Variability in Phelan‐McDermid syndrome: The impact of the <i>PNPLA3</i> p.I148M polymorphism

Boccuto, Luigi; Abenavoli, Ludovico; Cascio, Lauren; Srikanth, Sujata; DuPont, Barbara R.; Mitz, Andrew R.; Rogers, R. Curtis; Phelan, Katy

doi:10.1111/cge.13451

Cited by 11 publications

(14 citation statements)

References 5 publications

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“…PNPLA3 has been associated with liver dysfunction in two individuals with PMS. 47 SULT4A1 is speculated to be part of a contiguous gene syndrome proximal to small 22q13 deletions within the PMS population. 10 Our hypothesis for this study was that SHANK3 may not be the only gene involved in the pathogenesis of seizures in PMS, as has been noted in the literature related to SHANK3 mutations in mice as well.…”

Section: Genetic Associationsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Genetic Associationsmentioning

confidence: 99%

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

et al. 2021

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“…Some studies have identified specific genes within the commonly deleted 22q13.3 region as potential contributors to the PMS phenotypes [26,27], suggesting, among the others, a role for the SULT4A1 gene in speech delay and abnormal cerebellar development and function, BRD1 in neuropsychiatric disorders [28], and GRAMD4, SCO2, and TYMP in mitochondrial abnormalities [29]. Moreover, the loss of one allele of the PNPLA3 gene due to a large 22q13.3 deletion can unmask a heterozygous variant, increasing the risk of liver disease, leading to gastrointestinal issues and abnormal responses to various drugs [30].…”

Section: Pathogenic Molecular Mechanisms In Pmsmentioning

confidence: 99%

Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome

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Meaddough

Sarasua

et al. 2021

Genes

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Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from < 50kb to > 9Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS.

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“…Clinical features are summarized in Table 3 with details following. Clinical traits for patients 2 and 5 were described in detail in a previous study [35] and only the most relevant features are reported herein. PMS 1.…”

Section: Clinical Features Of Selected Individuals With Pmsmentioning

confidence: 99%

Position effects of 22q13 rearrangements on candidate genes in Phelan-McDermid syndrome

et al. 2021

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Phelan-McDermid syndrome (PMS) is a multi-system disorder characterized by significant variability in clinical presentation. The genetic etiology is also variable with differing sizes of deletions in the chromosome 22q13 region and types of genetic abnormalities (e.g., terminal or interstitial deletions, translocations, ring chromosomes, or SHANK3 variants). Position effects have been shown to affect gene expression and function and play a role in the clinical presentation of various genetic conditions. This study employed a topologically associating domain (TAD) analysis approach to investigate position effects of chromosomal rearrangements on selected candidate genes mapped to 22q13 in 81 individuals with PMS. Data collected were correlated with clinical information from these individuals and with expression and metabolic profiles of lymphoblastoid cells from selected cases. The data confirmed TAD predictions for genes encompassed in the deletions and the clinical and molecular data indicated clear differences among individuals with different 22q13 deletion sizes. The results of the study indicate a positive correlation between deletion size and phenotype severity in PMS and provide evidence of the contribution of other genes to the clinical variability in this developmental disorder by reduced gene expression and altered metabolomics.

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Variability in Phelan‐McDermid syndrome: The impact of the PNPLA3 p.I148M polymorphism

Cited by 11 publications

References 5 publications

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

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

Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome

Position effects of 22q13 rearrangements on candidate genes in Phelan-McDermid syndrome

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