{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T03:00:28Z","timestamp":1773111628488,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,12,4]],"date-time":"2021-12-04T00:00:00Z","timestamp":1638576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007741","name":"University of Hyderabad","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007741","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder caused by mutational inactivation of a developmental pathway responsible for generation of tissues of ectodermal origin. The X\u2010linked form accounts for the majority of HED cases and is caused by <jats:italic>Ectodysplasin<\/jats:italic> (<jats:italic>EDA<\/jats:italic>) pathogenic variants. We performed a combined analysis of 29 X\u2010linked hypohidrotic ectodermal dysplasia (XLHED) families (including 12 from our previous studies). In addition to the classical triad of symptoms including loss (or reduction) of ectodermal structures, such as hair, teeth, and sweat glands, we detected additional HED\u2010related clinical features including facial dysmorphism and hyperpigmentation in several patients. Interestingly, global developmental delay was identified as an unusual clinical symptom in many patients. More importantly, we identified 22 causal pathogenic variants that included 15 missense, four small in\u2010dels, and one nonsense, splice site, and large deletion each. Interestingly, we detected 12 unique (India\u2010specific) pathogenic variants. Of the 29 XLHED families analyzed, 11 (38%) harbored pathogenic variant localized to the furin cleavage site. A comparison with HGMD revealed significant differences in the frequency of missense pathogenic variants; involvement of specific exons and\/or protein domains and transition\/transversion ratios. A significantly higher proportion of missense pathogenic variants (33%) localized to the EDA furin cleavage when compared to HGMD (7%), of which p.R155C, p.R156C, and p.R156H were detected in three families each. Therefore, the first comprehensive analysis of XLHED from India has revealed several unique features including unusual clinical symptoms and high frequency of furin cleavage site pathogenic variants.<\/jats:p>","DOI":"10.1002\/ajmg.a.62579","type":"journal-article","created":{"date-parts":[[2021,12,4]],"date-time":"2021-12-04T13:47:52Z","timestamp":1638625672000},"page":"788-805","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>Ectodysplasin<\/i> pathogenic variants affecting the furin\u2010cleavage site and unusual clinical features define X\u2010linked hypohidrotic ectodermal dysplasia in India"],"prefix":"10.1002","volume":"188","author":[{"given":"Ajay Kumar","family":"Chaudhary","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Oncology Centre for DNA Fingerprinting and Diagnostics  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishwarya","family":"Gholse","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Biology, Department of Systems and Computational Biology, School of Life Sciences University of Hyderabad  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hampapathalu Adimurthy","family":"Nagarajaram","sequence":"additional","affiliation":[{"name":"Laboratory of Computational Biology, Department of Systems and Computational Biology, School of Life Sciences University of Hyderabad  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashwin Bhikaji","family":"Dalal","sequence":"additional","affiliation":[{"name":"Diagnostics Division Centre for DNA Fingerprinting and Diagnostics  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neerja","family":"Gupta","sequence":"additional","affiliation":[{"name":"Division of Genetics, Department of Pediatrics All India Institute of Medical Sciences  New Delhi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8413-3454","authenticated-orcid":false,"given":"Atanu Kumar","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Christian Medical College and Hospital  Vellore India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8973-370X","authenticated-orcid":false,"given":"Sumita","family":"Danda","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Christian Medical College and Hospital  Vellore India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rekha","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Mahatma Gandhi Medical College and Hospital  Jaipur India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hariharan V.","family":"Sankar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics SAT Hospital, Medical College  Trivandrum India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gandham SriLakshmi","family":"Bhavani","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Kasturba Medical College Manipal Academy of Higher Education  Manipal India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0139-8239","authenticated-orcid":false,"given":"Katta M.","family":"Girisha","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Kasturba Medical College Manipal Academy of Higher Education  Manipal India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6624-082X","authenticated-orcid":false,"given":"Shubha Rao","family":"Phadke","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Sanjay Gandhi Postgraduate Institute of Medical Sciences  Lucknow India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7122-3197","authenticated-orcid":false,"given":"Prajnya","family":"Ranganath","sequence":"additional","affiliation":[{"name":"Diagnostics Division Centre for DNA Fingerprinting and Diagnostics  Hyderabad India"},{"name":"Department of Medical Genetics Nizam's Institute of Medical Sciences  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1967-5249","authenticated-orcid":false,"given":"Murali Dharan","family":"Bashyam","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology Centre for DNA Fingerprinting and Diagnostics  Hyderabad India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,12,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21642"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-1110-1"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(05)80360-2"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0073705"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24692"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2011.10707.x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24189"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2010.04.008"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.13587"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2016.06.012"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.131076098"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21384"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.5.21.3403"},{"issue":"1","key":"e_1_2_10_16_1","first-page":"82","article-title":"Pymol: An open\u2010sourced molecular graphics tool","volume":"40","author":"DeLano W. L.","year":"2002","journal-title":"CCP4 Newsletter On Protein Crystallography"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr245"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-013-1985-8"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/85837"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.3109\/08830185.2015.1055331"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12404"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/elps.1150181505"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1985.tb00233.x"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/414913a"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.2142\/biophysics.1.55"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0895-409"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-021-01735-2"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.86"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/ced.13241"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2008.01037.x"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1747.1999.00656.x"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/14.7.617"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1086\/301984"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjd.15045"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320530207"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.053"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-019-0174-9"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2007.08231.x"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(00)02024-2"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1714322"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.084012"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101280200"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0154884"},{"key":"e_1_2_10_44_1","first-page":"12","article-title":"Two cases in which the skin, hair and teeth were very imperfectly developed","volume":"31","author":"Thurnam J.","year":"1848","journal-title":"Proceedings of the Royal Society of Medicine"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13353-015-0307-4"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5200635"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32864"},{"issue":"1","key":"e_1_2_10_48_1","first-page":"97","article-title":"Recent advances in understanding of the molecular basis of anhidrotic ectodermal dysplasia: Discovery of a ligand, ectodysplasin a and its two receptors","volume":"43","author":"Wisniewski S. A.","year":"2002","journal-title":"Journal of Applied Genetics"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2016.75"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62579","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.62579","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62579","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T00:02:38Z","timestamp":1692576158000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.62579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,4]]},"references-count":48,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,3]]}},"alternative-id":["10.1002\/ajmg.a.62579"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.62579","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,4]]},"assertion":[{"value":"2021-07-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-12-04","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}