Rare Genetic Variants Underlying Primary Immunodeficiency: Clinical, Pulmonary, and Genetic Insights from Two Pediatric Cases
Sikhayeva N. Volodchenko S. Kovzel E. Toleuzhanova A. Romanova A. Tortayeva G. Sagandykova Y. Morenko M. Bolatov A. Akhmetollayev I. Shakirova A. Tagaeva M.
November 2025Multidisciplinary Digital Publishing Institute (MDPI)
Genes
2025#16Issue 11
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–telangiectasia. 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.
ataxia-telangiectasia , fbln5 , granulomatous skin lesions , Lax skin syndrome , pediatric rare diseases , primary immunodeficiency , pulmonary fibrosis , whole-exome sequencing
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National Center for Biotechnology, Korgalzhyn Highway 13/5, Astana, 010000, Kazakhstan
National Holding «QazBioPharm», Korgalzhyn Highway 13/5, Astana, 010000, Kazakhstan
“University Medical Center” Corporate Fund, St. Kerey, Zhanibek Khandar Khanov 5/1, Astana, 010000, Kazakhstan
Department of Pediatrics with Courses in Allergology, Immunology, Hematology, and Endocrinology, School of Medicine, “Medical University of Astana” NAO, Beibitshilik Street 49/A, Astana, 010000, Kazakhstan
Medical School, Shenzhen University, 3688 Nanhai Road, Shenzhen, 518060, China
Division of Strategic Development and Science, “Human Research & Development” LLP, Qabanbay Batyr Ave. 11/2, Astana, 010000, Kazakhstan
National Center for Biotechnology
National Holding «QazBioPharm»
“University Medical Center” Corporate Fund
Department of Pediatrics with Courses in Allergology
Medical School
Division of Strategic Development and Science
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