Genotype-Phenotype Associations in Phelan-McDermid Syndrome: Insights into Novel Genes Beyond SHANK3

Abstract

Phelan-McDermid syndrome (PMS; #MIM: 606232) is a rare neurodevelopmental disorder primarily caused by the haploinsufficiency of the SHANK3 gene, most often due to deletions encompassing the gene or single nucleotide variants within it. Individuals with PMS display a wide range of clinical abnormalities and considerable genetic heterogeneity. This study aims to investigate genotype-phenotype correlations in a cohort of 213 individuals with PMS and to identify novel candidate genes, beyond SHANK3, that may contribute to the syndrome's diverse clinical manifestations. Unsupervised clustering based on deletion size and Global Functional Assessment of the Patient (GFAP, previously described and developed by our group), along with additional analytical approaches, were employed to explore genotype-phenotype relationships. Deletion size within the 22q13.3 region emerged as a major determinant of phenotype, with larger deletions associated with more severe global functional impairment. Furthermore, CERK, TBC1D22A, CELSR1, and GRAMD4 were identified as candidate genes within 22q13.3, potentially contributing to core PMS phenotypes, and their putative interactions were explored. Our findings support the central role of SHANK3 in PMS, while also indicating that it does not account for the full phenotypic spectrum. This study underscores the variable impact of distinct genetic alterations in PMS and proposes additional loci implicated in its pathogenesis. These insights may inform future therapeutic strategies, emphasizing the importance of patient stratification and precision medicine.

Keywords: 22q13.33 chromosomal region; Phelan–McDermid syndrome (PMS); SHANK3; genotype–phenotype correlation; haploinsufficiency.

Figure 1

Comparison of the different patient subgroups based on their mean GFAP values (arbitrary units) and standard deviations. Asterisks (*) indicate statistically significant differences (p ≤ 0.01). Numbers within the black bars represent the mean ± standard deviation of the deletion size for each corresponding group.

Figure 2

Correlation between deletion size and GFAP score. The scatter plot illustrates a positive correlation between deletion size and GFAP scores, with larger deletions corresponding to more severe phenotypes and higher GFAP values. The red trend line highlights the overall linear relationship. The arrow denotes a potential inflection point beyond which functional outcomes appear to worsen more markedly.

Figure 3

Representation of deletion-based clusters and SHANK3 variants as a function of GFAP scores. Asterisks (*) indicate statistically significant differences (p < 0.05). The ampersand symbol (&) denotes a trend toward significance that does not reach the conventional threshold of statistical significance (p ≥ 0.05).

Figure 4

Graphical representation using the UCSC Genome Browser of patients with and without nephro-urological alterations. (A) Patients without nephro-urological alterations; (B) patients with nephro-urological alterations; (C) comparison of the haploinsufficiency regions between groups A and B. Genomic coordinates are based on the GRCh38 (hg38) reference assembly.

Figure 5

Graphical representation using the UCSC Genome Browser of patients with and without lymphedema. (A) Patients without lymphedema; (B) patients with lymphedema; (C) comparison of the haploinsufficiency regions between groups A and B. Genomic coordinates are based on the GRCh38 (hg38) reference genome.

Figure 6

Visualization of genes and genomic regions within 22q13.31–q13.33 identified as highly or moderately susceptible to haploinsufficiency. Genomic coordinates are based on the GRCh38 (hg38) reference assembly. Based on the scores, genes were categorized as follows: Red: Score > 30, classified as highly haploinsufficient; Yellow: Score > 20, classified as moderately haploinsufficient.

Figure 7

Interaction networks of selected haploinsufficient genes generated using STRING (https://string-db.org/ (accessed on 16 February 2015)). (A) Proteins interacting with GRAMD4; (B) Proteins interacting with PIM3; (C) Proteins interacting with ZBED4.

Figure 8

Schematic pathway diagram illustrating the interactions between genes and their associated contributions to phenotypic manifestations in Phelan–McDermid syndrome. Blue nodes represent genes (e.g., SHANK3, GRAMD4, CELSR1), while boxes denote phenotypes and functional disruptions, including seizures, cranial abnormalities, and lipid metabolism dysfunctions, among others. Connecting lines indicate putative interactions/connections, illustrating how gene disruptions may lead to specific clinical outcomes in PMS. ASD; Autism spectrum disorder.