# Rare Genetic Variants Underlying Primary Immunodeficiency: Clinical, Pulmonary, and Genetic Insights from Two Pediatric Cases

## TL;DR

This paper reports two rare genetic immune disorders in children from Kazakhstan, highlighting the importance of genetic testing in diagnosing and understanding these conditions.

## Contribution

The study identifies two novel genetic variants in underrepresented Central Asian populations with primary immunodeficiency.

## Key findings

- A novel homozygous FBLN5 variant was found in a child with bronchopulmonary disease and connective tissue abnormalities.
- A heterozygous ATM variant was identified in an adolescent with neurodegeneration and chronic pancreatitis.
- Genomic diagnostics were crucial for diagnosing atypical presentations of primary immunodeficiency disorders.

## Abstract

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.