Utilization of Next-generation Sequencing to Define the Role of Heterozygous Variants in Immunodeficiency

Overview

Journal J Allergy Clin Immunol Glob

Specialty Allergy & Immunology

Date 2024 May 27

PMID 38800615

Authors

Yehonatan Pasternak

Linda Vong

Daniele Merico

Laura Abrego Fuentes

Ori Scott

Marina Sham

Meghan Fraser

Abby Watts-Dickens

Jessica Willett Pachul

Vy H D Kim

Christian R Marshall

Stephen Scherer

Chaim M Roifman

Affiliations

Soon will be listed here.

Abstract

Background: Forkhead box protein N1 (FOXN1) transcription factor plays an essential role in the development of thymic epithelial cells, required for T-cell differentiation, maturation, and function. Biallelic pathogenic variants in cause severe combined immunodeficiency (SCID). More recently, heterozygous variants in identified by restricted gene panels, were also implicated with causing a less severe and variable immunodeficiency.

Objective: We undertook longitudinal follow-up and advanced genetic investigations, including whole exome sequencing and whole genome sequencing, of newborns with a heterozygous variant in

Methods: Five patients (3 female, 2 male) have been followed since they were first detected with low T-cell receptor excision circles during newborn screening for SCID. Patients underwent immune evaluation as well as genetic testing, including a primary immunodeficiency panel, whole exome sequencing, and whole genome sequencing in some cases.

Results: Median follow-up time was 6.5 years. Initial investigations revealed low CD3 T lymphocytes in all patients. One patient presented with extremely low lymphocyte counts and depressed phytohemagglutinin responses leading to a tentative diagnosis of SCID. Over a period of 2 years, CD3 T-cell counts rose, although in some patients it remained borderline low. One of 5 children continues to experience recurrent upper respiratory infections and asthma episodes. The remaining are asymptomatic except for eczema in 2 of 5 cases. Lymphocyte proliferation responses to phytohemagglutinin were initially low in 3 patients but normalized by age 10 months. In 3 of 5 cases, T lymphocyte counts remain low/borderline low.

Conclusion: In cases of monoallelic variants, using whole exome sequencing and whole genome sequencing to rule out possible other significant pathogenic variants allowed us to proceed with confidence in a conservative manner, even in extreme cases consistent with newborn screen-positive early presentation of SCID.

Citing Articles

Pre-T cell receptor-α immunodeficiency detected exclusively using whole genome sequencing.

Merico D, Sharfe N, Dadi H, Thiruvahindrapuram B, de Rijke J, Dahi Z NPJ Genom Med. 2025; 10(1):2.

PMID: 39805825 PMC: 11730320. DOI: 10.1038/s41525-024-00453-5.

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