{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T07:19:15Z","timestamp":1778224755858,"version":"3.51.4"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T00:00:00Z","timestamp":1736294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"PCSIR","award":["ref. SW(HQ)DRS-2\/2021\/2065"],"award-info":[{"award-number":["ref. SW(HQ)DRS-2\/2021\/2065"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Novel <jats:italic>denovo<\/jats:italic> variants of exome sequences are major cause of pathogenic neurodevelopmental disorders with a dominant genetic mechanism that emphasize their heterogeneity and complex phenotypes. White Sutton syndrome and Gabriele-de-Vries syndrome are congenital neuro-impairments with overlap of severe intellectual disability, microcephaly, convulsions, seizures, delayed development, dysmorphism of faces, retinal diseases, movement disorders and autistic traits. <jats:italic>POGZ<\/jats:italic> gene codes for pogo transposable element-derived zinc-finger protein and <jats:italic>YY1<\/jats:italic> gene regulates transcription, chromatin, and RNA-binding proteins that have been associated with White Sutton and Gabriele-de-Vries syndromes, in recent data. We present probands of two unrelated consanguineous families with complicated, unexplained neurocognitive syndromic characteristics clinically undiagnosed. Objectives of the study were to identify altered genetics and protein characteristics underlying molecular pathological pathways in both the patients. Whole exome sequencing identifies novel, <jats:italic>denovo<\/jats:italic> missense variant NM_015100.4: c.776 C&gt;T (p. Pro259Leu) in exons 19 of <jats:italic>POGZ<\/jats:italic> gene and non-frameshift variant NM_003403.5: c.141_143delGGA (p. Glu47del) in exon 1 of <jats:italic>YY1<\/jats:italic> gene for White Sutton syndrome in eight years five-month-old girl and Gabriele-de-Vries syndrome in seven years eight months old boy residing in Rawalpindi and Chakwal districts of Punjab, Pakistan respectively. Protein modelling for identified variants predicts size and conformation modifications in mutated amino acid residues that lead to damaging effects in the conserved domains expressed as neurological pathophysiology. The present study widens the diversely ethnic and highly inbred gene pool of Punjab, Pakistan population for spontaneously originated deleterious mutations and contributes to the continuously expanding phenotypic canvas. Molecular genetic identification and personalized diagnosis for the patients suffering from complicated neurodevelopmental phenotypes, for better care, management of day-to-day activities and prolonged life span are the utmost hopes.<\/jats:p>","DOI":"10.1371\/journal.pone.0315597","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T19:26:32Z","timestamp":1736364392000},"page":"e0315597","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Denovo variants in POGZ and YY1 genes: The novel mega players for neurodevelopmental syndromes in two unrelated consanguineous families"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3957-9596","authenticated-orcid":true,"given":"Behjat Ul","family":"Mudassir","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mujaddid","family":"Mudassir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamal B.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3413-0578","authenticated-orcid":true,"given":"Zehra","family":"Agha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"issue":"1","key":"pone.0315597.ref001","doi-asserted-by":"crossref","DOI":"10.1146\/annurev-genet-061323-044915","article-title":"Meiosis: Dances Between Homologs","volume":"57","author":"D. Zickler","year":"2023","journal-title":"Annu. Rev. Genet."},{"issue":"6","key":"pone.0315597.ref002","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1002\/ajmg.a.63177","article-title":"\u201cPAK1 c.1409 T > a (p. Leu470Gln) de novo variant affects the protein kinase domain, leading to epilepsy, macrocephaly, spastic quadriplegia, and hydrocephalus: Case report and review of the literature,\u201d","volume":"191","author":"M. L. Corriveau","year":"2023","journal-title":"Am. J. Med. Genet"},{"issue":"10","key":"pone.0315597.ref003","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1002\/ajmg.a.63309","article-title":"The contribution of mosaicism to genetic diseases and de novo pathogenic variants","volume":"191","author":"R. J. Tinker","year":"2023","journal-title":"Am. J. Med. Genet. A."},{"issue":"1","key":"pone.0315597.ref004","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s13073-017-0498-x","article-title":"Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications","volume":"9","author":"A. B. Wilfert","year":"2017","journal-title":"Genome Med."},{"issue":"1","key":"pone.0315597.ref005","doi-asserted-by":"crossref","DOI":"10.1038\/s41380-022-01876-1","article-title":"Neurodevelopmental disorders\u2014high-resolution rethinking of disease modeling","volume":"28","author":"K. Khodosevich","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"pone.0315597.ref006","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.seizure.2023.03.002","article-title":"Who cares? A scoping review on intellectual disability, epilepsy and social care","volume":"107","author":"H. Newman","year":"2023","journal-title":"Seizure Eur. J. Epilepsy"},{"issue":"10399","key":"pone.0315597.ref007","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/S0140-6736(23)01048-6","article-title":"Adult epilepsy","volume":"402","author":"A. A. Asadi-Pooya","year":"2023","journal-title":"The Lancet"},{"issue":"4","key":"pone.0315597.ref008","article-title":"Congenital Microcephaly: A Debate on Diagnostic Challenges and Etiological Paradigm of the Shift from Isolated\/Non-Syndromic to Syndromic Microcephaly","volume":"12","author":"M. Asif","year":"2023","journal-title":"Art. no. 4"},{"key":"pone.0315597.ref009","first-page":"2023","article-title":"First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations | Molecular Syndromology | Karger Publishers","volume":"20","journal-title":"Accessed"},{"issue":"10","key":"pone.0315597.ref010","doi-asserted-by":"crossref","first-page":"e20517","DOI":"10.1016\/j.heliyon.2023.e20517","article-title":"Computer aided diagnosis of neurodevelopmental disorders and genetic syndromes based on facial images\u2013A systematic literature review","volume":"9","author":"F. Rosindo Daher De Barros","year":"2023","journal-title":"Heliyon"},{"key":"pone.0315597.ref011","unstructured":"\u201cNeurodevelopmental disorders: research and interventions beyond classifications | SpringerLink.\u201d Accessed: Nov. 20, 2023. [Online]. Available: https:\/\/link.springer.com\/article\/10.1007\/s00702-023-02596-8."},{"issue":"1","key":"pone.0315597.ref012","article-title":"Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring","volume":"13","author":"D. Nagy","year":"2022","journal-title":"GenesArt. no. 1"},{"issue":"2","key":"pone.0315597.ref013","doi-asserted-by":"crossref","DOI":"10.3390\/brainsci13020231","article-title":"The Genetics of Intellectual Disability","volume":"13","author":"S. Jansen","year":"2023","journal-title":"Brain Sci."},{"issue":"7487","key":"pone.0315597.ref014","doi-asserted-by":"crossref","DOI":"10.1038\/nature12929","article-title":"De novo mutations in schizophrenia implicate synaptic networks","volume":"506","author":"M. Fromer","year":"2014","journal-title":"Nature"},{"issue":"7831","key":"pone.0315597.ref015","doi-asserted-by":"crossref","DOI":"10.1038\/s41586-020-2832-5","article-title":"Evidence for 28 genetic disorders discovered by combining healthcare and research data","volume":"586","author":"J. Kaplanis","year":"2020","journal-title":"Nature"},{"issue":"8","key":"pone.0315597.ref016","doi-asserted-by":"crossref","DOI":"10.1038\/nn.4589","article-title":"Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains","volume":"20","author":"M. R. Geisheker","year":"2017","journal-title":"Nat. Neurosci."},{"issue":"7642","key":"pone.0315597.ref017","article-title":"Prevalence and architecture of de novo mutations in developmental disorders","volume":"542","author":"J. F. McRae","year":"2017","journal-title":"Nature"},{"issue":"3","key":"pone.0315597.ref018","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.ajhg.2017.08.004","article-title":"Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes","volume":"101","author":"S. H. Lelieveld","year":"2017","journal-title":"Am. J. Hum. Genet."},{"issue":"1","key":"pone.0315597.ref019","first-page":"8","article-title":"Discriminative features in White-Sutton syndrome: literature review and first report in Iran","volume":"34","author":"E. Esmaeilzadeh","year":"2024","journal-title":"Psychiatr. Genet."},{"issue":"6","key":"pone.0315597.ref020","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1136\/jmg-2023-109508","article-title":"Exploring the molecular pathways linking sleep phenotypes and POGZ-associated neurodevelopmental disorder","volume":"61","author":"B. P. Marquezini","year":"2024","journal-title":"J. Med. Genet."},{"issue":"9","key":"pone.0315597.ref021","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1093\/brain\/awac152","article-title":"A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders","volume":"145","author":"M. Conrow-Graham","year":"2022","journal-title":"Brain"},{"key":"pone.0315597.ref022","doi-asserted-by":"crossref","first-page":"148071","DOI":"10.1016\/j.gene.2023.148071","article-title":"Targeted sequencing identifies risk variants in 202 candidate genes for neurodevelopmental disorders","volume":"897","author":"N. Pang","year":"2024","journal-title":"Gene"},{"issue":"1","key":"pone.0315597.ref023","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1002\/ajmg.a.61380","article-title":"Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome),","volume":"182","author":"N. Assia Batzir","year":"2020","journal-title":"Am. J. Med. Genet"},{"key":"pone.0315597.ref024","doi-asserted-by":"crossref","first-page":"63","DOI":"10.2147\/TACG.S369483","article-title":"A Novel POGZ Variant in a Patient with Intellectual Disability and Obesity","volume":"15","author":"S. Giraldo-Ocampo","year":"2022","journal-title":"Appl. Clin. Genet."},{"key":"pone.0315597.ref025","doi-asserted-by":"crossref","first-page":"103727","DOI":"10.1016\/j.mcn.2022.103727","article-title":"Loss of POGZ alters neural differentiation of human embryonic stem cells","volume":"120","author":"L. Deng","year":"2022","journal-title":"Mol. Cell. Neurosci."},{"key":"pone.0315597.ref026","unstructured":"\u201cPathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes | Nature Communications.\u201d Accessed: Nov. 11, 2023. [Online]. Available: https:\/\/www.nature.com\/articles\/s41467-020-14697-z."},{"issue":"1","key":"pone.0315597.ref027","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12887-023-03972-9","article-title":"White-Sutton syndrome and congenital heart disease: case report and literature review","volume":"23","author":"J. Duan","year":"2023","journal-title":"BMC Pediatr."},{"issue":"1","key":"pone.0315597.ref028","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13052-021-01101-9","article-title":"Expanding the neurological and behavioral phenotype of White-Sutton syndrome: a case report","volume":"47","author":"B. Donnarumma","year":"2021","journal-title":"Ital. J. Pediatr."},{"key":"pone.0315597.ref029","first-page":"e2281","article-title":"Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review","author":"J. Yang","year":"2023","journal-title":"Mol. Genet. Genomic Med."},{"key":"pone.0315597.ref030","article-title":"Clinical features of patients with Yin Yang 1 deficiency causing Gabriele\u2010de Vries syndrome: A new case and review of the literature"},{"issue":"4","key":"pone.0315597.ref031","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1097\/MCD.0000000000000385","article-title":"Report of an unusual association of hydrosyringomyelia with Gabriele-de Vries syndrome in an Asian-Indian patient","volume":"30","author":"S. Balakrishnan","year":"2021","journal-title":"Clin. Dysmorphol."},{"issue":"9","key":"pone.0315597.ref032","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1002\/ajmg.a.61731","article-title":"Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome)","volume":"182","author":"M. T. Carminho-Rodrigues","year":"2020","journal-title":"Am. J. Med. Genet. A."},{"issue":"6","key":"pone.0315597.ref033","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.ajhg.2017.05.006","article-title":"YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction","volume":"100","author":"M. Gabriele","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"pone.0315597.ref034","article-title":"A rare epilepsy phenotype in Gabriele-de Vries syndrome: A new case and literature review. | EBSCOhost.\u201d","author":"H. Woo"},{"issue":"12","key":"pone.0315597.ref035","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.1002\/ajmg.a.40626","article-title":"A case of YY1-associated syndromic learning disability or Gabriele-de Vries syndrome with myasthenia gravis","volume":"176","author":"J. A. Morales-Rosado","year":"2018","journal-title":"Am. J. Med. Genet"},{"key":"pone.0315597.ref036","doi-asserted-by":"crossref","unstructured":"\u201cFirst Reported Case of Gabriele-de Vries Syndrome with Spinal Dysraphism.\u201d Accessed: Oct. 21, 2024. [Online]. Available: https:\/\/www.mdpi.com\/2227-9067\/10\/4\/623.","DOI":"10.3390\/children10040623"},{"key":"pone.0315597.ref037","unstructured":"\u201cA 9\u2010month\u2010old Chinese patient with Gabriele\u2010de Vries syndrome due to novel germline mutation in the YY1 gene\u2014Tan\u20142021\u2014Molecular Genetics & Genomic Medicine\u2014Wiley Online Library.\u201d Accessed: Nov. 17, 2023. [Online]. Available: https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.1582."},{"issue":"1","key":"pone.0315597.ref038","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-015-0253-0","article-title":"POGZ truncating alleles cause syndromic intellectual disability","volume":"8","author":"J. White","year":"2016","journal-title":"Genome Med."},{"issue":"7","key":"pone.0315597.ref039","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1002\/ajmg.a.38255","article-title":"Expanding the phenotypic spectrum of truncating POGZ mutations: Association with CNS malformations, skeletal abnormalities, and distinctive facial dysmorphism","volume":"173","author":"M. L. Dentici","year":"2017","journal-title":"Am. J. Med. Genet"},{"issue":"4","key":"pone.0315597.ref040","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/jhg.2015.156","article-title":"A novel de novo POGZ mutation in a patient with intellectual disability","volume":"61","author":"B. Tan","year":"2016","journal-title":"J. Hum. Genet."},{"issue":"5","key":"pone.0315597.ref041","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jaapos.2022.05.007","article-title":"Congenital corneal opacities as a new feature in an unusual case of White-Sutton syndrome","volume":"26","author":"M. F. Villalba","year":"2022","journal-title":"J. Am. Assoc. Pediatr. Ophthalmol. Strabismus"},{"issue":"5","key":"pone.0315597.ref042","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1148\/rg.2016160031","article-title":"White Matter Diseases with Radiologic-Pathologic Correlation","volume":"36","author":"N. Sarbu","year":"2016","journal-title":"RadioGraphics"},{"issue":"3","key":"pone.0315597.ref043","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/cge.13894","article-title":"Neuropsychological study in 19 French patients with White-Sutton syndrome and POGZ mutations","volume":"99","author":"A. Garde","year":"2021","journal-title":"Clin. Genet."},{"key":"pone.0315597.ref044","unstructured":"\u201cFrontiers | The Why of YY1: Mechanisms of Transcriptional Regulation by Yin Yang 1.\u201d Accessed: Nov. 18, 2023. [Online]. Available: https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2020.592164\/full."},{"issue":"21","key":"pone.0315597.ref045","doi-asserted-by":"crossref","first-page":"9804","DOI":"10.1073\/pnas.88.21.9804","article-title":"Isolation of a candidate repressor\/activator, NF-E1 (YY-1, delta), that binds to the immunoglobulin kappa 3\u2019 enhancer and the immunoglobulin heavy-chain mu E1 site,\u201d","volume":"88","author":"K. Park","year":"1991","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"8","key":"pone.0315597.ref046","doi-asserted-by":"crossref","first-page":"4339","DOI":"10.1021\/acs.chemrev.7b00470","article-title":"Beyond Transcription: Roles of Transcription Factors in Pre-mRNA Splicing","volume":"118","author":"X. Rambout","year":"2018","journal-title":"Chem. Rev."},{"issue":"6","key":"pone.0315597.ref047","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.molcel.2018.11.022","article-title":"Defining the Transcriptional Ecosystem","volume":"72","author":"M. A. D. Silveira","year":"2018","journal-title":"Mol. Cell"},{"key":"pone.0315597.ref048","unstructured":"\u201cIdentification of a likely pathogenic variant of YY1 in a patient with developmental delay.\u201d Accessed: Nov. 18, 2023. [Online]. Available: https:\/\/www.e-kjgm.org\/journal\/view.html?uid=324&&vmd=Full."},{"issue":"8","key":"pone.0315597.ref049","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/sj.onc.1209080","article-title":"Transcription factor YY1: structure, function, and therapeutic implications in cancer biology","volume":"25","author":"S. Gordon","year":"2006","journal-title":"Oncogene"},{"issue":"12","key":"pone.0315597.ref050","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.1093\/hmg\/ddv083","article-title":"HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain","volume":"24","author":"L. A. Jolly","year":"2015","journal-title":"Hum. Mol. Genet."},{"issue":"6","key":"pone.0315597.ref051","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/cge.13848","article-title":"Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE","volume":"98","author":"G. H. Seo","year":"2020","journal-title":"Clin. Genet."},{"key":"pone.0315597.ref052","article-title":"Gabriele-de Vries Syndrome Synonym: YY1 Intellectual Disability Syndrome","author":"M. Gabriele","year":"2019"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0315597","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T19:26:49Z","timestamp":1736364409000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0315597"}},"subtitle":[],"editor":[{"given":"Nejat","family":"Mahdieh","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,8]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0315597","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,8]]}}}