# Centralized rapid genetic diagnosis of combined immunodeficiency in Japan

## TL;DR

This study shows how rapid genetic testing in Japan helps diagnose severe immune disorders in children, leading to timely and effective treatments.

## Contribution

The study introduces a centralized genetic testing approach for combined immunodeficiency in Japan, improving diagnosis and treatment linkage.

## Key findings

- 70.8% of infants with low TREC were genetically diagnosed with SCID/AT, compared to 26.5% of older children.
- Genetic diagnosis was rare in patients with normal TREC, with only 6.9% identified.
- Over 80% of diagnosed patients in Japan were linked to appropriate treatments after diagnosis.

## Abstract

Severe combined immunodeficiency (SCID) is a pediatric emergency, and rapid genetic diagnosis is necessary for proper patient management, leading to successful stem cell transplantation and gene therapy. Ataxia telangiectasia (AT) requires early diagnosis to prevent infectious diseases and early detection of cancer. We aimed to diagnose patients with SCID/AT as quickly as possible and link them to the best treatments via the primary immunodeficiency database in Japan (PIDJ) network.

For 111 patients with suspected combined immunodeficiency, including SCID/AT, we analyzed T‐cell receptor excision circle (TREC) and sequenced 29 causative genes of SCID, including ATM, by ion semiconductor sequencing using multiplex polymerase chain reaction amplicons. In some cases, DNA extracted from dried blood spots was used for the analysis.

Approximately 70.8% of 0–1‐year‐old patients and 26.5% of the patients >2 years old with low TREC were diagnosed genetically, including ADA, ATM, IL2RG, IL7R, JAK3, RAG1, RAG2, DCLRE1C, NHEJ1, and LIG4. However, only 6.9% of patients with normal TREC were genetically diagnosed (STIM1 and ATM) in our panel. In Japan, all patients had been genetically diagnosed after infection or other life‐threatening conditions, and >80% of patients are linked to appropriate treatment after diagnosis.

Target gene sequencing, including SCID and AT genes, was useful for the diagnosis of patients with combined immunodeficiency with low TREC and to lead them to prompt treatment and better prognosis.