Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental
Tess Levy1,2, Jennifer H Foss-Feig1,2, Catalina Betancur3
1Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Insights
Genetic alterations in Phelan-McDermid syndrome (PMS) correlate with distinct clinical outcomes. Class I deletions or variants are linked to better cognition but skill regressions, while Class II deletions are associated with medical issues.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Human Physiology
Background:
- Phelan-McDermid syndrome (PMS) is characterized by diverse developmental, medical, cognitive, and behavioral issues.
- Existing research suggests genotype-phenotype correlations may explain the broad clinical spectrum observed in PMS.
Purpose of the Study:
- To investigate genotype-phenotype associations in a large cohort of individuals with PMS.
- To identify specific genetic alterations and their impact on developmental trajectories, cognitive abilities, and medical comorbidities.
Main Methods:
- Genotyping classified deletions into Class I (SHANK3-related) and Class II (other deletions) or sequence variants.
- Phenotype data collected prospectively via direct evaluation, caregiver interviews, questionnaires, and medical history.
- Statistical analyses performed to compare outcomes between genotype groups.
Main Results:
- Class I deletions/variants associated with fewer developmental delays and higher cognition but increased skill regressions compared to Class II.
- Class II deletions linked to higher prevalence of medical conditions like renal and spine abnormalities, and ataxic gait.
- Class I deletions/variants showed a greater likelihood of psychiatric diagnoses (bipolar disorder, depression, schizophrenia); autism spectrum disorder prevalence was similar across groups.
Conclusions:
- This study provides the most extensive genotype-phenotype analysis in PMS to date.
- Specific genetic alterations in PMS significantly influence clinical functioning, developmental trajectories, and comorbidities.
- Findings aid in understanding and managing PMS based on individual genetic profiles.
Abstract:
Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of developmental, medical, cognitive and behavioral abnormalities. Previous literature has begun to elucidate genotype-phenotype associations that may contribute to the wide spectrum of features. Here, we report results of genotype-phenotype associations in a cohort of 170 individuals with PMS. Genotypes were defined as Class I deletions (including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B), Class II deletions (all other deletions) or sequence variants. Phenotype data were derived prospectively from direct evaluation, caregiver interview and questionnaires, and medical history. Analyses revealed individuals with Class I deletions or sequence variants had fewer delayed developmental milestones and higher cognitive ability compared to those with Class II deletions but had more skill regressions. Individuals with Class II deletions were more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait. Those with Class I deletions or sequence variants were more likely to have psychiatric diagnoses including bipolar disorder, depression, and schizophrenia. Autism spectrum disorder diagnoses did not differ between groups. This study represents the largest and most rigorous genotype-phenotype analysis in PMS to date and provides important information for considering clinical functioning, trajectories and comorbidities as a function of specific genetic alteration.
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