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

Abstract

Phelan–McDermid syndrome (PMS) is a multi-systemic disorder characterized by both genetic and phenotypic variability. Genetic abnormalities causing PMS span from pathogenic variants of the SHANK3 gene to chromosomal rearrangements affecting the 22q13 region and leading to the loss of up to over nine megabases. The clinical presentation of individuals with PMS includes intellectual disability, neonatal hypotonia, delayed or absent speech, developmental delay, and minor dysmorphic facial features. Several other features may present with differences in age of onset and/or severity: seizures, autism, regression, sleep disorders, gastrointestinal problems, renal disorders, dysplastic toenails, and disrupted thermoregulation. Among the causes of this phenotypic variability, the size of the 22q13 deletion has effects that may be influenced by environmental factors interacting with haploinsufficiency or hemizygous variants of certain genes. Another mechanism linking environmental factors and phenotypic variability in PMS involves the loss of one copy of genes like BRD1 or CYP2D6, located at 22q13 and involved in the regulation of genomic methylation or pharmacokinetics, which are also influenced by external agents, such as diet and drugs. Overall, several non-mutually exclusive genetic and epigenetic mechanisms interact with environmental factors and may contribute to the clinical variability observed in individuals with PMS. Characterization of such factors will help to better manage this disorder.

How Genetics and Genomics Advances Are Rewriting Pediatric Cancer Research and Clinical Care

“…NGS approaches help to identify the phenotypic variability in several syndromes [ 187 ], and characterize different driver genomic alterations, thereby allowing for the stratification of the main pediatric cancer subtypes. Furthermore, these studies have made it possible to evaluate high-risk and relapsed/refractory cases, thus guiding and speeding up the design of new clinical trials in the formulation of increasingly personalized therapies.…”

The psychiatric risk gene BRD1 modulates mitochondrial bioenergetics by transcriptional regulation

“…In addition, rare disruptive variants in BRD1 have been reported in both SZ and autism spectrum disorder (ASD) cases [ 9 , 15 – 17 ]. Patients with 22q13 microdeletions, which among other genes span BRD1 , further present with varying constellations of neurological, somatic, and behavioral symptoms including among many others neonatal hypotonia, developmental delay, intellectual disability, ASD, speech delay, elevated pain threshold, and seizures [ 18 , 19 ]. Intriguingly, these patients can also present with psychiatric disorders like OCD, affective disorder, and atypical bipolar [ 20 ], whereas SZ is not as common [ 21 , 22 ].…”