Anxiety disorder is a common psychopathological comorbidity in patients with SHANK pathogenic variants: description of five new cases - Report - MDSpire
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Anxiety disorder is a common psychopathological comorbidity in patients with SHANK pathogenic variants: description of five new cases
Prevalence of Anxiety Disorders in Patients with SHANK Gene Variants: Five New Cases
Overview
This report describes five patients with pathogenic variants in SHANK1, SHANK2, and SHANK3 genes identified among a cohort of 115 individuals with mild or borderline intellectual disability and psychiatric comorbidities. The findings highlight a prevalent neuropsychiatric phenotype, particularly anxiety disorders, associated with SHANK gene variants.
Background
Intellectual disability (ID), especially mild intellectual disability (MID) or borderline intellectual functioning (BIF), frequently co-occurs with psychiatric disorders. Genetic causes account for up to 50% of ID cases, with many genes implicated in neurodevelopmental disorders converging on synaptic biology pathways. SHANK family genes encode scaffold proteins critical for synapse formation and function, and variants in these genes have been linked to autism spectrum disorder (ASD), cognitive impairment, and neuropsychiatric conditions. Whole exome sequencing has facilitated the identification of pathogenic single nucleotide variants in SHANK genes, with SHANK3 variants being the most studied, while SHANK1 and SHANK2 variants remain less commonly reported.
Data Highlights
Patient
Gene
Variant Type
Inheritance
Neuropsychiatric Features
1
SHANK1
Loss of function (nonsense)
De novo
Anxiety, ASD traits
2
SHANK1
Loss of function (nonsense)
Not specified
Anxiety, cognitive delay
3
SHANK2
Pathogenic variant
Not specified
Mild to moderate ID, ASD, speech delay
4
SHANK3
Pathogenic variant
Not specified
Less severe speech impairment, motor deficits
5
SHANK3
Pathogenic variant
Not specified
Neuropsychiatric disturbances
Key Findings
Five patients with pathogenic or likely pathogenic variants in SHANK1, SHANK2, and SHANK3 were identified, representing 4.3% of the studied cohort.
Two SHANK1 variants were loss of function nonsense mutations predicted to undergo nonsense mediated decay and absent from population databases.
Neuropsychiatric phenotypes, especially anxiety disorders, were prevalent across patients with SHANK gene variants.
SHANK2 variants were associated with mild to moderate intellectual disability, autism spectrum disorder, and speech delay.
SHANK3 pathogenic variants presented with less severe speech and motor impairments compared to copy number variant deletions.
Clinical Implications
Clinicians should consider genetic testing for SHANK gene variants in patients presenting with mild to borderline intellectual disability accompanied by psychiatric comorbidities, particularly anxiety disorders and ASD traits. Early identification of SHANK-related synaptopathies can guide tailored neuropsychiatric evaluation and management strategies. Awareness of the phenotypic spectrum associated with SHANK variants may improve diagnostic accuracy and patient care.
Conclusion
This report expands the clinical spectrum of SHANK gene variants by highlighting a common neuropsychiatric phenotype, notably anxiety disorders, in patients with mild intellectual disability. These findings underscore the importance of genetic analysis in neurodevelopmental and psychiatric comorbidities.
References
Spataro et al., 2023 -- Genetic Analysis and Variant Classification in Neurodevelopmental Disorders
American College of Medical Genetics and Genomics (ACMG) Guidelines, 2015 -- Standards for Variant Interpretation
