{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T02:30:47Z","timestamp":1761186647456,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan","award":["AP19678933"],"award-info":[{"award-number":["AP19678933"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Inborn errors of immunity (IEIs), formerly known as primary immunodeficiency disorders, are a heterogeneous group of genetic diseases characterized by recurrent infections and multisystem involvement. Although more than 500 distinct entities have been identified, reports from Central Asia remain scarce. This study describes two rare pediatric IEI cases from Kazakhstan, highlighting the importance of genomic diagnostics in underrepresented regions. Methods: Two unrelated male patients with early-onset recurrent infections and systemic complications were evaluated at the University Medical Center, Astana. Clinical and laboratory assessments included immunophenotyping, imaging, and histopathology. Whole-genome sequencing (WGS) was performed, followed by Sanger confirmation and segregation analysis when feasible. Variants were classified according to ACMG\/AMP guidelines. Results: The first case involved a child with recurrent bronchopulmonary disease, pulmonary fibrosis, and connective tissue abnormalities, found to carry a novel homozygous FBLN5:c.53del frameshift variant consistent with autosomal recessive cutis laxa type 1A. The second case concerned an adolescent with progressive neurodegeneration, granulomatous skin lesions, and chronic pancreatitis, who was identified with a heterozygous pathogenic ATM:c.4828dup variant, confirming ataxia\u2013telangiectasia. Both patients required lifelong subcutaneous immunoglobulin therapy. Consanguinity contributed to the genetic risk in the first case, while the second case demonstrated diagnostic delays that emphasized the value of genetic testing. Conclusions: These cases underscore the clinical heterogeneity of IEIs and illustrate the essential role of genomic diagnostics in elucidating atypical presentations. Documenting rare variants and unconventional phenotypes enhances global knowledge, elevates awareness in resource-limited regions, and emphasizes the necessity for early, multidisciplinary care and the enhancement of national registries for rare immunogenetic disorders.<\/jats:p>","DOI":"10.3390\/genes16111247","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:14:02Z","timestamp":1761182042000},"page":"1247","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rare Genetic Variants Underlying Primary Immunodeficiency: Clinical, Pulmonary, and Genetic Insights from Two Pediatric Cases"],"prefix":"10.3390","volume":"16","author":[{"given":"Nurgul","family":"Sikhayeva","sequence":"first","affiliation":[{"name":"National Center for Biotechnology, Korgalzhyn Highway 13\/5, Astana 010000, Kazakhstan"},{"name":"National Holding \u00abQazBioPharm\u00bb, Korgalzhyn Highway 13\/5, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana","family":"Volodchenko","sequence":"additional","affiliation":[{"name":"\u201cUniversity Medical Center\u201d Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5\/1, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Kovzel","sequence":"additional","affiliation":[{"name":"\u201cUniversity Medical Center\u201d Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5\/1, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1477-8780","authenticated-orcid":false,"given":"Aiganym","family":"Toleuzhanova","sequence":"additional","affiliation":[{"name":"\u201cUniversity Medical Center\u201d Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5\/1, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4483-0493","authenticated-orcid":false,"given":"Aliya","family":"Romanova","sequence":"additional","affiliation":[{"name":"National Center for Biotechnology, Korgalzhyn Highway 13\/5, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gulnar","family":"Tortayeva","sequence":"additional","affiliation":[{"name":"\u201cUniversity Medical Center\u201d Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5\/1, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6593-4050","authenticated-orcid":false,"given":"Yelena","family":"Sagandykova","sequence":"additional","affiliation":[{"name":"\u201cUniversity Medical Center\u201d Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5\/1, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Morenko","sequence":"additional","affiliation":[{"name":"Department of Pediatrics with Courses in Allergology, Immunology, Hematology, and Endocrinology, School of Medicine, \u201cMedical University of Astana\u201d NAO, Beibitshilik Street 49\/A, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-4623","authenticated-orcid":false,"given":"Aidos","family":"Bolatov","sequence":"additional","affiliation":[{"name":"Medical School, Shenzhen University, 3688 Nanhai Road, Shenzhen 518060, China"},{"name":"Division of Strategic Development and Science, \u201cHuman Research & Development\u201d LLP, Qabanbay Batyr Ave. 11\/2, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilyas","family":"Akhmetollayev","sequence":"additional","affiliation":[{"name":"National Center for Biotechnology, Korgalzhyn Highway 13\/5, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anar","family":"Shakirova","sequence":"additional","affiliation":[{"name":"\u201cUniversity Medical Center\u201d Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5\/1, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariya","family":"Tagaeva","sequence":"additional","affiliation":[{"name":"\u201cUniversity Medical Center\u201d Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5\/1, Astana 010000, Kazakhstan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sikhayeva, N., Kovzel, E., Volodchenko, S., Toleuzhanova, A., Tortayeva, G., Bukibayeva, G., Zhussupbayeva, Z., and Morenko, M. 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