Incomplete penetrance in primary immunodeficiency: a skeleton in the closet.

Abstract:

:Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.

journal_name

Hum Genet

journal_title

Human genetics

authors

Gruber C,Bogunovic D

doi

10.1007/s00439-020-02131-9

subject

Has Abstract

pub_date

2020-06-01 00:00:00

pages

745-757

issue

6-7

eissn

0340-6717

issn

1432-1203

pii

10.1007/s00439-020-02131-9

journal_volume

139

pub_type

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