{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:25:34Z","timestamp":1789647934673,"version":"4.0.0"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Phelan\u2013McDermid 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.<\/jats:p>","DOI":"10.3390\/genes13030528","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:26:22Z","timestamp":1647811582000},"page":"528","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Phenotypic Variability in Phelan\u2013McDermid Syndrome and Its Putative Link to Environmental Factors"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2017-4270","authenticated-orcid":false,"given":"Luigi","family":"Boccuto","sequence":"first","affiliation":[{"name":"Healthcare Genetics Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Mitz","sequence":"additional","affiliation":[{"name":"Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5922-1524","authenticated-orcid":false,"given":"Ludovico","family":"Abenavoli","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Sarasua","sequence":"additional","affiliation":[{"name":"Healthcare Genetics Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Bennett","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Indiana University School of Medicine\/Riley Hospital for Children, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis","family":"Rogers","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"DuPont","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center, Greenwood, SC 29646, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Phelan","sequence":"additional","affiliation":[{"name":"Genetics Laboratory, Florida Cancer Specialists &Research Institute, Fort Myers, FL 33916, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,17]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Mirzaa, G.M., and Amemiya, A. (1993). Phelan-McDermid Syndrome. GeneReviews\u00ae, University of Washington."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1866-1955-6-39","article-title":"Phelan-McDermid syndrome: A review of the literature and practice parameters for medical assessment and monitoring","volume":"6","author":"Kolevzon","year":"2014","journal-title":"J. Neurodev. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Phelan, K., Rogers, R.C., and Boccuto, L. (2021). Deletion 22q13 syndrome: Phelan\u2013McDermid syndrome. Cassidy and Allanson\u2019s Management of Genetic Syndromes, Wiley.","DOI":"10.1002\/9781119432692.ch22"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/s00439-014-1423-7","article-title":"Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome","volume":"133","author":"Sarasua","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/2040-2392-4-18","article-title":"Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency","volume":"4","author":"Soorya","year":"2013","journal-title":"Mol. Autism"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s13229-018-0205-9","article-title":"Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations","volume":"9","author":"Siper","year":"2018","journal-title":"Mol. Autism"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1002\/ajmg.a.36513","article-title":"Interstitial 22q13 deletions not involving SHANK3 gene: A new contiguous gene syndrome","volume":"164","author":"Disciglio","year":"2014","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13023-022-02180-5","article-title":"Phelan-McDermid syndrome: A classification system after 30 years of experience","volume":"17","author":"Phelan","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41431-017-0042-x","article-title":"Identification of 22q13 genes most likely to contribute to Phelan McDermid syndrome","volume":"26","author":"Mitz","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1002\/ajmg.a.62222","article-title":"Genotype-phenotype correlation in Phelan-McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes","volume":"185","author":"Ricciardello","year":"2021","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41525-017-0035-2","article-title":"A framework to identify contributing genes in patients with Phelan-McDermid syndrome","volume":"2","author":"Tabet","year":"2017","journal-title":"NPJ Genom. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"490","DOI":"10.5604\/01.3001.0010.0274","article-title":"Genetic and Epigenetic Profile of Patients With Alcoholic Liver Disease","volume":"16","author":"Boccuto","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6969","DOI":"10.3748\/wjg.v19.i41.6969","article-title":"PNPLA3 I148M polymorphism and progressive liver disease","volume":"19","author":"Dongiovanni","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/cge.13451","article-title":"Variability in Phelan-McDermid syndrome: The impact of the PNPLA3 p.I148M polymorphism","volume":"94","author":"Boccuto","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6489","DOI":"10.1038\/s41598-020-63579-3","article-title":"Hepatocyte-specific deletion of Ppar\u03b1 promotes NAFLD in the context of obesity","volume":"10","author":"Polizzi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.ajpath.2016.10.022","article-title":"Global Deletion of Glutathione S-Transferase A4 Exacerbates Developmental Nonalcoholic Steatohepatitis","volume":"187","author":"Ronis","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/j.jhep.2018.12.037","article-title":"Hepatic PPAR\u03b1 is critical in the metabolic adaptation to sepsis","volume":"70","author":"Paumelle","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"19544","DOI":"10.1038\/srep19544","article-title":"Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome","volume":"6","author":"Frye","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Srikanth, S., Jain, L., Zepeda-Mendoza, C., Cascio, L., Jones, K., Pauly, R., DuPont, B., Rogers, C., Sarasua, S., and Phelan, K. (2021). Position effects of 22q13 rearrangements on candidate genes in Phelan-McDermid syndrome. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253859"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.ajhg.2013.04.005","article-title":"Mutations in SCO2 are associated with autosomal-dominant high-grade myopia","volume":"92","author":"Powell","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/15513","article-title":"Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene","volume":"23","author":"Papadopoulou","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1124\/dmd.119.089714","article-title":"Interaction of the Brain-Selective Sulfotransferase SULT4A1 with Other Cytosolic Sulfotransferases: Effects on Protein Expression and Function","volume":"48","author":"Idris","year":"2020","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1124\/dmd.119.088047","article-title":"SULT4A1 Protects Against Oxidative-Stress Induced Mitochondrial Dysfunction in Neuronal Cells","volume":"47","author":"Hossain","year":"2019","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1124\/dmd.117.077560","article-title":"Generation and Characterization of SULT4A1 Mutant Mouse Models","volume":"46","author":"Garcia","year":"2018","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cores, \u00c1., Piquero, M., Villacampa, M., Le\u00f3n, R., and Men\u00e9ndez, J.C. (2020). NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases. Biomolecules, 10.","DOI":"10.3390\/biom10060904"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kim, M.J., and Jeon, J.H. (2022). Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052846"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2668","DOI":"10.1002\/ajmg.a.40666","article-title":"Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders","volume":"176","author":"Li","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Almandil, N.B., Alkuroud, D.N., AbdulAzeez, S., AlSulaiman, A., Elaissari, A., and Borgio, J.F. (2019). Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16040658"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tzanoulinou, S., Musardo, S., Contestabile, A., Bariselli, S., Casarotto, G., Magrinelli, E., Jiang, Y.H., Jabaudon, D., and Bellone, C. (2022). Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism. Mol. Psychiatry, 1\u201315.","DOI":"10.1101\/2021.10.13.464215"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.biopsych.2016.08.037","article-title":"The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice","volume":"82","author":"Qvist","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4495","DOI":"10.1007\/s12035-021-02432-8","article-title":"Inactivation of the Schizophrenia-associated BRD1 gene in Brain Causes Failure-to-thrive, Seizure Susceptibility and Abnormal Histone H3 Acetylation and N-tail Clipping","volume":"58","author":"Paternoster","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13148-020-00990-7","article-title":"DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome","volume":"13","author":"Schenkel","year":"2021","journal-title":"Clin. Epigenet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1089\/omi.2018.0033","article-title":"Genomics and Epigenomics of Congenital Heart Defects: Expert Review and Lessons Learned in Africa","volume":"22","author":"Thomford","year":"2018","journal-title":"Omics J. Integr. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Tseng, C.J., McDougle, C.J., Hooker, J.M., and Z\u00fcrcher, N.R. (2021). Epigenetics of Autism Spectrum Disorder: Histone Deacetylases. Biol. Psychiatry.","DOI":"10.1016\/j.biopsych.2021.11.021"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13229-022-00487-5","article-title":"Nonshared environmental factors in the aetiology of autism and other neurodevelopmental conditions: A monozygotic co-twin control study","volume":"13","author":"Isaksson","year":"2022","journal-title":"Mol. Autism"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Dyar, B., Meaddough, E., Sarasua, S.M., Rogers, C., Phelan, K., and Boccuto, L. (2021). Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome. Genes, 12.","DOI":"10.3390\/genes12081192"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Taylor, C., Crosby, I., Yip, V., Maguire, P., Pirmohamed, M., and Turner, R.M. (2020). A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes, 11.","DOI":"10.3390\/genes11111295"},{"key":"ref_38","first-page":"511","article-title":"Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models","volume":"108","author":"Rice","year":"2000","journal-title":"Environ. Health Perspect."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1101\/gad.333906.119","article-title":"Phf21b imprints the spatiotemporal epigenetic switch essential for neural stem cell differentiation","volume":"34","author":"Basu","year":"2020","journal-title":"Genes Dev."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/528\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:37:55Z","timestamp":1760135875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/3\/528"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,17]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["genes13030528"],"URL":"https:\/\/doi.org\/10.3390\/genes13030528","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,17]]}}}