Familial Hemophagocytic Lymphohistiocytosis (FHL) Panel

Hemophagocytic Lymphohistiocytosis (HLH) is a rapidly progressing, hyperinflammatory condition in which activated T cells and macrophages infiltrate numerous organs. Clinical manifestations include fever, hepatosplenomegaly, pancytopenia, hemophagocytosis, severely attenuated or absent NK cell function, elevated iron levels, and elevated soluble CD25 (Henter et al. 2007. PubMed ID: 16937360). Familial (primary) HLH (FHL) and sporadic (secondary) HLH are clinically similar, and both types are often, but not always, triggered by viral infections (Epstein-Barr virus, EBV), rheumatic disorders, and malignancies. The incidence of FHL is approximately 1 in 50,000 live births with 70-80% of patients showing clinical symptoms during infancy (Aricò et al. 1996. PubMed ID: 8637226; Janka. 1983. PubMed ID: 6354720). Though rare, cases of late-onset, adult FHL have been reported in patients ranging in age from their twenties to sixties (Allen et al. 2001. PubMed ID: 11410413; Clementi et al. 2002. PubMed ID: 12229880; Nagafuji et al. 2007. PubMed ID: 17606450). Males with HLH may have X-linked Lymphoproliferative Disorder (XLP) that may include gammaglobulinemia, and lymphoma (Coffey et al. 1998. PubMed ID: 9771704; Arico et al. 2001. PubMed ID: 11159547; Rigaud et al. 2006. PubMed ID: 17080092; Booth et al. 2011. PubMed ID: 20926771).

FHL is primarily an autosomal recessive or X-linked disorder, though a few autosomal dominant conditions are associated with FHL (see below). Over 75% of FHL cases can be attributed to pathogenic variants in one of six genes: PRF1 (FHL Type 2), UNC13D (FHL Type 3), STX11 (FHL Type 4), STXBP2 (FHL Type 5), and the XIAP and SH2D1A genes (both are associated with X-linked FHL). Pathogenic variants in PRF1 account for 20-40% of all FHL cases and pathogenic variants in UNC13D, STX11, and STXBP2 account for approximately 20-25%, 14%, and 10% of FHL cases, respectively (Gholam et al. 2011. PubMed ID: 21303357). Around 60% of X-linked FHL is caused by pathogenic variants in the SH2D1A gene (Coffey et al. 1998. PubMed ID: 9771704; Gilmour et al. 2000. PubMed ID: 10898506; Yin et al. 1999. PubMed ID: 10598819; Nichols et al. 1998. PubMed ID: 9811875).

Several other disorders and genes are associated with FHL including the following: Griscelli syndrome (RAB27A; Meschede et al. 2008. PubMed ID: 19030707), Chediak-Higashi syndrome (LYST; Karim et al. 2002. PubMed ID: 11857544), Hermansky-Pudlak syndrome (AP3B1; Clark et al. 2003. PubMed ID: 14566336, BLOC1S6; Badolato et al. 2012. PubMed ID: 22461475), Lymphoproliferative syndrome 1 (ITK; Linka et al. 2012. PubMed ID: 22289921), Immunodeficiency 41 with lymphoproliferations and autoimmunity (IL2RA; Goudy et al. 2013. PubMed ID: 23416241), Immunodeficiency due to purine nucleoside phosphorylase deficiency (PNP; Al-Mousa et al. 2016. PubMed ID: 26915675), X-linked immunodeficiency (IL2RG; Puck et al. 1997. PubMed ID: 9058718, MAGT1; Li et al. 2011. PubMed ID: 21796205), Lymphoproliferative syndrome 2 (CD27; Salzer et al. 2013. PubMed ID: 22801960), Lysinuric protein intolerance (SLC7A7; Font-Llitjos et al. 2009. PubMed ID: 18716612), severe combined immunodeficiency (ADA; Valerio et al. 1986. PubMed ID: 3007108), Wiskott-Aldrich syndrome (WAS; Jin et al. 2004. PubMed ID: 15284122), Hyper-IgD syndrome (MVK; Mandey et al. 2006. PubMed ID: 16835861), X-linked Agammaglobulinemia (BTK; Conley et al. 1998. PubMed ID: 9545398), combined immunodeficiency (CD70; Izawa et al. 2017. PubMed ID: 28011863), familial Mediterranean fever (MEFV; French FMF Consortium. 1997. PubMed ID: 9288094), Autoinflamation (autosomal recessive and autosomal dominant inheritance, NLRC4; Canna et al. 2014. PubMed ID: 25217959), Multisystem inflammatory disease (autosomal dominant inheritance, NLRP3; Jesus et al. 2008. PubMed ID: 18080732), Periodic fever (autosomal dominant inheritance, TNFRSF1A; Cantarini et al. 2012. PubMed ID: 22884554).

Causative variants in the FHL-associated genes are primarily missense/nonsense variants, splice-site variants, and small insertions and deletions. Large, multi-exon and whole gene deletions have been reported in some of the most common FHL associated genes including STX11 and RAB27A, and particularly the X-linked genes XIAP and SH2D1A in which deletions make up ~ 17% and 20% of the unique reported pathogenic variants, respectively. Large deletions and/or duplications have also been reported in the AP3B1, IL2RG, MAGT1, SLC7A7, ADA, WAS, MVK, and BTK genes and generally make up a small fraction of the unique pathogenic variants reported for each gene.

This test does include analysis of a known pathogenic inversion involving the UNC13D gene that was observed in 7% of FHL patients in one report (Meeths et al. 2011. PubMed ID: 21931115; Qian et al. 2014. PubMed ID: 24470399).

See individual gene test descriptions for information on molecular biology of gene products.

Over 75% of Familial Hemophagocytic Lymphohistiocytosis (FHL) cases can be attributed to pathogenic variants in one of six genes: PRF1 (FHL Type 2), UNC13D (FHL Type 3), STX11 (FHL Type 4), STXBP2 (FHL Type 5), and the XIAP and SH2D1A genes (both are associated with X-linked FHL). Pathogenic variants in PRF1 account for 20-40% of all FHL cases and pathogenic variants in UNC13D, STX11, and STXBP2 account for approximately 20-25%, 14%, and 10% of FHL cases, respectively (Gholam et al. 2011. PubMed ID: 21303357). Around 60% of X-linked FHL is caused by variants in the SH2D1A gene (Coffey et al. 1998. PubMed ID: 9771704; Gilmour et al. 2000. PubMed ID: 10898506; Yin et al. 1999. PubMed ID: 10598819; Nichols et al. 1998. PubMed ID: 9811875).

Large, multi-exon and whole gene deletions have been reported in some of the most common FHL associated genes, including STX11 and RAB27A, and particularly the X-linked genes XIAP and SH2D1A in which deletions make up ~ 17% and 20% of the unique reported pathogenic variants, respectively. Large deletions and/or duplications have also been reported in the AP3B1, IL2RG, MAGT1, SLC7A7, ADA, WAS, MVK, and BTK genes and generally make up a small fraction of the unique pathogenic variants reported for each gene.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 99.8% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).