Dissecting the 22q13 region to explore the genetic and phenotypic diversity of patients with Phelan-McDermid syndrome

Vitrac, Aline; Leblond, Claire S.; Rolland, Thomas; Cliquet, Freddy; Mathieu, Alexandre; Maruani, Anna; Delorme, Richard; Schön, Michael P.; Grabrucker, Andreas M.; Ravenswaaij-Arts, Conny M. A. van; Phelan, Katy; Tabet, Anne‐Claude; Bourgeron, Thomas

doi:10.1016/j.ejmg.2023.104732

Cited by 11 publications

(21 citation statements)

References 116 publications

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“…We did not recalculate PIF values. Recent studies agree with our prediction that larger populations will continue to show an essentially uniform distribution of deletion sizes, 3,4,35 although there is some evidence for recurrent breakpoints. 4,38 We introduced PIF because of its clinical significance.…”

Section: Xrcc6supporting

confidence: 88%

“…55 An apparent enigma has been assigning diversity (including severity) of phenotypes to deletion size in the face of diverse phenotypes among SHANK3 variants. 3,[12][13][14] The human phenotype diversity from different SHANK3 variants may be attributable to the complexity of the gene and evidence for multiple pathogenic pathways. 4,86 Chromosomal deletions operate primarily through complete removal of genes, which is a LoF mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…4,86 Chromosomal deletions operate primarily through complete removal of genes, which is a LoF mechanism. Owing to the roughly uniform distribution of terminal deletion sizes in identified PMS cases 3,6 (discussed in Reference 26), the mean size deletion removes over 40 genes. Terminal deletions almost always remove all of SHANK3.…”

Section: Discussionmentioning

confidence: 99%

“…The vast majority of chromosome 22q13.3 deletions are terminal (PMS-SHANK3 related) of sizes ranging from about 100 kb to 9.3 Mb (roughly chr22:41518468-50 818 468). 3,4,6 Loss of these genes contributes to ID and ASD, as well as other characteristics of PMS. 4,25 Including SHANK3, 18 of these genes were identified in our earlier study as intolerant to heterozygous loss-of-function (genes with a high probability of being loss-of-function intolerant, high pLI genes).…”

mentioning

confidence: 99%

“…Since our original work, 26 others have repeated and extended the survey of genes associated with PMS using multiple and partially overlapping approaches to classifying the genes. 3,4,13 The present review draws from primary research publications since 2017 that might further illuminate the molecular interactions between SHANK3, and other genes disrupted by terminal deletions of 22q13.3 (see Methods).…”

mentioning

confidence: 99%

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

Mitz,

Boccuto,

Thurm

2024

Clinical Genetics

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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.

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