{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:12:40Z","timestamp":1785413560432,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01AR077563"],"award-info":[{"award-number":["R01AR077563"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01AR077563"],"award-info":[{"award-number":["R01AR077563"]}],"id":[{"id":"https:\/\/ror.org\/006zn3t30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inherited ichthyoses are clinically and genetically heterogeneous disorders of cornification caused by disruption of epidermal barrier genes involved in keratinization and lipid homeostasis. Pathogenic variants in more than 50 genes have been implicated in nonsyndromic ichthyosis vulgaris (IV) and autosomal recessive congenital ichthyosis (ARCI). Here, we investigated the genetic basis of ichthyosis in four consanguineous Pakistani families presenting with IV or ARCI phenotypes. Exome sequencing followed by segregation analysis identified pathogenic variants in four established ichthyosis-associated genes: CYP4F22, FLG, ALOX12B, and NIPAL4. Identified variants include one novel nonsense allele of CYP4F22 (c.296G&gt;A; p.Trp99*) and three known variants previously not reported in the Pakistani population. These known variants include a nonsense change in FLG, a frameshift allele of ALOX12B, and a missense variant in NIPAL4. Standardized phenotypic annotation using Human Phenotype Ontology terms revealed overlapping but variable clinical features across families, consistent with known genotype\u2013phenotype heterogeneity in inherited ichthyosis. In silico protein modeling using AlphaFold2 and Ramachandran plot analysis predicted structural perturbations associated with the identified variants, supporting their pathogenic relevance. Publicly available scRNAseq datasets revealed greater heterogeneity of keratinocyte-associated expression patterns of these ichthyosis-associated genes in aging samples. Collectively, our findings expand the allelic and phenotypic spectrum of inherited ichthyosis in the Pakistani population and highlight the utility of comprehensive genetic analysis in consanguineous families for accurate molecular diagnosis, genetic counseling, and disease epidemiology.<\/jats:p>","DOI":"10.3390\/ijms27104639","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T13:53:24Z","timestamp":1779371604000},"page":"4639","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Pathogenic Variants in CYP4F22, FLG, ALOX12B, and NIPAL4 in a Case Series of Inherited Ichthyosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Malali Abdul","family":"Sattar","sequence":"first","affiliation":[{"name":"Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amna Aurang","family":"Zaib","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"},{"name":"Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54590, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda","family":"Abbasi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0875-4611","authenticated-orcid":false,"given":"Mirza Zain Ul","family":"Abideen","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saima","family":"Riazuddin","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"},{"name":"Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54590, Pakistan"},{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2914-4502","authenticated-orcid":false,"given":"Zubair M.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"},{"name":"Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54590, Pakistan"},{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"},{"name":"Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3894-3085","authenticated-orcid":false,"given":"Muhammad","family":"Naeem","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jaad.2009.11.020","article-title":"Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sor\u00e8ze 2009","volume":"63","author":"Oji","year":"2010","journal-title":"J. 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