{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T09:57:16Z","timestamp":1753869436313,"version":"3.41.2"},"reference-count":42,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T00:00:00Z","timestamp":1682726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Autosomal recessive cutis laxa type 2A (ARCL2A; OMIM: 219200) is characterized by neurovegetative, developmental and progeroid elastic skin anomalies. It is caused by biallelic variation in ATPase, H<jats:sup>+<\/jats:sup> transporting V0 subunit A2 (<jats:italic>ATP6V0A2<\/jats:italic>; OMIM: 611716) located on chromosome 12q24.31. Autosomal recessive cutis laxa type 3A (ARCL3A; OMIM: 219150) is another subclinical type characterized by short stature, ophthalmological abnormalities and a progeria\u2010like appearance. The ARCL3A is caused by loss of function alterations in the aldehyde dehydrogenase 18 family member A1 (<jats:italic>ALDH18A1<\/jats:italic>; OMIM: 138250) gene located at chromosome 10q24.1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing (WES), and Sanger sequencing were performed for molecular diagnosis. 3D protein modeling was performed to investigate the deleterious effect of the variant on protein structure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, clinical and molecular diagnosis were performed for two families, ED\u201001 and DWF\u201041, which displayed hallmark features of ARCL2A and ARCL3A, respectively. Three affected individuals in the ED\u201001 family (IV\u20104, IV\u20105 and V\u20103) displayed sagging loose skin, down\u2010slanting palpebral fissures, excessive wrinkles on the abdomen, hands and feet, and prominent veins on the trunk. Meanwhile the affected individuals in the DWF\u201041 family (V\u20102 and V\u20103) had progeroid skin, short stature, dysmorphology, low muscle tone, epilepsy, lordosis, scoliosis, delayed puberty and internal genitalia. WES in the index patient (ED\u201001: IV\u20104) identified a novel homozygous deletion (NM_012463.3: c.1977_1980del; p.[Val660LeufsTer23]) in exon 16 of the <jats:italic>ATP6V0A2<\/jats:italic> while in DWF\u201041 a novel homozygous missense variant (NM_001323413.1:c.1867G&gt;A; p.[Asp623Asn]) in exon 15 of the <jats:italic>ALDH18A1<\/jats:italic> was identified. Sanger validation in all available family members confirmed the autosomal recessive modes of inheritances in each family. Three dimensional <jats:italic>in\u2010silico<\/jats:italic> protein modeling suggested deleterious impact of the identified variants. Furthermore, these variants were assigned class 1 or \u201cpathogenic\u201d as per guidelines of American College of Medical Genetics 2015. Screening of ethnically matched healthy controls (<jats:italic>n<\/jats:italic>\u00a0=\u2009200 chromosomes), excluded the presence of these variations in general population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>To the best of our knowledge, this is the first report of <jats:italic>ATP6V0A2<\/jats:italic> and <jats:italic>ALDH18A1<\/jats:italic> variations in the Pakhtun ethnicity of Pakistani population. The study confirms that WES can be used as a first\u2010line diagnostic test in patients with cutis laxa, and provides basis for population screening and premarital testing to reduce the diseases burden in future generations.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.3522","type":"journal-article","created":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T08:45:07Z","timestamp":1682757907000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Two novel homozygous variants of <i>ATP6V0A2<\/i> and <i>ALDH18A1<\/i> lead to autosomal recessive cutis laxa type 2 and 3 in two Pakistani families"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1261-2990","authenticated-orcid":false,"given":"Qaiser","family":"Zaman","sequence":"first","affiliation":[{"name":"Department of Zoology Government Postgraduate College Dargai, Malakand  Dargai Pakistan"},{"name":"Higher Education Department  Peshawar, Khyber Pakhunkhwa Pakistan"},{"name":"Department of Zoology Abdul Wali Khan University Mardan  Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aiman","family":"Iftikhar","sequence":"additional","affiliation":[{"name":"Department of Zoology Government Postgraduate College Dargai, Malakand  Dargai Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gauhar","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Zoology Abdul Wali Khan University Mardan  Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qadeem","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Zoology Government Postgraduate College Dargai, Malakand  Dargai Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"family":"Najumuddin","sequence":"additional","affiliation":[{"name":"National Center for Bioinformatics Quaid\u2010I\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amin","family":"Jan","sequence":"additional","affiliation":[{"name":"Department of Physiology North\u2010West School of Medicine Peshawar  Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamshid","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Zoology Government Postgraduate College Dargai, Malakand  Dargai Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Anas","sequence":"additional","affiliation":[{"name":"Department of Zoology Government Postgraduate College Dargai, Malakand  Dargai Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"family":"Laiba","sequence":"additional","affiliation":[{"name":"Department of Zoology Government Postgraduate College Dargai, Malakand  Dargai Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Umair","sequence":"additional","affiliation":[{"name":"Medical Genomics Research Department, King Abdullah International Medical Research Center King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs  Riyadh Saudi Arabia"},{"name":"Department of Life Sciences, School of Science University of Management and Technology  Lahore Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osama Yousef","family":"Muthaffar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angham Abdulrhman","family":"Abdulkareem","sequence":"additional","affiliation":[{"name":"Center of Excellence in Genomic Medicine Research King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Faculty of Science, Department of Biochemistry King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fehmida","family":"Bibi","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Special Infectious Agents Unit, King Fahd Medical Research Centre King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Imran","family":"Naseer","sequence":"additional","affiliation":[{"name":"Center of Excellence in Genomic Medicine Research King Abdulaziz University  Jeddah Saudi Arabia"},{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences King Abdulaziz University  Jeddah Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3421-0079","authenticated-orcid":false,"given":"Musharraf","family":"Jelani","sequence":"additional","affiliation":[{"name":"Rare Diseases Genetics and Genomics, Centre for Omic Sciences Islamia College Peshawar  Khyber Pakhtunkhwa Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"issue":"145","key":"e_1_2_11_2_1","article-title":"Severe phenotype of De Barsy syndrome in two siblings with novel mutations in the ALDH18A1 gene","volume":"5","author":"Smigiel R","year":"2017","journal-title":"J Clin Med Genomics"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2022.104568"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.4103\/2229\u20105178.190512"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.22"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399\u20100004.1973.tb01141.x"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097\u20102765(03)00397\u20106"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201361"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32143"},{"issue":"3","key":"e_1_2_11_10_1","first-page":"305","article-title":"Dwarfism, oligophrenia and degeneration of the elastic tissue in skin and cornea. A new syndrome?","volume":"23","author":"De Barsy AM","year":"1968","journal-title":"Helv Paediatr Acta"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.19.2853"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010022\u201001013\u20102"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.413"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2008.91"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.34057"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2014.05.003"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv143"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.08.001"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv247"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgc4.1621"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62856"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13848"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14010145"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.01.008"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.09.003"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003828\u20101"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.3"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3330"},{"key":"e_1_2_11_33_1","first-page":"396","volume-title":"Methods in enzymology","author":"Eisenberg D","year":"1997"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2007.45"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp148"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCD.0b013e3282f4a964"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15824"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50821"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes14020328"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.1047474"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12040461"},{"journal-title":"J Gene Med","article-title":"Rare genetic disorders: beyond whole\u2010exome sequencing","author":"Umair M","key":"e_1_2_11_42_1"},{"issue":"2","key":"e_1_2_11_43_1","first-page":"90","article-title":"Whole exome sequencing as a diagnostic tool for genetic disorders in Pakistan","volume":"57","author":"Umair M","year":"2018","journal-title":"Pak J Med Res"}],"container-title":["The Journal of Gene Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jgm.3522","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,2]],"date-time":"2023-10-02T02:12:36Z","timestamp":1696212756000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jgm.3522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,29]]},"references-count":42,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1002\/jgm.3522"],"URL":"https:\/\/doi.org\/10.1002\/jgm.3522","archive":["Portico"],"relation":{},"ISSN":["1099-498X","1521-2254"],"issn-type":[{"type":"print","value":"1099-498X"},{"type":"electronic","value":"1521-2254"}],"subject":[],"published":{"date-parts":[[2023,4,29]]},"assertion":[{"value":"2023-02-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e3522"}}