A Familial Chromosome 4p16.3 Terminal Microdeletion That Does Not Cause Wolf-Hirschhorn (4p-) syndrome

A Familial Chromosome 4p16.3 Terminal Microdeletion That Does Not Cause Wolf-Hirschhorn (4p-) syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Familial Chromosome 4p16.3 Terminal Microdeletion That Does Not Cause Wolf-Hirschhorn (4p-) syndrome Mayowa Azeez Osundiji, Eva Kahn, Brendan Lanpher This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4566567/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Nov, 2024 Read the published version in Chromosome Research → Version 1 posted 9 You are reading this latest preprint version Abstract Chromosome 4p16.3 microdeletions are known to cause Wolf–Hirschhorn syndrome (WHS), which is characterized by a distinct craniofacial gestalt and multiple congenital malformations. The 4p16.3 region encompasses WHS critical region 1 (WHSCR1) and 2 (WHSCR2). The WHSCR contains several genes that have been implicated in the WHS phenotype including: WHS candidate 1 [ WHSC1 (aka NSD2 , OMIM 602952)], WHS candidate 2 [ WHSC2 (aka NELFA , OMIM 606026)], and LETM1 (OMIM 604407). Although several patients harboring 4p16.3 microdeletions that are associated with WHS phenotypes have been reported, the precise molecular underpinnings of WHS are subjects of active investigations. The potential role(s) of genes within the 4p16.3 are increasingly being investigated. Here we report the first documented case of 4p16.3 terminal microdeletion that is not associated with the characteristic WHS phenotype. We studied Individual A (7-months-old female) and her father, Individual B (27-year-old), who both carry a terminal 4p16.3 microdeletion (about 555kb) that is distal to the WHSCR [(WHSCR1) and (WHSCR2)], and does not include WHSC1 , WHSC2 , or LETM1 . Overall, our findings expand the phenotypic spectrum associated with 4p16.3 micro deletions and suggest that, in some individuals, microdeletions within 4p16.3 region may not be sufficient to cause WHS. WHS microdeletion chromosome Figures Figure 1 INTRODUCTION Wolf-Hirschhorn syndrome (WHS, OMIM 194190) is a chromosomal disorder that is characterized by a distinct craniofacial gestalt [the Greek-warrior helmet appearance (wide forehead with prominent glabella), large and protruding eyes, hypertelorism, down-turned corners of the mouth, and micrognathia], pre and post-natal growth restriction (including microcephaly), intellectual disability, hypotonia, seizures and congenital malformations ( 1 ). Heterozygous partial deletion of the distal segment of the p arm of chromosome 4 (4p) results in WHS. The initial cases of WHS were mapped to the 4pter region using conventional cytogenetic techniques ( 2 – 4 ). WHS cases in the clinical scientific literature have been quite diverse, ranging from isolated 4p heterozygous deletions without other cytogenetic abnormalities to cases of complex cytogenetic profiles that comprise of derivative forms of chromosome 4 possibly arising from a ring chromosome 4, a 4p-mosaicism, or an unbalanced translocation ( 5 ). WHS phenotype varies from mild to severe depending, at least in part, on the size and location of the deleted segment around the 4p16.3 region ( 6 – 8 ). Genetic testing technologies have evolved significantly in the last few decades resulting in an improved mapping of the 4p16.3 region ( 6 , 9 – 11 ). Since the initial discovery of WHS in the 1960s ( 2 – 4 ), several patients who harbor 4p16.3 microdeletions that are associated with milder WHS phenotypes have been reported ( 6 , 8 , 12 ). These observations have led to the notion that WHS phenotypes potentially result from the cumulative effect of the combined haploinsufficiency of several causative genes around the 4p16.3 region. Studies of the 4p16.3 region subsequently identified the WHS critical region (WHSCR) 1 and 2, WHSCR1 and WHSCR2 ( 6 , 11 ). Candidate genes within the WHSCR that may underpin the WHS phenotype have been described including: WHS candidate 1 [WHSC1 (aka NSD2, OMIM 602952)], WHS candidate 2 [WHSC2 (aka NELFA, OMIM 606026)], and LETM1 (OMIM 604407). Haploinsufficiency of the WHSC1 and/or WHSC2 gene is potentially associated with many of the characteristic features of WHS, including the distinctive facial appearance and developmental delay ( 13 ), ( 1 ), ( 6 ). Deletion of the LETM1 gene appears to be associated with WHS-associated seizure disorder ( 14 ), ( 15 ), however haploinsufficiency of LETM1 independently appears insufficient in epileptogenesis and seizure genesis ( 16 ). There is growing evidence that loss of the MSX1 gene [(OMIM 142983) located proximal to 4p16.3, on 4p16.2] may be responsible for the dental abnormalities as well as cleft lip and/or palate that can be seen in WHS ( 17 ), ( 18 ). The potential role(s) of other genes around the 4p16.3 region are subjects of ongoing investigations. Here we report the first documented case of 4p16.3 terminal microdeletion that is NOT associated with the characteristic WHS phenotype. The familial 4p16.3 microdeletion identified in this study overlaps partly with the distal segment of the WHSCR. The novel 4p16.3 microdeletion does not include WHSC1 , WHSC2 , LETM1 or MSX1 . CLINICAL REPORT Patients and Methods We recruited a family [Individual A (proband, 7-months-old) and Individual B (proband’s father, 27-years-old)] with a history of 4p deletion that was detected over 2 decades ago, when Individual B was in early childhood. The precise details of the cytogenetic techniques originally used to detect the 4p deletion were unavailable. Informed consent was obtained from the family. We investigated the location (deletion breakpoints) and size of the familial 4p deletion in Individual A using chromosomal microarray followed by metaphase fluorescence in situ hybridization (FISH) studies from Individual B using a locus specific probe (CTD-2300P12). The chromosomal microarray test utilized in this study applies greater than 1.9 million copy number probes and about 750,000 single nucleotide polymorphism (SNP) probes. Individual A (Proband) Our index case, Individual A, was assessed in genetics clinic in the context of her family history of 4p deletion. She was conceived naturally by 29-year-old Gravida 3 Para 2 mother and 26-year-old father. There were reportedly no concerns during pregnancy. There was no genetic testing completed in utero . There was no history of intrauterine growth restriction (IUGR). She was born by spontaneous vaginal delivery at 39 weeks. Her birth weight was 3.92 kg (around 50 th centile). Her Apgar scores were 8 at 1 minute and 9 at 5 minutes. There were no perinatal concerns. Her postnatal course was unremarkable. Individual A was breastfeeding, growing (within normal limits), and doing well overall during her last visit to genetics clinic. There has been no known history of WHS related clinical features such as feeding difficulties, failure to thrive, microcephaly, seizures, hypotonia, or congenital malformations. She has been attaining all her developmental milestones appropriately. With regards to gross motor millstones, she sat independently and was crawling as well as attempting to stand up by pulling-up on nearby support at her last clinic visit at 7 months of age. From a fine motor standpoint, she was batting at objects, practicing raking grasp and transferring objects from hand to hand. She babbles some nonspecific sounds and expresses her emotions adequately. Individual A’s parents report that she plays well with her older sibling. Individual A’s biological parents are of European descent. The family history was significant for Individual A’s father (Individual B) and paternal uncle, who were previously diagnosed with WHS over two decades ago reportedly based on findings of chromosome 4p deletion. Individual A was non-dysmorphic. She did not have the Greek-warrior helmet facial appearance that characterizes WHS. Growth parameters and physical examination findings across all pertinent systems in WHS for Individual A were all within normal limits. Her head circumference was 42.8 cm (around 40th centile), length was 67 cm (around 60th centile) and weight was 7.6 kg (around 55th centile). She was normocephalic, with no apparent cranial asymmetry, or scalp defects. Chromosomal SNP microarray for Individual A showed a terminal deletion at 4p16.3 comprising about 555 kilobase of genomic DNA from position 68,345 to 623,209 [arr(hg19)4p16.3(68,345-623,209)] as depicted by UCSC Genome Browser (Figure 1). The deletion was also identified by metaphase FISH studies using a probe within the deleted region (CTD-2300P12). The deleted interval involves twelve known genes namely: ZNF595, ZNF718, ZNF876P, ZNF732, ZNF141, MIR571, ABCA11P, ZNF721, PIGG, TMEM271, LOC105374338, PDE6B. Individual B Individual B, 27-year-old male, accompanied Individual A to genetics clinic. Individual B is Individual A’s biological father. Individual B reports that he was doing well overall during the clinic visit. Individual B reports that he had a past medical history of failure to thrive, slightly enlarged kidneys and atrial septal defect that resolved spontaneously. His final adult height is 5 ft 5 inches (around 5th centile). Individual B reports a history of seizures episodes (possibly 1 or 2) in childhood that did not require long-term antiepileptic medication, attention-deficit/hyperactivity disorder (ADHD), learning challenges requiring some form of individualized education program, and humoral immunodeficiency diagnosis. Individual B reports that his family history is limited because he was adopted out of his biological family. Individual B recalls that his biological brother, who was also adopted out of his biological family, had a history 4p deletion. Individual B’s brother reportedly had abnormal brain imaging findings (possibly periventricular leukomalacia), neurodevelopmental delays, hypotonia, ataxia, ADHD/anxiety, and final adult height of 5 feet 6 inches (around 10th centile). With regards to physical examination, Individual B appeared normocephalic and non-dysmorphic. He did not have the Greek-warrior helmet craniofacial appearance. Individual B’s head circumference was 54.9 cm (around 40th centile). Other physical examination findings across all pertinent systems in WHS for Individual B were all within normal limits. FISH studies on metaphase cells (n=10, peripheral blood mononuclear cells) suggested that the 4p16.3 microdeletion (about 555 kb) originally detected in Individual A was inherited from Individual B. DISCUSSIONS Chromosome 4p16.3 microdeletions are known to cause WHS, which is associated with significant morbidity and mortality ( 1 ). We report the first documented case of 4p16.3 terminal microdeletion (about 555 kb) that is not associated with the characteristic WHS phenotype. The clinical manifestations of WHS are related to haploinsufficiency of multiple genes on the short arm of chromosome 4, around the WHSCR, especially: WHSC1, WHSC2, LETM1, and MSX1 ( 1 , 13 , 14 , 18 ). The 4p16.3 terminal microdeletion in Individual A and B reported in the present study overlaps partly with the distal segment of WHSCR around the PIGG (phosphatidylinositol glycan anchor biosynthesis class G) gene (Fig. 1 ). The novel 4p16.3 microdeletion described here does not include WHSC1 , WHSC2 , LETM1 or MSX1 . The clinical significance of this familial 4p16.3 terminal microdeletion is yet to be fully determined. Haploinsufficiency of the twelve genes in the deleted segment has not been clearly associated with any known WHS phenotype(s). Three out of the twelve genes within the novel 4p16.3 microdeletion are OMIM morbid, namely: PIGG , PDE6B and ZNF141 . PIGG causes autosomal recessive conditions (OMIM 616917, and 619812). Although there is growing evidence that haploinsufficiency of PIGG and other genes (LETM1, CPLX1, CTBP1) within the WHSCR may contribute synergistically to the increased risk of seizures in WHS ( 19 ), the clinical significance of haploinsufficiency of PIGG on its own is yet to be fully defined. ZNF141 causes an autosomal recessive form of polydactyl (OMIM 615226), while PDE6B can cause autosomal dominant night blindness (OMIM 163500) and autosomal recessive retinitis pigmentosa (OMIM 613801). The phenotype of patients with WHS is highly variable ( 5 , 7 , 20 ). Microdeletions within the WHSCR associated with milder phenotypes have been described but these included WHSC1 ( 8 ) and/or WHSC2 ( 7 ), ( 6 ). Although Individual A and B do not have the characteristic features of WHS, the clinical significance of the novel 4p16.3 terminal microdeletion currently remains unclear. Renal anomalies and some types of immunodeficiency disorders have been described as potentially rare manifestations of 4p16.3 microdeletions ( 20 ). The genetic mechanisms of renal abnormalities and immunodeficiency in 4p16.3 microdeletions are unclear. Individual B’s history raises questions on the potential contribution(s) of haploinsufficiency of genes within the novel 4p16.3 microdeletion to kidney development and immune function. Our findings broaden the phenotypic spectrum associated with 4p16.3 microdeletions and suggest that, in some individuals, microdeletions within 4p16.3 region may not be sufficient to cause WHS. Accurate diagnosis of microdeletion syndromes like WHS is crucial for prognostication, surveillance, and overall clinical management. Our observations further highlight some of the clinical significance of molecular cytogenetic techniques such as SNP microarray for accurate diagnosis of chromosomal microdeletion syndromes. Abbreviations Wolf-Hirschhorn syndrome (WHS), WHS critical region (WHSCR), WHS candidate (WHSC), attention-deficit/hyperactivity disorder (ADHD), fluorescence in situ hybridization (FISH), single nucleotide polymorphism (SNP), intrauterine growth restriction (IUGR) Declarations Funding: This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution Author Contributions: Conceptualization-M.A.O., E.K., and B.L; Methodology-M.A.O., E.K., and B.L; Data Analysis- M.A.O., E.K., and B.L; Writing (original draft)-M.A.O; Writing (reviewing and editing); M.A.O., E.K., and B.L; Supervision- B.L. Acknowledgments: The authors thank the patients and families whose participation made this project possible, and the many healthcare providers involved in their care. Data Availability: The authors confirm that the data supporting the findings of this study are available within the article. References Battaglia A, Carey JC, South ST. Wolf-Hirschhorn syndrome: A review and update. Am J Med Genet C Semin Med Genet. 2015;169(3):216–23. Hirschhorn K, Cooper HL, Firschein IL. Deletion of short arms of chromosome 4–5 in a child with defects of midline fusion. Humangenetik. 1965;1(5):479–82. Wolf U, Reinwein H, Porsch R, Schroter R, Baitsch H. [Deficiency on the short arms of a chromosome No. 4]. Humangenetik. 1965;1(5):397–413. Hirschhorn K, Cooper HL. Chromosomal aberrations in human disease. A review of the status of cytogenetics in medicine. Am J Med. 1961;31:442–70. Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, et al. On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am J Med Genet C Semin Med Genet. 2008;148C(4):257–69. Rauch A, Schellmoser S, Kraus C, Dorr HG, Trautmann U, Altherr MR, et al. First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Am J Med Genet. 2001;99(4):338–42. Titomanlio L, Romano A, Conti A, Genesio R, Salerno M, De Brasi D, et al. Mild Wolf-Hirschhorn phenotype and partial GH deficiency in a patient with a 4p terminal deletion. Am J Med Genet A. 2004;127A(2):197–200. Okamoto N, Ohmachi K, Shimada S, Shimojima K, Yamamoto T. 109 kb deletion of chromosome 4p16.3 in a patient with mild phenotype of Wolf-Hirschhorn syndrome. Am J Med Genet A. 2013;161A(6):1465–9. Estabrooks LL, Rao KW, Driscoll DA, Crandall BF, Dean JC, Ikonen E, et al. Preliminary phenotypic map of chromosome 4p16 based on 4p deletions. Am J Med Genet. 1995;57(4):581–6. Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, et al. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet. 2003;72(3):590–7. Wright TJ, Ricke DO, Denison K, Abmayr S, Cotter PD, Hirschhorn K, et al. A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol Genet. 1997;6(2):317–24. Gandelman KY, Gibson L, Meyn MS, Yang-Feng TL. Molecular definition of the smallest region of deletion overlap in the Wolf-Hirschhorn syndrome. Am J Hum Genet. 1992;51(3):571–8. Barrie ES, Alfaro MP, Pfau RB, Goff MJ, McBride KL, Manickam K, et al. De novo loss-of-function variants in NSD2 (WHSC1) associate with a subset of Wolf-Hirschhorn syndrome. Cold Spring Harb Mol Case Stud. 2019;5(4). Jiang D, Zhao L, Clish CB, Clapham DE. Letm1, the mitochondrial Ca2+/H + antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome. Proc Natl Acad Sci U S A. 2013;110(24):E2249-54. Zhang X, Chen G, Lu Y, Liu J, Fang M, Luo J, et al. Association of mitochondrial letm1 with epileptic seizures. Cereb Cortex. 2014;24(10):2533–40. Zollino M, Orteschi D, Ruiter M, Pfundt R, Steindl K, Cafiero C, et al. Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder. Epilepsia. 2014;55(6):849–57. Rjiba K, Ayech H, Kraiem O, Slimani W, Jelloul A, Ben Hadj Hmida I, et al. Disorders of sex development in Wolf-Hirschhorn syndrome: a genotype-phenotype correlation and MSX1 as candidate gene. Mol Cytogenet. 2021;14(1):12. Nieminen P, Kotilainen J, Aalto Y, Knuutila S, Pirinen S, Thesleff I. MSX1 gene is deleted in Wolf-Hirschhorn syndrome patients with oligodontia. J Dent Res. 2003;82(12):1013–7. Correa T, Mayndra M, Santos-Reboucas CB. Distinct Epileptogenic Mechanisms Associated with Seizures in Wolf-Hirschhorn Syndrome. Mol Neurobiol. 2022;59(5):3159–69. Gavril EC, Luca AC, Curpan AS, Popescu R, Resmerita I, Panzaru MC, et al. Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review. Children (Basel). 2021;8(9). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 07 Nov, 2024 Read the published version in Chromosome Research → Version 1 posted Editorial decision: Revision requested 09 Aug, 2024 Reviews received at journal 07 Aug, 2024 Reviewers agreed at journal 07 Aug, 2024 Reviews received at journal 12 Jul, 2024 Reviewers agreed at journal 02 Jul, 2024 Reviewers invited by journal 02 Jul, 2024 Editor assigned by journal 20 Jun, 2024 Submission checks completed at journal 18 Jun, 2024 First submitted to journal 11 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4566567","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":321857566,"identity":"21fa71da-6455-459b-a539-0c28bac66c83","order_by":0,"name":"Mayowa Azeez Osundiji","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Mayowa","middleName":"Azeez","lastName":"Osundiji","suffix":""},{"id":321857567,"identity":"9d20fa41-940f-475e-95cd-4f7de0612068","order_by":1,"name":"Eva Kahn","email":"","orcid":"","institution":"Mayo Clinic","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Kahn","suffix":""},{"id":321857568,"identity":"a315ca09-8960-4ddd-a9f6-c7b7600429dd","order_by":2,"name":"Brendan Lanpher","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIiWNgGAWjYBACAyBmBjHsQQQPA4McVIKZsBbDBogWY+K1GByAaElsIKiF/eyxxwUV9xgMZx8+9uBNzZ30te1nDB8wVFjD9GJq4clLN55xppjBni8t3XDOsWe5287kGBswnEnHrYUhx0yaty2BwbCHx0yah+1w7rYDOWYSjG2HcWvhfwPU8i+BweAM/zdpnn+H083OvwFq+YdHiwTIlgaQFh42oHWHE8xugGxpwKfljbkxz7EEHsMeNjPJuX2HDbfdeFZskHAs3RiXFvv+HLPHPDUJcvY8zM8k3nw7LG92Pnnjgw811rK4tAABG4jgQRLgMGBIwK0crgUZsD/Ar2EUjIJRMApGGgAAVgxVYCBSJTkAAAAASUVORK5CYII=","orcid":"","institution":"Mayo Clinic","correspondingAuthor":true,"prefix":"","firstName":"Brendan","middleName":"","lastName":"Lanpher","suffix":""}],"badges":[],"createdAt":"2024-06-12 00:23:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4566567/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4566567/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10577-024-09757-9","type":"published","date":"2024-11-07T15:57:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60446804,"identity":"8f1e4def-30a7-417f-8c01-59a9e972014b","added_by":"auto","created_at":"2024-07-16 21:57:11","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":194091,"visible":true,"origin":"","legend":"\u003cp\u003eLocation of the submicroscopic 4p16.3 microdeletion [arr(hg19)4p16.3(68,345-623,209)], overlapping partly with the distal part of WHSCR around the PIGG gene locus. The relative size of the microdeletion at 4p16.3 is highlighted. The ensemble genes within this region include: \u0026nbsp;ZNF595, ZNF718, ZNF876P, ZNF732, ZNF141, MIR571, ABCA11P, ZNF721, PIGG, TMEM271, LOC105374338, PDE6B.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4566567/v1/545204fb65e00a5ecbf04dc5.jpg"},{"id":68750067,"identity":"41b5e1cd-4b75-4c3c-8f55-e71c1f8740e7","added_by":"auto","created_at":"2024-11-11 16:09:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":428266,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4566567/v1/958574f6-6365-49c0-8cef-0a6b78589e5e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eA Familial Chromosome 4p16.3 Terminal Microdeletion That Does Not Cause Wolf-Hirschhorn (4p-) syndrome\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eWolf-Hirschhorn syndrome (WHS, OMIM 194190) is a chromosomal disorder that is characterized by a distinct craniofacial gestalt [the Greek-warrior helmet appearance (wide forehead with prominent glabella), large and protruding eyes, hypertelorism, down-turned corners of the mouth, and micrognathia], pre and post-natal growth restriction (including microcephaly), intellectual disability, hypotonia, seizures and congenital malformations (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Heterozygous partial deletion of the distal segment of the p arm of chromosome 4 (4p) results in WHS. The initial cases of WHS were mapped to the 4pter region using conventional cytogenetic techniques (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). WHS cases in the clinical scientific literature have been quite diverse, ranging from isolated 4p heterozygous deletions without other cytogenetic abnormalities to cases of complex cytogenetic profiles that comprise of derivative forms of chromosome 4 possibly arising from a ring chromosome 4, a 4p-mosaicism, or an unbalanced translocation (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWHS phenotype varies from mild to severe depending, at least in part, on the size and location of the deleted segment around the 4p16.3 region (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Genetic testing technologies have evolved significantly in the last few decades resulting in an improved mapping of the 4p16.3 region (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Since the initial discovery of WHS in the 1960s (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), several patients who harbor 4p16.3 microdeletions that are associated with milder WHS phenotypes have been reported (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). These observations have led to the notion that WHS phenotypes potentially result from the cumulative effect of the combined haploinsufficiency of several causative genes around the 4p16.3 region. Studies of the 4p16.3 region subsequently identified the WHS critical region (WHSCR) 1 and 2, WHSCR1 and WHSCR2 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Candidate genes within the WHSCR that may underpin the WHS phenotype have been described including: WHS candidate 1 [WHSC1 (aka NSD2, OMIM 602952)], WHS candidate 2 [WHSC2 (aka NELFA, OMIM 606026)], and LETM1 (OMIM 604407). Haploinsufficiency of the WHSC1 and/or WHSC2 gene is potentially associated with many of the characteristic features of WHS, including the distinctive facial appearance and developmental delay (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Deletion of the LETM1 gene appears to be associated with WHS-associated seizure disorder (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), however haploinsufficiency of \u003cem\u003eLETM1\u003c/em\u003e independently appears insufficient in epileptogenesis and seizure genesis (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). There is growing evidence that loss of the MSX1 gene [(OMIM 142983) located proximal to 4p16.3, on 4p16.2] may be responsible for the dental abnormalities as well as cleft lip and/or palate that can be seen in WHS (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The potential role(s) of other genes around the 4p16.3 region are subjects of ongoing investigations. Here we report the first documented case of 4p16.3 terminal microdeletion that is NOT associated with the characteristic WHS phenotype. The familial 4p16.3 microdeletion identified in this study overlaps partly with the distal segment of the WHSCR. The novel 4p16.3 microdeletion does not include \u003cem\u003eWHSC1\u003c/em\u003e, \u003cem\u003eWHSC2\u003c/em\u003e, \u003cem\u003eLETM1\u003c/em\u003e or \u003cem\u003eMSX1\u003c/em\u003e.\u003c/p\u003e"},{"header":"CLINICAL REPORT","content":"\u003cp\u003e\u003cu\u003ePatients and Methods\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eWe recruited a family [Individual\u0026nbsp;A (proband, 7-months-old) and Individual B (proband’s father, 27-years-old)] with a history of\u0026nbsp;4p deletion that was detected over 2 decades ago, when Individual B was in early childhood. The precise details of the cytogenetic techniques originally used to detect the 4p deletion were unavailable. Informed consent was obtained from the family.\u0026nbsp;We investigated the location (deletion breakpoints) and size of the familial\u0026nbsp;4p deletion in Individual A using\u0026nbsp;chromosomal microarray followed by\u0026nbsp;metaphase fluorescence \u003cem\u003ein situ\u003c/em\u003e hybridization (FISH) studies from Individual B using a locus specific probe (CTD-2300P12). The chromosomal microarray test utilized in this study applies greater than 1.9 million copy number probes and about 750,000 single nucleotide polymorphism (SNP) probes.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eIndividual A (Proband)\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eOur index case,\u0026nbsp;Individual A, was assessed in genetics clinic in the context of her family history of 4p deletion. She was conceived naturally by 29-year-old Gravida 3 Para 2 mother and 26-year-old father. \u0026nbsp;There were reportedly no concerns during pregnancy. There was no genetic testing completed \u003cem\u003ein utero\u003c/em\u003e.\u0026nbsp; There was no history of \u003cem\u003eintrauterine growth restriction\u003c/em\u003e (IUGR).\u0026nbsp;She was born by spontaneous vaginal delivery\u0026nbsp;at 39 weeks. Her birth weight was 3.92 kg (around 50\u003csup\u003eth\u003c/sup\u003e centile). Her Apgar scores were 8 at 1 minute and 9 at 5 minutes.\u0026nbsp;There were no perinatal concerns. Her postnatal course was unremarkable. \u0026nbsp; Individual A was breastfeeding, growing (within normal limits), and doing well overall during her last visit to genetics clinic. There has been no known history of WHS related clinical features such as feeding difficulties, failure to thrive, microcephaly, seizures, hypotonia, or congenital malformations.\u0026nbsp;She has been attaining\u0026nbsp;all her developmental milestones appropriately. With regards to gross motor millstones, she sat independently and was crawling as well as attempting to stand up by pulling-up on nearby support at her last clinic visit at 7 months of age. From a fine motor standpoint, she was batting at objects, practicing\u0026nbsp;raking grasp\u0026nbsp;and transferring objects from\u0026nbsp;hand to hand.\u003c/p\u003e\n\u003cp\u003eShe babbles some\u0026nbsp;nonspecific\u0026nbsp;sounds and expresses\u0026nbsp;her\u0026nbsp;emotions\u0026nbsp;adequately. Individual A’s parents report that she plays well with her older sibling.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIndividual A’s biological parents are of European descent. The family history was significant for Individual A’s father (Individual B) and paternal uncle, who were previously diagnosed with WHS over two decades ago reportedly based on findings of chromosome 4p deletion. \u0026nbsp; Individual A was non-dysmorphic. She did not have the Greek-warrior helmet facial appearance that characterizes WHS. \u0026nbsp;Growth parameters and physical examination findings across all pertinent systems in WHS for Individual A were all within normal limits. Her head circumference was 42.8 cm (around 40th centile), length was 67 cm (around 60th centile) and weight was 7.6 kg (around 55th centile). She was normocephalic, with no apparent cranial asymmetry, or scalp defects. Chromosomal SNP microarray for Individual A showed a terminal deletion at 4p16.3 comprising about 555 kilobase of genomic DNA from position 68,345 to 623,209 [arr(hg19)4p16.3(68,345-623,209)]\u0026nbsp;as depicted by UCSC Genome Browser (Figure 1). The deletion was also identified by metaphase FISH studies using a probe within the deleted region (CTD-2300P12). The deleted interval involves twelve known genes namely: ZNF595, ZNF718, ZNF876P, ZNF732, ZNF141, MIR571, ABCA11P, ZNF721, PIGG, TMEM271, LOC105374338, PDE6B.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eIndividual B\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIndividual B, 27-year-old male, accompanied Individual A to genetics clinic. Individual B is Individual A’s biological father. Individual B reports that he was doing well overall during the clinic visit. Individual B reports that he had a past medical history of failure to thrive, slightly enlarged kidneys and atrial septal defect that resolved spontaneously. His\u0026nbsp;final adult height is 5 ft 5 inches (around 5th centile). Individual B reports a history of\u0026nbsp;seizures episodes (possibly 1 or 2) in childhood that did not require long-term antiepileptic medication, \u003cem\u003eattention-deficit/hyperactivity disorder\u003c/em\u003e (ADHD), learning challenges requiring some form of individualized education program, and humoral immunodeficiency diagnosis.\u003c/p\u003e\n\u003cp\u003eIndividual B reports that his family history is limited because he was adopted out of his biological family. Individual B recalls that his biological brother, who was also adopted out of his biological family, had a history 4p deletion. Individual B’s brother reportedly had abnormal brain imaging\u0026nbsp;findings (possibly periventricular leukomalacia),\u0026nbsp;neurodevelopmental delays, hypotonia,\u0026nbsp;ataxia, ADHD/anxiety, and final adult height of\u0026nbsp;5 feet 6 inches (around\u0026nbsp;10th centile).\u003c/p\u003e\n\u003cp\u003eWith regards to physical examination, Individual B appeared normocephalic and non-dysmorphic. \u0026nbsp;He did not have the Greek-warrior helmet craniofacial appearance. \u0026nbsp;Individual B’s head circumference was 54.9 cm (around 40th centile). Other physical examination findings across all pertinent systems in WHS for Individual B were all within normal limits. FISH studies on metaphase cells (n=10, peripheral blood mononuclear cells) suggested that the 4p16.3 microdeletion (about 555 kb) originally detected in Individual A was inherited from Individual B.\u003c/p\u003e"},{"header":"DISCUSSIONS","content":"\u003cp\u003eChromosome 4p16.3 microdeletions are known to cause WHS, which is associated with significant morbidity and mortality (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). We report the first documented case of 4p16.3 terminal microdeletion (about 555 kb) that is not associated with the characteristic WHS phenotype. The clinical manifestations of WHS are related to haploinsufficiency of multiple genes on the short arm of chromosome 4, around the WHSCR, especially: WHSC1, WHSC2, LETM1, and MSX1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). The 4p16.3 terminal microdeletion in Individual A and B reported in the present study overlaps partly with the distal segment of WHSCR around the PIGG (phosphatidylinositol glycan anchor biosynthesis class G) gene (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The novel 4p16.3 microdeletion described here does not include \u003cem\u003eWHSC1\u003c/em\u003e, \u003cem\u003eWHSC2\u003c/em\u003e, \u003cem\u003eLETM1\u003c/em\u003e or \u003cem\u003eMSX1\u003c/em\u003e.\u003c/p\u003e \u003cp\u003eThe clinical significance of this familial 4p16.3 terminal microdeletion is yet to be fully determined. Haploinsufficiency of the twelve genes in the deleted segment has not been clearly associated with any known WHS phenotype(s). Three out of the twelve genes within the novel 4p16.3 microdeletion are OMIM morbid, namely: \u003cem\u003ePIGG\u003c/em\u003e, \u003cem\u003ePDE6B\u003c/em\u003e and \u003cem\u003eZNF141\u003c/em\u003e. \u003cem\u003ePIGG\u003c/em\u003e causes autosomal recessive conditions (OMIM 616917, and 619812). Although there is growing evidence that haploinsufficiency of \u003cem\u003ePIGG\u003c/em\u003e and other genes (LETM1, CPLX1, CTBP1) within the WHSCR may contribute synergistically to the increased risk of seizures in WHS (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), the clinical significance of haploinsufficiency of \u003cem\u003ePIGG\u003c/em\u003e on its own is yet to be fully defined. \u003cem\u003eZNF141\u003c/em\u003e causes an autosomal recessive form of polydactyl (OMIM 615226), while \u003cem\u003ePDE6B\u003c/em\u003e can cause autosomal dominant night blindness (OMIM 163500) and autosomal recessive retinitis pigmentosa (OMIM 613801).\u003c/p\u003e \u003cp\u003eThe phenotype of patients with WHS is highly variable (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Microdeletions within the WHSCR associated with milder phenotypes have been described but these included WHSC1 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) and/or WHSC2 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Although Individual A and B do not have the characteristic features of WHS, the clinical significance of the novel 4p16.3 terminal microdeletion currently remains unclear. Renal anomalies and some types of immunodeficiency disorders have been described as potentially rare manifestations of 4p16.3 microdeletions (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The genetic mechanisms of renal abnormalities and immunodeficiency in 4p16.3 microdeletions are unclear. Individual B\u0026rsquo;s history raises questions on the potential contribution(s) of haploinsufficiency of genes within the novel 4p16.3 microdeletion to kidney development and immune function.\u003c/p\u003e \u003cp\u003eOur findings broaden the phenotypic spectrum associated with 4p16.3 microdeletions and suggest that, in some individuals, microdeletions within 4p16.3 region may not be sufficient to cause WHS. Accurate diagnosis of microdeletion syndromes like WHS is crucial for prognostication, surveillance, and overall clinical management. Our observations further highlight some of the clinical significance of molecular cytogenetic techniques such as SNP microarray for accurate diagnosis of chromosomal microdeletion syndromes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eWolf-Hirschhorn syndrome (WHS), WHS critical region\u0026nbsp;(WHSCR), WHS candidate (WHSC),\u0026nbsp;\u003cem\u003eattention-deficit/hyperactivity disorder\u003c/em\u003e (ADHD), fluorescence \u003cem\u003ein situ\u003c/em\u003e hybridization (FISH),\u0026nbsp;single nucleotide polymorphism (SNP), \u003cem\u003eintrauterine growth restriction\u003c/em\u003e (IUGR)\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor Contributions: Conceptualization-M.A.O., E.K., and B.L; Methodology-M.A.O., E.K., and B.L; Data Analysis- M.A.O., E.K., and B.L; Writing (original draft)-M.A.O; Writing (reviewing and editing); M.A.O., E.K., and B.L; Supervision- B.L.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e \u003cp\u003eThe authors thank the patients and families whose participation made this project possible, and the many healthcare providers involved in their care.\u003c/p\u003e\u003ch2\u003eData Availability:\u003c/h2\u003e \u003cp\u003eThe authors confirm that the data supporting the findings of this study are available within the article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBattaglia A, Carey JC, South ST. Wolf-Hirschhorn syndrome: A review and update. Am J Med Genet C Semin Med Genet. 2015;169(3):216\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirschhorn K, Cooper HL, Firschein IL. Deletion of short arms of chromosome 4\u0026ndash;5 in a child with defects of midline fusion. Humangenetik. 1965;1(5):479\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolf U, Reinwein H, Porsch R, Schroter R, Baitsch H. [Deficiency on the short arms of a chromosome No. 4]. Humangenetik. 1965;1(5):397\u0026ndash;413.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirschhorn K, Cooper HL. Chromosomal aberrations in human disease. A review of the status of cytogenetics in medicine. Am J Med. 1961;31:442\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, et al. On the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype correlation analysis of 80 patients and literature review. Am J Med Genet C Semin Med Genet. 2008;148C(4):257\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRauch A, Schellmoser S, Kraus C, Dorr HG, Trautmann U, Altherr MR, et al. First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Am J Med Genet. 2001;99(4):338\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTitomanlio L, Romano A, Conti A, Genesio R, Salerno M, De Brasi D, et al. Mild Wolf-Hirschhorn phenotype and partial GH deficiency in a patient with a 4p terminal deletion. Am J Med Genet A. 2004;127A(2):197\u0026ndash;200.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOkamoto N, Ohmachi K, Shimada S, Shimojima K, Yamamoto T. 109 kb deletion of chromosome 4p16.3 in a patient with mild phenotype of Wolf-Hirschhorn syndrome. Am J Med Genet A. 2013;161A(6):1465\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEstabrooks LL, Rao KW, Driscoll DA, Crandall BF, Dean JC, Ikonen E, et al. Preliminary phenotypic map of chromosome 4p16 based on 4p deletions. Am J Med Genet. 1995;57(4):581\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, et al. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet. 2003;72(3):590\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright TJ, Ricke DO, Denison K, Abmayr S, Cotter PD, Hirschhorn K, et al. A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol Genet. 1997;6(2):317\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGandelman KY, Gibson L, Meyn MS, Yang-Feng TL. Molecular definition of the smallest region of deletion overlap in the Wolf-Hirschhorn syndrome. Am J Hum Genet. 1992;51(3):571\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarrie ES, Alfaro MP, Pfau RB, Goff MJ, McBride KL, Manickam K, et al. De novo loss-of-function variants in NSD2 (WHSC1) associate with a subset of Wolf-Hirschhorn syndrome. Cold Spring Harb Mol Case Stud. 2019;5(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang D, Zhao L, Clish CB, Clapham DE. Letm1, the mitochondrial Ca2+/H\u0026thinsp;+\u0026thinsp;antiporter, is essential for normal glucose metabolism and alters brain function in Wolf-Hirschhorn syndrome. Proc Natl Acad Sci U S A. 2013;110(24):E2249-54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang X, Chen G, Lu Y, Liu J, Fang M, Luo J, et al. Association of mitochondrial letm1 with epileptic seizures. Cereb Cortex. 2014;24(10):2533\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZollino M, Orteschi D, Ruiter M, Pfundt R, Steindl K, Cafiero C, et al. Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder. Epilepsia. 2014;55(6):849\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRjiba K, Ayech H, Kraiem O, Slimani W, Jelloul A, Ben Hadj Hmida I, et al. Disorders of sex development in Wolf-Hirschhorn syndrome: a genotype-phenotype correlation and MSX1 as candidate gene. Mol Cytogenet. 2021;14(1):12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNieminen P, Kotilainen J, Aalto Y, Knuutila S, Pirinen S, Thesleff I. MSX1 gene is deleted in Wolf-Hirschhorn syndrome patients with oligodontia. J Dent Res. 2003;82(12):1013\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorrea T, Mayndra M, Santos-Reboucas CB. Distinct Epileptogenic Mechanisms Associated with Seizures in Wolf-Hirschhorn Syndrome. Mol Neurobiol. 2022;59(5):3159\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGavril EC, Luca AC, Curpan AS, Popescu R, Resmerita I, Panzaru MC, et al. Wolf-Hirschhorn Syndrome: Clinical and Genetic Study of 7 New Cases, and Mini Review. Children (Basel). 2021;8(9).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"chromosome-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"chrs","sideBox":"Learn more about [Chromosome Research](http://link.springer.com/journal/10577)","snPcode":"10577","submissionUrl":"https://submission.nature.com/new-submission/10577/3","title":"Chromosome Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"WHS, microdeletion, chromosome","lastPublishedDoi":"10.21203/rs.3.rs-4566567/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4566567/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eChromosome 4p16.3 microdeletions are known to cause Wolf–Hirschhorn syndrome (WHS), which is characterized by a distinct craniofacial gestalt and multiple congenital malformations. The 4p16.3 region encompasses WHS critical region 1 (WHSCR1) and 2 (WHSCR2). The WHSCR contains several genes that have been implicated in the WHS phenotype including: WHS candidate 1 [\u003cem\u003eWHSC1\u003c/em\u003e(aka \u003cem\u003eNSD2\u003c/em\u003e, OMIM 602952)], WHS candidate 2 [\u003cem\u003eWHSC2\u003c/em\u003e (aka \u003cem\u003eNELFA\u003c/em\u003e, OMIM 606026)], and \u003cem\u003eLETM1\u003c/em\u003e (OMIM 604407). Although several patients harboring 4p16.3 microdeletions that are associated with WHS phenotypes have been reported, the precise molecular underpinnings of WHS are subjects of active investigations. The potential role(s) of genes within the 4p16.3 are increasingly being investigated. Here we report the first documented case of 4p16.3 terminal microdeletion that is not associated with the characteristic WHS phenotype. We studied Individual A (7-months-old female) and her father, Individual B (27-year-old), who both carry a terminal 4p16.3 microdeletion (about 555kb) that is distal to the WHSCR [(WHSCR1) and (WHSCR2)], and does not include \u003cem\u003eWHSC1\u003c/em\u003e, \u003cem\u003eWHSC2\u003c/em\u003e, or \u003cem\u003eLETM1\u003c/em\u003e. Overall, \u003cem\u003eour findings expand \u003c/em\u003ethe \u003cem\u003ephenotypic spectrum\u003c/em\u003e associated with 4p16.3 micro\u003cem\u003edeletions\u003c/em\u003e and suggest that, in some individuals, microdeletions within 4p16.3 region may not be sufficient to cause WHS.\u003c/p\u003e","manuscriptTitle":"A Familial Chromosome 4p16.3 Terminal Microdeletion That Does Not Cause Wolf-Hirschhorn (4p-) syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 21:57:06","doi":"10.21203/rs.3.rs-4566567/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-09T20:27:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-07T23:47:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"90633527150117379948015963896989979072","date":"2024-08-07T23:44:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-13T03:48:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"55271965587840282589394410607802788526","date":"2024-07-02T17:26:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-02T17:22:55+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-20T17:41:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-18T12:16:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Chromosome Research","date":"2024-06-12T00:10:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"chromosome-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"chrs","sideBox":"Learn more about [Chromosome Research](http://link.springer.com/journal/10577)","snPcode":"10577","submissionUrl":"https://submission.nature.com/new-submission/10577/3","title":"Chromosome Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f1cb986a-82ec-415c-9ee2-83d7679a5aba","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-11T16:04:21+00:00","versionOfRecord":{"articleIdentity":"rs-4566567","link":"https://doi.org/10.1007/s10577-024-09757-9","journal":{"identity":"chromosome-research","isVorOnly":false,"title":"Chromosome Research"},"publishedOn":"2024-11-07 15:57:20","publishedOnDateReadable":"November 7th, 2024"},"versionCreatedAt":"2024-07-16 21:57:06","video":"","vorDoi":"10.1007/s10577-024-09757-9","vorDoiUrl":"https://doi.org/10.1007/s10577-024-09757-9","workflowStages":[]},"version":"v1","identity":"rs-4566567","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4566567","identity":"rs-4566567","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}