Table 4. Alternative pathways to... | American Society of Hematology

Table 4.

Alternative pathways to diagnose FHL: the genetic and the cellular pathways

Pathway	Predictive value	Recommended diagnostic follow-up
The genetic pathway: genetic observation
Biallelic combination of large deletions, nonsense variants, and other previously well-described disease-causing∗ genetic aberrations in FHL-associated genes	Sufficient for FHL diagnosis	Not necessary but functional validation can be supportive
Biallelic combination of large deletions, nonsense mutations, or previously described genetic aberrations with at least 1 rare missense or noncoding genetic aberration in an FHL-associated gene	Suspicion of FHL	Other diagnostic validation necessary, functional validation recommended
Genetic variant of unknown significance identified in an FHL-associated gene	Undetermined	Other diagnostic validation necessary, functional validation recommended
No genetic variants identified in FHL-associated genes	Undetermined	Other diagnostic validation necessary, functional validation can be supportive
The cellular pathway: functional cellular observation
Absent perforin expression or defective cytotoxic lymphocyte exocytosis†	Strong suspicion of FHL	Genetic analysis necessary
Low perforin expression or impaired cytotoxic lymphocyte exocytosis†	Suspicion of FHL	Genetic analysis necessary and repeated functional analyses recommended
Normal perforin expression and cytotoxic lymphocyte exocytosis†	FHL less likely	Genetic analyses suggested if FHL is clinically suspected

Pathway	Predictive value	Recommended diagnostic follow-up
The genetic pathway: genetic observation
Biallelic combination of large deletions, nonsense variants, and other previously well-described disease-causing∗ genetic aberrations in FHL-associated genes	Sufficient for FHL diagnosis	Not necessary but functional validation can be supportive
Biallelic combination of large deletions, nonsense mutations, or previously described genetic aberrations with at least 1 rare missense or noncoding genetic aberration in an FHL-associated gene	Suspicion of FHL	Other diagnostic validation necessary, functional validation recommended
Genetic variant of unknown significance identified in an FHL-associated gene	Undetermined	Other diagnostic validation necessary, functional validation recommended
No genetic variants identified in FHL-associated genes	Undetermined	Other diagnostic validation necessary, functional validation can be supportive
The cellular pathway: functional cellular observation
Absent perforin expression or defective cytotoxic lymphocyte exocytosis†	Strong suspicion of FHL	Genetic analysis necessary
Low perforin expression or impaired cytotoxic lymphocyte exocytosis†	Suspicion of FHL	Genetic analysis necessary and repeated functional analyses recommended
Normal perforin expression and cytotoxic lymphocyte exocytosis†	FHL less likely	Genetic analyses suggested if FHL is clinically suspected

With documented cases of Mendelian inheritance.

The definitions of defective, low, impaired, and normal are specific for each laboratory and cannot be generalized.