia, and akathisia with elevated creatine phosphokinase levels (1983 IU/L). This was suspected to be neuroleptic malignant syndrome (NMS). There is also a history of lithium-induced hypothyroidism. On presentation to our service, she continued to have tremulousness, tardive dyskinesia, oculogyric crisis with urinary incontinence; along with exacerbations of her mood and psychotic symptoms (overgrooming, disinhibited, and regressive behavior). For the past several months before her visit, she had been experiencing second and third-person auditory hallucinations, delusions of reference, and perseveration. She required assistance with her care. Considering the co-existence of her affective and psychotic symptoms as mentioned above, throughout the course of illness, a provisional diagnosis of schizoaffective disorder, unspecified with neurodevelopmental disorder ¹⁰ with neuroleptic sensitivity was made. She was observed to be clinically stable on quetiapine 300 mg/day and sodium valproate 1,200 mg/day.

Both Mr A and Ms B developed signs suggestive of NMS on their first exposure to antipsychotics.

Case 3

Ms C, a 17-year-old female with well-adjusted premorbid functioning, had recently developed an illness characterized by low mood, anhedonia, nihilistic delusions, reduced appetite, death wishes, and catatonic features (mutism, staring, immobility, negativism, withdrawal). On examination, rigidity, gegenhalten, autonomic hyperactivity, and ambitendency were seen. She scored 19/66 on the Bush–Francis Catatonia Rating Scale. ¹¹ The catatonic symptoms responded well to lorazepam and seven cycles of modified electroconvulsive therapy. She was discharged on lithium 750 mg/day, olanzapine 10 mg/day, and sertraline 100 mg/day with a diagnosis of catatonia associated with another mental disorder (single episode depressive disorder, severe, with psychotic symptoms). ¹⁰ Olanzapine and sertraline were initiated in view of her psychotic and depressive features as discussed earlier. Lithium was started considering the florid history of bipolar spectrum disorder in family members and presence of psychotic and catatonic features in the current episode, all of which are known indicators of bipolarity in an otherwise depressive episode. She is currently in clinical remission on the above medications.

Routine blood work and magnetic resonance imaging of the brain for all three individuals were unremarkable. We sent their peripheral blood samples for whole-exome sequencing due to their dense family history and heterogeneous clinical presentations. Genomic Deoxyribonucleic acid (DNA) was extracted from blood, and exonic regions were sequenced using a custom next-generation sequencing panel. Reads were aligned to Genome Reference Consortium Human (GRCh)38, and variants were called, annotated, and filtered based on quality, population frequency, and predicted functional impact. Variants were assessed using the Online Mendelian Inheritance in Man (OMIM) and in silico prediction tools, and classified according to the American College of Medical Genetics and Genomics guidelines.

The results revealed a c.2612A>C (p.Gln871Pro) variant in the MYT1L gene, shared by all three. The OMIM database shows that this gene (MYT1L, 613084) is associated with IDD #616521 (Intellectual Developmental Disorder, Autosomal Dominant 39; MRD39).

Discussion

We detected a novel MYT1L variant shared by three affected family members. The MYT1L gene, a zinc finger transcription factor located on the short arm of chromosome 2, is expressed in neural tissue and plays a role in genetic control. Its disruption is frequently linked to neuropsychiatric disorders. ⁶ The novel variant (Glu871Pro) reported in our cases, which substitutes glutamic acid with a rigid cyclic amino acid such as proline, is likely to alter the secondary and tertiary structure of the protein. This amino acid position is flanked by a disordered region (753–780) and a CCHHC-type 4 zinc finger domain (896–939) (data from UniProtKB). ¹² The observed mutation occurs in a well-conserved region, and the Predicted Loss of Function (pLoF) (0.09) suggests that the gene is intolerant of mutations. The specific variant is predicted to be deleterious by Sorting Intolerant from Tolerant (SIFT) (0.03) and ClinPred (0.91), has moderate damaging consequences per Variant Effect Predictor (VEP), and is deemed benign by PolyPhen (0.018), AlphaMissense (0.046), and evolutionary model of variant effect (EVE) (0.063). Three affected family members share the mutation and are thus likely to be clinically significant.

Partial duplications of MYT1L have been linked to schizophrenia (Lee et al., 2012), and several accounts of deletions associated with neurodevelopmental disorders, including intellectual disability (ID).^4–7,13 A systematic review by Mansfield et al. (2020) provides an updated review of published reports on the neuropsychiatric correlates of loss-of-function and duplication of MYT1L. ⁶ They analyzed 24 published reports of human subjects with MYT1L variants, identifying 78 non-overlapping cases. Of 27 duplications, all were partial, with a third being linked exclusively with schizophrenia. The chromosomal locations of schizophrenia associated duplications exhibited a distinct difference in the pattern of location from those associated with autism and/or ID. Of 51 published heterozygous loss-of-function variants, all but one were linked with ID, autism, or both, and one was detected in a person with no neuropsychiatric diagnosis. There were no reports of schizophrenia associated with loss-of-function variants of MYT1L (Fisher’s exact p < .00001, in contrast with all reported duplications) in this review. ⁶

A study conducted by Coursimault et al. (2022) reported an additional 40 novel cases of MYT1L-associated neurodevelopmental disorder and conducted a literature review of its clinical and molecular characteristics. ² The research established that the primary phenotypic characteristics of the MYT1L-related illness include developmental delay with language impairment (95%), ID (70%), overweight or obesity (58%), behavioral disorders (98%), and epilepsy (23%). The study also emphasized new clinical features, including learning problems without ID (30%) and eating challenges in infancy (18%). ² Another report by Bouassida et al. (2023) examining 16 new cases of 2p25.3 microduplications involving the MYT1L gene found that a spectrum of neuropsychiatric phenotypes with incomplete penetrance and variable expression characterizes these phenotypes. ¹³ The clinical features of these patients ranged from developmental and speech delays to autism spectrum disorder, ID, schizophrenia, and behavioral disorders. ¹³

According to Weigel et al. (2023), immature neurons harboring mutations in the autism-associated gene MYT1L are unable to repress genes that should be expressed exclusively in other cell types, leading to impaired neuronal maturation and hyperactive electrical signaling. ¹⁴ Their study suggests that MYT1L mutations destabilize neuronal cell fate and function, leading to autism spectrum disorder-associated phenotypes in both humans and mouse models. The study found that loss-of-function results in overlapping defects independent of the mutation type. They discovered that the loss of MYT1L leads to the upregulation of non-neuronal genes, most notably the cardiac voltage-gated sodium channel Sodium Voltage-Gated Channel Alpha Subunit 5 (SCN5A), which is normally lowly expressed in the brain. This upregulation triggers neuronal network hyperactivity. They also demonstrate that lamotrigine mitigates this excessive neuronal signaling in both human and murine neurons and alleviates hyperactivity in mice with MYT1L mutations. These preclinical studies showing lamotrigine’s success in the models open avenues for potential therapeutic interventions for individuals with MYT1L mutations, particularly those presenting with co-occurring epilepsy or hyperactivity. ¹⁴

The MYT1L gene is involved in the development of the nervous system, is expressed at critical developmental stages and throughout adult life (Figure 2a), and is expressed across several brain regions (Figure 2b). ¹⁵ The encoded MYT1L protein interacts with disrupted-in-schizophrenia (DISC1) (Figure 2c), variants in which are risk factors for both ID and schizophrenia/bipolar disorder. Both MYT1L and DISC1 have disordered regions that correspond to binding sites for other proteins, which may be critical for function, especially during neurodevelopment.^16–18 The research and clinical implications of these findings add further detail to the range of phenotypes linked to damaging variants in the MYT1L gene. Although the variant detected in all affected individuals was the same, the clinical phenotypes differed significantly, and all three were sensitive to neuroleptics. Overlaps between ID syndromes and psychoses have often been observed, along with pleiotropy and variable expressivity. Parkinsonian side-effects and malignant neuroleptic syndromes may have genetic contributions, and other myelin-related proteins have been linked to the development of catatonia-depression.^19–21

Figure 2.

AMY: Amygdaloid complex, MFC: Anterior cingulate (medial prefrontal) cortex, CGE: Caudal ganglionic eminence, CB: Cerebellum, DTH: Dorsal thalamus, DFC: Dorsolateral prefrontal cortex, HIP: Hippocampus, ITC: Inferolateral temporal cortex, LGE: Lateral ganglionic eminence, MGE: Medial ganglionic eminence, MD: Mediodorsal nucleus of thalamus, Ocx: Occipital neocortex, OFC: Orbital frontal cortex, PCx: Parietal neocortex, STC: Superior temporal cortex, IPC: Posteroventral (inferior) parietal cortex, A1C: Primary auditory cortex, M1C: Primary motor cortex, M1C-S1C: Primary motor-sensory cortex, S1C: Primary somatosensory cortex, V1C: Primary visual cortex, STR: Striatum, TCx: Temporal neocortex, URL: Upper rhombic lip, VFC: Ventrolateral prefrontal cortex.

Conclusion

It remains elusive, therefore, which factors and mechanisms are responsible for the varying presentations. Documenting the genetic landscape of rare variants across diverse populations and their clinical correlates is essential for a comprehensive understanding of the mechanisms underlying genotype–phenotype interactions in diseases, and for potentially identifying targets for intervention and providing insights into the genetics of neurodegenerative diseases and neuropsychiatric syndromes, which could inform breakthroughs in treatment options.

Supplementary Material

Supplemental material for this article is available online.