{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:22:57Z","timestamp":1793287377220,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>We describe a sporadic case of a pure, tandem, interstitial chromosome 4q duplication, arr[hg19] 4q28.1q32.3 (127,008,069-165,250,477) x3 in a boy born at 36 weeks of gestation. He presented with microcephaly (head circumference &amp;lt;1<jats:sup>st<\/jats:sup> percentile), short stature (height &amp;lt;2<jats:sup>nd<\/jats:sup> percentile) and poor weight gain (weight &amp;lt;3<jats:sup>rd<\/jats:sup> percentile). Hypospadias and horseshoe shaped kidneys were also revealed following a urinary tract ultrasound. Biochemical analysis revealed normal growth hormone and thyroid hormone levels. While gross and fine motor skill development was in line with his age, speech delay was observed. This patient adds to a group of more than 30 cases of pure 4q tandem duplication with common and differing phenotypic presentations. Using a retrospective analysis of previous case studies alongside the current case and bioinformatics analysis of the duplicated region, we deduced the most likely dosage sensitive genes for some of the major phenotypes in the patient. The positive predictive value (PPV) was calculated for each gene and phenotype and was derived by comparing the previously reported patients who have gene duplications and an associated phenotype versus those who had the gene duplications but were unaffected. Thus, the growth retardation phenotype may be associated with <jats:italic>NAA15<\/jats:italic> duplication, speech delay with <jats:italic>GRIA2<\/jats:italic> and microcephaly with <jats:italic>PLK4<\/jats:italic> duplication. Functional studies will help in confirming the observations and elucidating the mechanisms. However, our study highlights the importance of analysing case reports with pure duplications in defining phenotype-gene relationships and in improving our knowledge of the function of precise chromosomal regions.<\/jats:p>","DOI":"10.3389\/fendo.2021.783235","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T12:17:25Z","timestamp":1643890645000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly"],"prefix":"10.3389","volume":"12","author":[{"given":"Umm-Kulthum Ismail","family":"Umlai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basma","family":"Haris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Hussain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puthen Veettil","family":"Jithesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36396","article-title":"Molecular Characterization of Distal 4q Duplication in Two Patients Using Oligonucleotide Array-Based Comparative Genomic Hybridization (oaCGH) Analysis","volume":"164","author":"Thapa","year":"2014","journal-title":"Am J Med Genet Part A"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13073-019-0675-1","article-title":"From Cytogenetics to Cytogenomics: Whole-Genome Sequencing as a First-Line Test Comprehensively Captures the Diverse Spectrum of Disease-Causing Genetic Variation Underlying Intellectual Disability","volume":"11","author":"Lindstrand","year":"2019","journal-title":"Genome Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1002\/ajmg.1320570116","article-title":"Further Contribution to the Description of Phenotypes Associated With Partial 4q Duplication","volume":"57","author":"Zollino","year":"1995","journal-title":"Am J Med Genet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.46","article-title":"Recurrent 70.8\u2009Mb 4q22.2q32.3 Duplication Due to Ovarian Germinal Mosaicism","volume":"18","author":"Tosca","year":"2010","journal-title":"Eur J Hum Genet 2010 18:8"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19971212)73:2<119::AID-AJMG3>3.0.CO;2-P","article-title":"Familial Tandem Duplication of Bands Q31.1 to Q32.3 on Chromosome 4 With Mild Phenotypic Effect","volume":"73","author":"Goodman","year":"1997","journal-title":"J Med Genet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1001\/archneurol.2011.802","article-title":"Dive D. Partial Trisomy 4q Associated With Young-Onset Dopa-Responsive Parkinsonism","volume":"69","author":"Garraux","year":"2012","journal-title":"Arch Neurol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30643","article-title":"Duplication of Chromosome 4q: Renal Pathology of Two Siblings","volume":"134","author":"Otsuka","year":"2005","journal-title":"Am J Med Genet Part A"},{"key":"B8","first-page":"46","article-title":"A Case of an Interstitial Tandem .Direct Duplication of Long Arm of Chromosome 4: 46, XY, Dup (4) (Q25q31.3) De Novo","volume":"46","author":"Muraki","year":"1997","journal-title":"Hiroshima J Med Sci"},{"key":"B9","article-title":"MYOCLONIC ASTATIC EPILEPSY IN A PATIENT WITH A DE NOVO 4q21.22q21.23 MICRODUPLICATION - ProQuest","volume":"26","author":"Ottaviani","year":"2015","journal-title":"Genet Couns"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.anngen.2004.07.007","article-title":"Large Duplication 4q25-Q34 With Mild Clinical Effect","volume":"47","author":"Elghezal","year":"2004","journal-title":"Ann Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990903)86:1<51::AID-AJMG9>3.0.CO;2-W","article-title":"Partial Duplication of 4q12q13 Leads to a Mild Phenotype - PubMed","volume":"86","author":"Shashi","year":"1999","journal-title":"Americal J Med Genet"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3109\/13816819009012961","article-title":"Trisomy 4q With Morning Glory Disc Anomaly","volume":"11","author":"Nucci","year":"2009","journal-title":"Ophthalmic Paediatr Genet"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.5546\/aap.2012.e59","article-title":"Presentaci\u00f3n De Casos Cl\u00ednicos Duplicaci\u00f3n Parcial Del Cromosoma 4 Asociada Con Coloboma Ocular Bilateral Partial Duplication of Chromosome 4 in a Patient With Bilateral Ocular Coloboma","volume":"110","author":"Collia","year":"2012","journal-title":"Arch Argent Pediatr"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320460114","article-title":"Cytogenetic and Molecular Identification of a De Novo Direct Duplication of the Long Arm of Chromosome 4(Q21.3\u2192Q31.3)","volume":"46","author":"Jeziorowska","year":"1993","journal-title":"Am J Med Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19960329)62:3<297::AID-AJMG18>3.0.CO;2-F","article-title":"De Novo Interstitial Tandem Duplication of Chromosome 4(Q21-28)","volume":"62","author":"Guillen Navarro","year":"1996","journal-title":"Am J Med Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320390412","article-title":"Interstitial Tandem Direct Duplication of the Long Arm of Chromosome 4 (Q23-Q27) and Possible Assignment of the Structural Gene Encoding Human Aspartylglucosaminidase to This Segment","volume":"39","author":"Halal","year":"1991","journal-title":"Am J Med Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1754.2004.00411.x","article-title":"De Novo Interstitial Duplication 4(Q28.1q35) Associated With Choanal Atresia","volume":"40","author":"Lin","year":"2004","journal-title":"J Paediatrics Child Health"},{"key":"B18","article-title":"Midro AT. Partial Trisomy of Long Arm of Chromosome 4 as a Result of Dir Dup (4)(Q27q31.3) De Novo","volume":"17","author":"Hubert","year":"2006","journal-title":"Genet Couns (Geneva Switzerland)"},{"key":"B19","article-title":"Partial 4q Trisomy. Apropos of 3 Cases","volume":"18","author":"Dutrillaux","year":"1975","journal-title":"Ann Genet"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000013094","article-title":"Clinical, Cytogenetic, and Molecular Findings in a Fetus With Ultrasonic Multiple Malformations, 4q Duplication, and 7q Deletion: A Case Report and Literature Review","volume":"97","author":"Yue","year":"2018","journal-title":"Medicine"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1557","article-title":"High Risk for Unbalanced Segregation of Some Reciprocal Translocations: A Large Pedigree Containing Distal 4q Trisomy From T(4;7)(Q28;P22)","volume":"103","author":"Francisco-Bagnariolli","year":"2001","journal-title":"Am J Med Genet"},{"key":"B22","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1093\/bfgp\/elv020","article-title":"Human Inversions and Their Functional Consequences","volume":"14","author":"Puig","year":"2015","journal-title":"Briefings Funct Genomics"},{"key":"B23","unstructured":"Genotype\u2013phenotype Correlation in Fabry Disease\n            RiesM\n            GalA\n          Fabry Disease: Perspectives From 5 Years of FOS2006"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3792","article-title":"Targeted Sequencing Identifies 91 Neurodevelopmental-Disorder Risk Genes With Autism and Developmental-Disability Biases","volume":"49","author":"Stessman","year":"2017","journal-title":"Nat Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/ajmg.b.32574","article-title":"Exome Sequencing Reveals NAA15 and PUF60 as Candidate Genes Associated With Intellectual Disability","volume":"177","author":"Zhao","year":"2018","journal-title":"Am J Med Genet Part B: Neuropsychiatr Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/pcp\/pcy135","article-title":"N\u03b1-Acetyltransferases 10 and 15 are Required for the Correct Initiation of Endosperm Cellularization in Arabidopsis","volume":"59","author":"Chen","year":"2018","journal-title":"Plant Cell Physiol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ncomms8640","article-title":"Downregulation of N-Terminal Acetylation Triggers ABA-Mediated Drought Responses in Arabidopsis","volume":"6","author":"Linster","year":"2015","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/jxb\/erw257","article-title":"Protein N-Terminal Acetylation is Required for Embryogenesis in Arabidopsis","volume":"67","author":"Feng","year":"2016","journal-title":"J Exp Bot"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20150168","article-title":"The N-Terminal Acetyltransferase Naa10 is Essential for Zebrafish Development","volume":"35","author":"Ree","year":"2015","journal-title":"Biosci Rep"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgu132","article-title":"Inhibition of STAT5a by Naa10p Contributes to Decreased Breast Cancer Metastasis","volume":"35","author":"Zeng","year":"2014","journal-title":"Carcinogenesis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3258","article-title":"Arrest Defective 1 Autoacetylation Is a Critical Step in Its Ability to Stimulate Cancer Cell Proliferation","volume":"70","author":"Seo","year":"2010","journal-title":"Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/j.ajhg.2018.03.004","article-title":"Truncating Variants in NAA15 Are Associated With Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies","volume":"102","author":"Cheng","year":"2018","journal-title":"Am J Hum Genet"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009474","article-title":"Dosage Sensitivity Shapes the Evolution of Copy-Number Varied Regions","volume":"5","author":"Schuster-B\u00f6ckler","year":"2010","journal-title":"PloS One"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1207726109","article-title":"Gene Balance Hypothesis: Connecting Issues of Dosage Sensitivity Across Biological Disciplines","volume":"109","author":"Birchler","year":"2012","journal-title":"Proc Natl Acad Sci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1101\/gad.327494.119","article-title":"Protein Aggregation Mediates Stoichiometry of Protein Complexes in Aneuploid Cells","volume":"33","author":"Brennan","year":"2019","journal-title":"Genes Dev"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.97","article-title":"Partial Deletion of GLRB and GRIA2 in a Patient With Intellectual Disability","volume":"21","author":"Hackmann","year":"2012","journal-title":"Eur J Hum Genet"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-10910-w","article-title":"AMPA Receptor GluA2 Subunit Defects are a Cause of Neurodevelopmental Disorders","volume":"10","author":"Salpietro","year":"2019","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.11.004","article-title":"De Novo Variants in GRIA4 Lead to Intellectual Disability With or Without Seizures and Gait Abnormalities","volume":"101","author":"Martin","year":"2017","journal-title":"Am J Hum Genet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3122","article-title":"Mutations in PLK4, Encoding a Master Regulator of Centriole Biogenesis, Cause Microcephaly, Growth Failure and Retinopathy","volume":"46","author":"Martin","year":"2014","journal-title":"Nat Genet"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.7554\/ELIFE.46054","article-title":"Plk4 Promotes Centriole Duplication by Phosphorylating Stil to Link the Procentriole Cartwheel to the Microtubule Wall","volume":"8","author":"Moyer","year":"2019","journal-title":"eLife"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12031-021-01881-z","article-title":"Overexpression of the PLK4 Gene as a Novel Strategy for the Treatment of Autosomal Recessive Microcephaly by Improving Centrosomal Dysfunction","author":"Xu","year":"2021","journal-title":"J Mol Neurosci"},{"key":"B42","article-title":"Severe short stature, Growth Hormone (GH) Deficiency, Hypospadias, and Microcephaly: New Insights into the Role of Chromosome 4 Long Arm Duplication","volume":"89","author":"Haris","year":"2018","journal-title":"ESPE Abstracts"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.783235\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T12:17:34Z","timestamp":1643890654000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.783235\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,3]]},"references-count":42,"alternative-id":["10.3389\/fendo.2021.783235"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.783235","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,3]]},"article-number":"783235"}}