Phenotypic Variability in Phelan–McDermid Syndrome and Its Putative Link to Environmental Factors

chromosome 22 – Phelan-McDermid syndrome deletion at 22q13

Phelan-McDermid Syndrome phenotypic variability and its link to environmental factors.

Phelan-McDermid Syndrome (PMS) is categorized by different genetic abnormalities in the SHANK3 gene, chromosomal rearrangements and/or deletion at 22q13. The size of deletion may vary from 100 Kb to over 9 Mb and large deletions may involve many additional genes. It remains difficult to understand the complexity of the genotype-phenotype correlation for Phelan-McDermid Syndrome due to the wide array of its causes and how it looks in patients. The authors address other contributing factors in PMS phenotype, emphasizing 1) how haploinsufficiency for other genes in 22q13 can alter the reaction of metabolic pathways to environmental factors and 2) how there can be more downstream effects, where the environment can affect regulation via epigenetics. Regarding the former, an example of haploinsufficiency in 22q13 are PNPLA3 and PPARA variants which could lead to liver metabolic dysfunction. This reduction in metabolism could be amplified by environment like a high-calorie diet or alcohol. Similarly, haploinsufficiency of SCO2, TYMP, and SULT4A1 disrupt mitochondrial function, and certain drugs can worsen its effects like chemotherapeutics or by a lack of anti-oxidants. The authors also explain this multifactorial nature of PMS in SHANK3 variants where an inflammatory response acts on a gene, Trpv4, to indirectly disrupt SHANK3 at postsynaptic density. Regarding the authors’ second mechanism, the loss of one copy of BRD1 can lead to a genome wide methylation due to its involvement in histone acetylation. Patients with 22q13 deletions that include BRD1 may find pharmacogenomic counseling beneficial in identifying what drugs to avoid. CYP2D6 is involved in the metabolism of certain drugs as it is a part of a group of cytochrome p450 proteins; thus, a mutation in CYP2D6 could affect responses to several drugs. Although environmental factors do not have causative role in PMS, understanding their patient specific effects could improve clinical treatment.

Boccuto L. et al. “Phenotypic Variability in Phelan–McDermid Syndrome and Its Putative Link to Environmental Factors”. “Genes” (Basel) 2022, v.13:528.

Chromosome Disorder Outreach Inc. medical geneticist and medical advisor Dr. Iosif Lurie M.D. Ph.D examines newly published research studies to locate the most important and relevant for our members. Synopses of these articles are then posted to our website’s research pages. For more information on any article please contact info@chromodisorder.org