Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome

Abstract

Chromosome 22q13.3 deletion (Phelan McDermid) syndrome (PMS) is a rare genetic neurodevelopmental disorder resulting from deletions or other genetic variants on distal 22q. Pathological variants of the SHANK3 gene have been identified, but terminal chromosomal deletions including SHANK3 are most common. Terminal deletions disrupt up to 108 protein-coding genes. The impact of these losses is highly variable and includes both significantly impairing neurodevelopmental and somatic manifestations. The current review combines two metrics, prevalence of gene loss and predicted loss pathogenicity, to identify likely contributors to phenotypic expression. These genes are grouped according to function as follows: molecular signaling at glutamate synapses, phenotypes involving neuropsychiatric disorders, involvement in multicellular organization, cerebellar development and functioning, and mitochondrial. The likely most impactful genes are reviewed to provide information for future clinical and translational investigations.

Fig. 1

Gene selection and classification pipeline. PMS genes were selected for classification through a “functional discovery” literature review, as described in Materials and methods. PMS genes were independently rank ordered based on “probability of loss of function intolerance” (pLI) scores from the ExAC database (http://exac.broadinstitute.org/) and the population impact factor (PIF), as described in Materials and methods. Two overlapping groups were created: Group I (High pLI, pLI > 0.9 and PIF > 0.5) and Group II (High PIF, pLI > 0.7 and PIF > 0.95). Genes in either group with sufficient information were included in the gene reviews along with incidentally associated genes (see Table 1). Numbers in brackets are number of genes. Groups I and II share six genes

Fig. 2

Gene function discovery for 12 phenotype characteristics. Top part of figure shows the 12 characteristics + unclassified plotted across 9.2 Mbp of 22q13.3. The terminus is at the right edge of the plot. Numbers below the top plot show chromosome locations in millions of bp (Mbp) referenced to human genome build hg38. The bottom part is an expanded plot of the distal 1 Mbp of the chromosome. Symbols are the same within a characteristic. Pleiotropic genes are represented more than once in some cases. pLI estimation is evaluated separately.There are 64 unclassified genes, only genes with pLI>9 are plotted

Fig. 3

Probability of LoF intolerance for PMS genes. Genes with high pLI scores (p > 0.9) are plotted as a function of chromosome position. Inset graph expands the distal chromosome. Each gene is assigned to only one class