Genetic and metabolic profiling of individuals with Phelan‐McDermid syndrome presenting with seizures

Abstract

Phelan-McDermid syndrome (PMS) (OMIM*606232) is a rare genetic disorder characterized by intellectual disability, autistic features, speech delay, minor dysmorphia, and seizures. This study was conducted to investigate the prevalence of seizures and the association with genetic and metabolic features since there has been little research related to seizures in PMS. For 57 individuals, seizure data was collected from caregiver interviews, genetic data from existing cytogenetic records and Sanger sequencing for nine 22q13 genes, and metabolic profiling from the Phenotype Mammalian MicroArray (PM-M) developed by Biolog. Results showed that 46% of individuals had seizures with the most common type being absence and grand-mal seizures.Seizures were most prevalent in individuals with pathogenic SHANK3 mutations (70%), those with deletion sizes >4 Mb (16%), and those with deletion sizes <4 Mb (71%) suggesting involvement of genes in addition to SHANK3. Additionally, a 3 Mb genomic region on 22q13.31 containing the gene TBC1D22A, was found to be significantly associated with seizure prevalence. A distinct metabolic profile was identified for individuals with PMS with seizures and suggested among other features a disrupted utilization of main energy sources using Biolog plates. The results of this study will be helpful for clinicians and families in anticipating seizures in these children and for researchers to identify candidate genes for the seizure phenotype.

Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

“…SHANK3 is a scaffolding protein of the postsynaptic density of glutamatergic synapses 11 , 12 , 13 ; additional disrupted genes within larger class II mutations have been implicated in processes related to stress and inflammation, mitochondrial function, neuronal differentiation, and cellular metabolism. 5 , 14 , 15 , 16 Molecular profiling of tissues derived from PMS participants, albeit scarce, confirm these functional categories and support the notion of unique molecular programs underlying distinct clinical subtypes. For example, increased severity of PMS phenotypes and larger 22q13.3 deletions have been associated with alterations in mitochondrial complex I and IV activity, 14 changes in peripheral blood epi-signatures enriched for neuronal development and intracellular signaling, 15 and metabolomic changes implicated in metabolic stress and response to cytokines regulating inflammation, 15 , 16 all poised to influence neurodevelopment.…”

“… 5 , 14 , 15 , 16 Molecular profiling of tissues derived from PMS participants, albeit scarce, confirm these functional categories and support the notion of unique molecular programs underlying distinct clinical subtypes. For example, increased severity of PMS phenotypes and larger 22q13.3 deletions have been associated with alterations in mitochondrial complex I and IV activity, 14 changes in peripheral blood epi-signatures enriched for neuronal development and intracellular signaling, 15 and metabolomic changes implicated in metabolic stress and response to cytokines regulating inflammation, 15 , 16 all poised to influence neurodevelopment. Notably, even transcriptomics of peripheral blood and postmortem brain tissue from participants with idiopathic ASD implicate changes related to inflammation, cellular proliferation/metabolism and immune dysfunction, 17 , 18 , 19 supporting the notion that ongoing dysregulation of the immune system echoes alterations in the central nervous system (CNS).…”

Head Size in Phelan–McDermid Syndrome: A Literature Review and Pooled Analysis of 198 Patients Identifies Candidate Genes on 22q13

“…There are three genes that are proposed as the main candidates for macrocephaly ( TBC1D22A , CELSR1 , and GRAMD4 ) given their location in the highly associated genomic regions, proposed function, or high probability of loss of function intolerance [ 71 ]. TBC1D22A has been associated with structural or functional abnormalities of the head or the central nervous system (CNS), such as seizures, schizophrenia, or bipolar disorder [ 72 , 73 ]. Boucherie et al (2018) found Celsr1-deficient mice to have microcephaly and cortical hypoplasia [ 74 ].…”

Large deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

“…SHANK3 is a scaffolding protein of the postsynaptic density of glutamatergic synapses [11][12][13] ; additional disrupted genes within larger Class II mutations have been implicated in processes related to stress and inflammation, mitochondrial function, neuronal differentiation, and cellular metabolism [14][15][16][17] . Molecular profiling of tissues derived from PMS participants, albeit scarce, confirm these functional categories and support the notion of unique molecular programs underlying distinct clinical subtypes.…”

“…Molecular profiling of tissues derived from PMS participants, albeit scarce, confirm these functional categories and support the notion of unique molecular programs underlying distinct clinical subtypes. For example, increased severity of PMS phenotypes and larger 22q13.3 deletions have been associated with alterations in mitochondrial complex I and IV activity 15 , changes in peripheral blood epi-signatures enriched for neuronal development and intracellular signaling 16 , and metabolomic changes implicated in metabolic stress and response to cytokines regulating inflammation [16][17] , all poised to influence neurodevelopment. Notably, even transcriptomics of peripheral blood and postmortem brain tissue from participants with idiopathic ASD implicate changes related to inflammation, cellular proliferation/metabolism and immune dysfunction [18][19][20] , supporting the notion that ongoing dysregulation of the immune system echoes alterations in the central nervous system (CNS).…”