{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T12:50:06Z","timestamp":1774270206316,"version":"3.50.1"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T00:00:00Z","timestamp":1572825600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T00:00:00Z","timestamp":1572825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lebanese American University, School Research and Development Council","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diagn Pathol"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case presentation<\/jats:title><jats:p>Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in<jats:italic>PGAP3<\/jats:italic>was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings have illustrated the genomic profile of<jats:italic>PGAP3<\/jats:italic>-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13000-019-0902-5","type":"journal-article","created":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T13:03:24Z","timestamp":1572872604000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review"],"prefix":"10.1186","volume":"14","author":[{"given":"Layal","family":"Abi Farraj","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wassim Daoud","family":"Khatoun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naji","family":"Abou Chebel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor","family":"Wakim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katia","family":"Dawali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2107-9929","authenticated-orcid":false,"given":"Michella","family":"Ghassibe-Sabbagh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,11,4]]},"reference":[{"issue":"1","key":"902_CR1","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1111\/cge.13033","volume":"93","author":"MS Abdel-Hamid","year":"2018","unstructured":"Abdel-Hamid MS, Issa MY, Otaify GA, et al. PGAP3-related hyperphosphatasia with mental retardation syndrome: report of 10 new patients and a homozygous founder mutation. Clin Genet. 2018;93(1):84\u201391.","journal-title":"Clin Genet"},{"issue":"12","key":"902_CR2","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1038\/gim.2016.37","volume":"18","author":"M Abouelhoda","year":"2016","unstructured":"Abouelhoda M, Sobahy T, El-Kalioby M, et al. Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden. Genet Med. 2016;18(12):1244\u20139.","journal-title":"Genet Med"},{"issue":"7","key":"902_CR3","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1136\/jmedgenet-2017-105110","volume":"55","author":"M Basha","year":"2018","unstructured":"Basha M, Demeer B, Revencu N, et al. Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and\/or palate in genes mutated in well-known syndromes. J Med Genet. 2018;55(7):449\u201358.","journal-title":"J Med Genet"},{"key":"902_CR4","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/978-94-017-7197-9_16","volume":"76","author":"DE Cole","year":"2015","unstructured":"Cole DE, Thompson MD. Neurogenetic Aspects of Hyperphosphatasia in Mabry Syndrome. Subcell Biochem. 2015;76:343\u201361.","journal-title":"Subcell Biochem"},{"issue":"5","key":"902_CR5","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","volume":"43","author":"MA DePristo","year":"2011","unstructured":"DePristo MA, Banks E, Poplin R, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491\u20138.","journal-title":"Nat Genet"},{"key":"902_CR6","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1242\/dev.103.Supplement.41","volume":"103","author":"MW Ferguson","year":"1988","unstructured":"Ferguson MW. Palate development. Development. 1988;103:41\u201360.","journal-title":"Development"},{"key":"902_CR7","doi-asserted-by":"crossref","unstructured":"Fryns JP, de Ravel TJ. London Dysmorphology Database, London Neurogenetics Database and Dysmorphology Photo Library on CD-ROM [Version 3] 2001R. M. Winter, M. Baraitser, Oxford University Press, ISBN 019851\u2013780, pound sterling 1595. Hum Genet. 2002;111(1):113.","DOI":"10.1007\/s00439-002-0759-6"},{"issue":"1","key":"902_CR8","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1186\/s12887-019-1440-8","volume":"19","author":"L Fu","year":"2019","unstructured":"Fu L, Liu Y, Chen Y, Yuan Y, Wei W. Mutations in the PIGW gene associated with hyperphosphatasia and mental retardation syndrome: a case report. BMC Pediatr. 2019;19(1):68.","journal-title":"BMC Pediatr"},{"issue":"2","key":"902_CR9","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.ajhg.2011.01.003","volume":"88","author":"M Ghassibe-Sabbagh","year":"2011","unstructured":"Ghassibe-Sabbagh M, Desmyter L, Langenberg T, et al. FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish. Am J Hum Genet. 2011;88(2):150\u201361.","journal-title":"Am J Hum Genet"},{"issue":"Suppl 4","key":"902_CR10","first-page":"20","volume":"2","author":"M Ghassibe","year":"2006","unstructured":"Ghassibe M, Bayet B, Revencu N, et al. Orofacial clefting: update on the role of genetics. B-ENT. 2006;2(Suppl 4):20\u20134.","journal-title":"B-ENT"},{"issue":"2","key":"902_CR11","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.ejmg.2010.01.002","volume":"53","author":"D Horn","year":"2010","unstructured":"Horn D, Schottmann G, Meinecke P. Hyperphosphatasia with mental retardation, brachytelephalangy, and a distinct facial gestalt: delineation of a recognizable syndrome. Eur J Med Genet. 2010;53(2):85\u20138.","journal-title":"Eur J Med Genet"},{"issue":"2","key":"902_CR12","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.ajhg.2013.12.012","volume":"94","author":"MF Howard","year":"2014","unstructured":"Howard MF, Murakami Y, Pagnamenta AT, et al. Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation. Am J Hum Genet. 2014;94(2):278\u201387.","journal-title":"Am J Hum Genet"},{"issue":"6","key":"902_CR13","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nprot.2015.053","volume":"10","author":"LA Kelley","year":"2015","unstructured":"Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10(6):845\u201358.","journal-title":"Nat Protoc"},{"issue":"8","key":"902_CR14","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1002\/humu.23006","volume":"37","author":"A Knaus","year":"2016","unstructured":"Knaus A, Awaya T, Helbig I, et al. Rare noncoding mutations extend the mutational Spectrum in the PGAP3 subtype of Hyperphosphatasia with mental retardation syndrome. Hum Mutat. 2016;37(8):737\u201344.","journal-title":"Hum Mutat"},{"issue":"10","key":"902_CR15","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/ng.653","volume":"42","author":"PM Krawitz","year":"2010","unstructured":"Krawitz PM, Schweiger MR, Rodelsperger C, et al. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet. 2010;42(10):827\u20139.","journal-title":"Nat Genet"},{"issue":"16","key":"902_CR16","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Handsaker B, Wysoker A, et al. The sequence alignment\/map format and SAMtools. Bioinformatics. 2009;25(16):2078\u20139.","journal-title":"Bioinformatics."},{"issue":"1","key":"902_CR17","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/S0022-3476(70)80047-6","volume":"77","author":"CC Mabry","year":"1970","unstructured":"Mabry CC, Bautista A, Kirk RF, et al. Familial hyperphosphatase with mental retardation, seizures, and neurologic deficits. J Pediatr. 1970;77(1):74\u201385.","journal-title":"J Pediatr"},{"issue":"9","key":"902_CR18","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna A, Hanna M, Banks E, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297\u2013303.","journal-title":"Genome Res"},{"issue":"9703","key":"902_CR19","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1016\/S0140-6736(09)60695-4","volume":"374","author":"PA Mossey","year":"2009","unstructured":"Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft lip and palate. Lancet. 2009;374(9703):1773\u201385.","journal-title":"Lancet."},{"issue":"3","key":"902_CR20","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1055\/s-0037-1599148","volume":"6","author":"S Nampoothiri","year":"2017","unstructured":"Nampoothiri S, Hebbar M, Roy AG, et al. Hyperphosphatasia with mental retardation syndrome due to a novel mutation in PGAP3. J Pediatr Genet. 2017;6(3):191\u20133.","journal-title":"J Pediatr Genet"},{"issue":"6","key":"902_CR21","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/ejhg.2017.32","volume":"25","author":"AT Pagnamenta","year":"2017","unstructured":"Pagnamenta AT, Murakami Y, Taylor JM, et al. Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders. Eur J Hum Genet. 2017;25(6):669\u201379.","journal-title":"Eur J Hum Genet"},{"key":"902_CR22","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/1745-6150-6-37","volume":"6","author":"J Pei","year":"2011","unstructured":"Pei J, Millay DP, Olson EN, Grishin NV. CREST--a large and diverse superfamily of putative transmembrane hydrolases. Biol Direct. 2011;6:37.","journal-title":"Biol Direct"},{"issue":"5","key":"902_CR23","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1111\/cge.12547","volume":"88","author":"RJ Pengelly","year":"2015","unstructured":"Pengelly RJ, Upstill-Goddard R, Arias L, et al. Resolving clinical diagnoses for syndromic cleft lip and\/or palate phenotypes using whole-exome sequencing. Clin Genet. 2015;88(5):441\u20139.","journal-title":"Clin Genet"},{"key":"902_CR24","doi-asserted-by":"publisher","first-page":"18005","DOI":"10.1038\/hgv.2018.5","volume":"5","author":"T Sakaguchi","year":"2018","unstructured":"Sakaguchi T, Zigman T, Petkovic Ramadza D, et al. A novel PGAP3 mutation in a Croatian boy with brachytelephalangy and a thin corpus callosum. Hum Genome Var. 2018;5:18005.","journal-title":"Hum Genome Var"},{"issue":"6","key":"902_CR25","doi-asserted-by":"publisher","first-page":"650","DOI":"10.3928\/23258160-20150610-09","volume":"46","author":"CC Swinney","year":"2015","unstructured":"Swinney CC, Han DP, Karth PA. Incontinentia Pigmenti: a comprehensive review and update. Ophthalmic Surg Lasers Imaging Retina. 2015;46(6):650\u20137.","journal-title":"Ophthalmic Surg Lasers Imaging Retina"},{"issue":"9","key":"902_CR26","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1007\/s00439-015-1575-0","volume":"134","author":"T Yavarna","year":"2015","unstructured":"Yavarna T, Al-Dewik N, Al-Mureikhi M, et al. High diagnostic yield of clinical exome sequencing in middle eastern patients with Mendelian disorders. Hum Genet. 2015;134(9):967\u201380.","journal-title":"Hum Genet"}],"container-title":["Diagnostic Pathology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13000-019-0902-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13000-019-0902-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13000-019-0902-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T13:26:24Z","timestamp":1664803584000},"score":1,"resource":{"primary":{"URL":"https:\/\/diagnosticpathology.biomedcentral.com\/articles\/10.1186\/s13000-019-0902-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,4]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["902"],"URL":"https:\/\/doi.org\/10.1186\/s13000-019-0902-5","relation":{},"ISSN":["1746-1596"],"issn-type":[{"value":"1746-1596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,4]]},"assertion":[{"value":"25 August 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The study was approved by the LAU Institutional Review Board and the Committee on Human Subjects in Research (CHSR) (approval no. LAU.SAS.MS1.23). Informed consent was obtained from participants. All experiments were carried out in accordance with relevant guidelines and regulations.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"123"}}