# Combined Immunodeficiency Associated with Two Novel CARMIL2 Mutations: A Case Series

## TL;DR

This paper reports five new cases of a rare immune disorder caused by CARMIL2 gene mutations, including a first-time link to a severe parasitic infection.

## Contribution

The study identifies two novel CARMIL2 mutations and reports the first case of visceral leishmaniasis associated with this condition.

## Key findings

- Five Palestinian patients with CARMIL2 mutations showed diverse immunologic symptoms and infections.
- Two novel homozygous CARMIL2 variants were identified through whole-exome sequencing.
- Recurrent visceral leishmaniasis was observed in one patient, a previously unreported manifestation.

## Abstract

Combined immunodeficiency due to CARMIL2 mutations is a rare autosomal recessive primary immunodeficiency characterized by impaired T-cell activation and function, leading to diverse clinical manifestations. Fewer than 50 cases have been reported worldwide. We describe the clinical and genetic features of five patients from Palestine with homozygous CARMIL2 mutations, including the first documented case of recurrent visceral leishmaniasis associated with this gene defect. This retrospective case series was conducted using whole-exome sequencing to confirm the diagnosis. All patients exhibited significant immunologic symptoms, including chronic dermatitis, cutaneous warts, recurrent respiratory infections, and mucocutaneous candidiasis. Two developed cytomegalovirus-related disease. Genetic analysis revealed two novel homozygous variants: NM_001317026.3:c.1865 C > T (p.Ala622Val) in four patients, and c.1973 C > T (p.Ala658Val) in one. Notably, one adult male developed recurrent visceral leishmaniasis, an unusual presentation not previously reported in the context of CARMIL2 deficiency. Consanguinity was identified in two families. All patients required immunomodulatory therapy, and four were evaluated for hematopoietic stem cell transplantation. This case series underscores the clinical heterogeneity of CARMIL2-associated immunodeficiency and highlights the importance of genetic testing in patients with recurrent or atypical infections, particularly in populations with a high prevalence of consanguinity. The novel link to visceral leishmaniasis expands the known phenotypic spectrum of this condition.

The online version contains supplementary material available at 10.1007/s10875-025-01956-1.