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The Evolving Genetic Landscape of Phelan-McDermid Syndrome and Implications for Diagnostics 

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
Phelan-McDermid Syndrome (PMS) is a neurodevelopmental disorder caused by disruptions to the SHANK3 gene on chromosome 22q13, encoding a scaffolding protein crucial for synaptic function and neuronal development. PMS presents heterogeneously with intellectual disability, speech impairment/absence, problems with social communication, motor impairments and features of autism spectrum disorder (ASD). SHANK3 deficiency is caused by various genetic abnormalities, including large chromosomal deletions and smaller variants within SHANK3 itself. Mutations in SHANK3 are among the most common genetic findings in ASD, affecting >1% of patients.  Understanding of the complex etiology of PMS is dynamic, with new insights revealing a greater contribution of small SHANK3 variants to PMS than previously anticipated. This shift has significant implications for diagnostic strategy, necessitating a renewed emphasis on high-quality utilization of next-generation sequencing (NGS) technologies.  Recognizing disparities in capabilities and coverage across U.S. diagnostic laboratories, we aim to highlight the emerging importance of a comprehensive sequencing-based approach to detecting SHANK3 variants and provide insights on current diagnostic testing.

 

Methods:
Prevalence estimates and detailed information about variants were compiled from published studies. Additional data were collected from a pool of 380 PMS patients seen at the Icahn School of Medicine at Mount Sinai from 1994-2023. Genetic abnormalities associated with PMS diagnoses were divided broadly into 22q13.3 deletions and SHANK3 sequence variants, which were further subdivided by structural rearrangement and mutation type. U.S. diagnostic laboratories’ coverage of these variant categories was assessed using publicly available information to identify gaps in the PMS diagnostic landscape.

 

Results:
Since its recognition, PMS diagnoses have emerged and risen dramatically. Previously published data provide a snapshot of the state of PMS etiology, with 22q13 deletions accounting for ~81% of cases and mutations within SHANK3 comprising between 8.6%-25%.  Among the Mount Sinai patient pool, these proportions are 68% and 32%, respectively. A chronological analysis of this same population reveals that PMS diagnoses were associated exclusively with deletions prior to 2010, after which SHANK3 variants began emerging and steadily grew to a comparable prevalence to large deletions by the mid 2010’s to present, suggesting that the true ratio of mutations to deletions is closer to 1:1. Furthermore, the age at which PMS resulting from SHANK3 mutations is diagnosed is higher than that of patients with 22q13.3 deletions, indicating that these forms of PMS may be more difficult to recognize and/or detect. SHANK3 variants are observed throughout the gene’s coding regions and across conserved protein domains.  U.S. laboratory diagnostic methods and capabilities were found to be widely variable, with significant gaps in coverage including incomplete analysis or total omission of SHANK3 in relevant sequencing panels, lack of deletion/duplication analysis of the gene, and reliance on exome sequencing that may not adequately identify large deletions.

 

Conclusion:
Due to the emerging importance of within-gene SHANK3 variants in PMS, it is imperative for laboratories to use NGS approaches with quality coverage across SHANK3 at sufficient depth to enable deletion/duplication analysis. With significant disparities in U.S. diagnostic laboratory modalities, PMS patients with sequence variants likely go erroneously undiagnosed every year. Because phenotypic severity is associated with 22q13.3 deletion size, this population may exhibit milder deficits than patients with large deletions; this makes recognizing symptoms and pursuing relevant genetic testing more challenging but also represents greater potential for responsiveness to therapeutic interventions. More work needs to be done to assess quality gaps and testing volumes of U.S. laboratories to evaluate and address the impact of suboptimal diagnostic practices on the PMS patient population.

 

Agenda

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