Clinical and genetic features of UNC13D deficiency with hypogammaglobulinemia

Linyan Xiong¹Qin Zhao^2,3,4,5Qian Zhao^2,3,4,5Zhiyong Zhang^1,2,3,4,5Yunfei An^1,2,3,4,5Xuemei Tang^1,2,3,4,5Hirokazu Kanegane⁶Xi Yang^1,2,3,4,5*Xiaodong Zhao^1,2,3,4,5*

• ¹Department of Rheumatology and Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, China
• ²Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
• ³National Clinical Research Centre for Child Health and Disorders, Chongqing, China
• ⁴China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China
• ⁵Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China
• ⁶Department of Child Health and Development, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

Background: UNC13D deficiency is the most common form of familial hemophagocytic lymphohistiocytosis (FHL) in Asia. Hypogammaglobulinemia is a rare phenotype observed in both patients with FHL3 and sporadic hemophagocytic lymphohistiocytosis (HLH). Our observations suggest that UNC13D deficiency with hypogammaglobulinemia presents a distinct clinical phenotype compared to other HLH patients. This finding provides valuable clinical insights and may contribute to a more comprehensive understanding of the disease, highlighting the need for further investigation into its genetic and clinical characteristics. Methods: We retrospectively analyzed the clinical features of five patients with UNC13D deficiency with hypogammaglobulinemia at our center, along with a literature review. The clinical findings were then compared with those of sporadic HLH patients presenting with hypogammaglobulinemia. Results: All patients experienced respiratory infections, with two patients showing recurrent episodes. Seizures were observed in 75% of the patients. HLH-related biomarkers were present in all patients. The four patients who did not undergo allogeneic hematopoietic stem cell transplantation (HSCT), all died. Eight variant sites were identified, with 25% located in exon 9 and another 25% in exon 20. The majority (66.67%) of the variants were found in the region responsible for interaction with RAB27α. UNC13D deficiency with hypogammaglobulinemia was associated with a higher frequency of respiratory manifestations, neurological involvement, and an increased mortality rate. Conclusions: Our study presents the first comprehensive description of the clinical features of UNC13D deficiency with hypogammaglobulinemia. Patients with this condition tend to exhibit more severe clinical manifestations and a poorer prognosis. Allogeneic HSCT may help mitigate immune dysregulation.