Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan-McDermid syndrome

Abstract

Chromosome 22q13.3 deletion (Phelan-McDermid) syndrome (PMS, OMIM 606232) is a rare genetic condition that impacts neurodevelopment. PMS most commonly results from heterozygous contiguous gene deletions that include the SHANK3 gene or likely pathogenic variants of SHANK3 (PMS-SHANK3 related). Rarely, chromosomal rearrangements that spare SHANK3 share the same general phenotype (PMS-SHANK3 unrelated). Very recent human and model system studies of genes that likely contribute to the PMS phenotype point to overlap in gene functions associated with neurodevelopment, synaptic formation, stress/inflammation and regulation of gene expression. In this review of recent findings, we describe the functional overlaps between SHANK3 and six partner genes of 22q13.3 (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, and TCF20), which suggest a model that explains the commonality between PMS-SHANK3 related and PMS-SHANK3 unrelated classes of PMS. These genes are likely not the only contributors to neurodevelopmental impairments in the region, but they are the best documented to date. The review provides evidence for the overlapping and likely synergistic contributions of these genes to the PMS phenotype.

Keywords: Phelan‐McDermid syndrome; gene expression; inflammation; neurodevelopment; synaptic function.

Figure 1.

Workflow of current study. The prior study (Mitz AR, Philyaw TJ, Boccuto L et al: Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome. Eur J Hum Genet 2018; 26: 293–302) was a review and multidimensional categorization of all 108 genes associated with the largest Phelan McDermid syndrome (PMS, OMIM 606232) terminal deletions of 22q13.3. The pipeline from that study is summarized in the upper half of the figure (c.f. Figure 1 of Mitz et al). The current study draws from both the earlier unbiased measures and efforts to find sufficient information on the molecular biology of each gene to review its probably role in PMS. PubMed (https://pubmed.ncbi.nlm.nih.gov/) was searched to collect new information on 17 protein coding genes, which led to the identification of six genes with substantial new information. These genes were re-evaluated using newer constraint metrics (gnomAD 4.0, https://gnomad.broadinstitute.org/) and then compared to SHANK3 to identify mechanistic overlap. ExAC pLI is Probability of being Loss-of-function Intolerant from the ExAC database, now available on the gnomAD database. PIF is Population Impact Factor, the proportion of terminal deletions missing the gene. Group I requires ExAC pLI > .9. Group II requires PIF > .95. Groups are not mutually exclusive. Numbers in brackets are numbers of genes.

Figure 2.

Genome browser snapshot and genes reviewed in this study. Custom tracks using the GRCh38/hg38 build of the UCSC Genome Browser (https://genome.ucsc.edu/index.html) locating SHANK3 and the six genes reviewed in the study (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, and TCF20).

Figure 3.

Overlapping contributions of SHANK3 to Phelan McDermid syndrome (PMS, OMIM 606232) with the genes reviewed in this study. Including SHANK3, seven genes of 22q13.3 have overlapping contributions to four key processes associated with the PMS phenotype: neurodevelopment, synaptic formation/maintenance, mitochondrial function/stress/inflammation/injury, and gene regulation/expression.