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Test Code LAB3800 ImmuneSeq Familial Hemophagocytic Lymphohistiocytosis (FHLH) DNA Sequencing

Clinical System Name

ImmuneSeq Familial Hemophagocytic Lymphohistiocytosis (FHLH) DNA Sequencing

Description

Clinical Features

Familial hemophagocytic lymphohistiocytosis (fHLH) is an immune disorder characterized by excessive activation of T lymphocytes and macrophages leading to hyperinflammation that results in organ dysfunction. The clinical presentation of fHLH is typically acute illness with a prolonged fever, cytopenias, and hepatosplenomegaly (Zhang et al., 2021). The laboratory findings strongly associated with fHLH include decreased expression of perforin and decreased NK cell degranulation as determined by the CD107a assay. Additional laboratory findings that may be suggestive of fHLH include hemophagocytosis observed in biopsied tissues, elevated levels of ferritin, IL-2 receptor, and serum cytokines, and increased expression of granzyme B and T cell HLA-DR (Zhang et al., 2021). The diagnosis of fHLH is established based on fulfillment of specific clinical and laboratory criteria and/or  identification of biallelic pathogenic variants in one of four genes (PRF1, STX11, STXBP2, or UNC13D) or a heterozygous gain-of-function variant in STXBP2. Several genetic conditions have been associated with predisposition to HLH including pigmentary disorders, X-linked lymphoproliferative diseases, and EBV susceptibility disease (Canna and Marsh, 2020). In addition, specific inborn errors of immunity can include HLH as a clinical feature and may be considered in the differential diagnosis of fHLH (Canna and Marsh, 2020; Zhang et al., 2021).

 

The Seattle Children’s Hospital Molecular Laboratory offers testing for 33 genes on the Familial Hemophagocytic Lymphohistiocytosis (fHLH) panel. Reported genes are listed below.

 

Prevalence

The estimated incidence of the fHLH has been reported as 1:50,000 births (Janka and zur Stadt, 2005).

 

Inheritance                                                                                

fHLH is typically inherited in an autosomal recessive matter as the result of biallelic pathogenic variants in the PRF1, STX11, STXBP2, or UNC13D genes. In rare cases, fHLH can result from a heterozygous gain-of-function variant in STXBP2 (Zhang et al., 2021).

 

ImmuneSeq Familial Hemophagocytic Lymphohistiocytosis (FHLH) DNA Sequencing​​: AP3B1, BTK, CEBPE, CD27, CD40LG, CD70, CTPS1, FAAP24, ITK, LRBA, LYST, MAGT1, MCM4, MVK, NFKB1, NLRC4, PIK3CD, PIK3R1, PNP, PRF1, PRKCD, RAB27A, RAC2, RASGRP1, RHOG, SH2D1A, SLC7A7, STK4, STX11, STXBP2, UNC13D**, WAS, XIAP

**The UNC13D 253 kb inversion described in the literature (Meeths et al., 2011) is outside of the target region and will not be detected by this assay.

 

Additional testing options - we offer the following additional options for custom Immunodeficiency testing:

 

Please contact LabGC@seattlechildrens.org if you would like to order reflexive testing after the original testing report has been issued.

Sample Requirements

Note: For patients who have had a whole blood transfusion, wait 10 days post transfusion to draw for genetic testing. No wait time is necessary for blood or saliva collection if the patient received leuko-reduced red cells or plasma.

 

Specimen: Whole blood

Container(s): Lavender/EDTA

Preferred Vol: 3 mL

Minimum Vol: 1 mL

Note: Heparin samples (Green tops) are unacceptable.

 

Specimen: Saliva collected using Oragene Dx OGD-575/675 collection kit.

Container: Oragene Dx OGD-575/675 collection kit

IMPORTANT NOTE: Manufacturer instructions must be followed. The Oragene Dx OGD575/675 kit is not for children under 6 months. Contact the lab directly for more information or to obtain a kit - 206-987-2617

 

Specimen: Extracted DNA (MUST specify source on requisition)

Preferred: 10µg

Minimum: 5µg

Note: Isolation of nucleic acids for clinical testing must be performed in a CLIA-certified
laboratory or a laboratory meeting equivalent requirements as determined by the CAP
and/or the CMS. DNA concentration minimum 50 µg/mL; 260/280 ratio 1.70-2.00.

 

Specimen: Skin biopsy (MUST specify source on requisition)

Preferred: 2-4 mm punch biopsy of skin collected under sterile conditions refrigerated with 1-3 mL of tissue transport medium.

Note:  DO NOT use formaldehyde, formalin, alcohol, or 5% dextrose. Do not freeze.

 

Specify tissue source and site on requisition.

Processing Instructions

 

Specimen Type Description

Temperature

 Storage instructions
Whole blood EDTA or ACD tube Refrigerate Molecular Genetics box in CPA refrigerator #2
Extracted DNA DNA aliquot tube Refrigerate Molecular Genetics box in CPA refrigerator #2
Saliva OGD-575/675 kit Room Temp Place in CPA Cytogenetics room temp box with requisition
Skin biopsy with 1-3 mL of tissue transport medium Refrigerate Molecular Genetics box in CPA refrigerator #2

Off-site collection: Refrigerate blood samples until ready to ship.  Transport blood, saliva, or DNA at room temperature via overnight shipping.

Stability

Stability

Specimen Type Temperature Time
Whole blood, extracted DNA RT 3-5 d
Whole blood, extracted DNA 2 - 8 C

7 d

Saliva, extracted from ORAgene Dx OGD-575/675

 Room temperature or refrigerated up to 2 weeks
Extracted DNA -20 C or -70 C  years
Skin biopsy Refrigerated (in medium) 3 days

Note: Whole blood samples > 7days may be submitted to be assessed by our lab for acceptability for testing.

Availability

STAT Performed TAT
Contact lab Monday - Friday 4-6 weeks

Performing Laboratory

Seattle Children's Laboratory

Department

Department:  Molecular Genetics Laboratory

Phone: 206-987-3872

Lab Client Services: 206-987-2617

Lab Genetic Counselor: LabGC@seattlechildrens.org

CPT Codes

81479

Methodology

Method: Next Generation Sequencing technology using an Illumina NextSeq instrument. Target region includes coding exons and a minimum of 10 bp of flanking intron boundaries of the genes tested. Target enrichment performed using a custom Integrated DNA Technologies (IDT) Exome Hyb Panel v2. 

 

Average coverage ~150x.

 

Limitations:

This testing is performed on an exome backbone with analysis restricted to the panel genes. This method can detect single nucleotide variants (SNVs), small deletions, small insertions, and copy number variants in the regions targeted. Some regions cannot be efficiently captured due to sequence homology or sequence properties. This method will not detect large insertions and deletions, complex indels, structural variants (e.g. inversions, translocations), short tandem repeats, or other complex variants. Variants located outside of targeted regions will not be detected.

 

Based on validation studies, the bioinformatics pipeline showed precision and detection >99% for SNVs in regions with coverage greater than 20x and high mapping quality. Sensitivity for CNVs involving multiple genes is >99% and sensitivity for intragenic CNVs is >90%. Mosaic sequence variants present at <25% allele frequency may not be reliably detected, and detection sensitivity is dependent on the nature of the variant. The sensitivity of detection of mosaic copy number variants has not been evaluated.

 

Reported Gene Lists

The Seattle Children's Hospital Molecular Laboratory offers different immune disorder panels based on clinical presentation with additional testing options. Reported gene lists are below and detailed descriptions are available. All panels include copy number analysis and may identify mosaicism.

 

ImmuneSeq Panel

Genes

Severe combined immunodeficiency (SCID) – 149 genes

ACD, ADA, AK2*, ARPC1B, ATM, BACH2, B2M, BCL10, BCL11B, BLM, CARD11, CARMIL2, CCBE1, CD247, CD27, CD28, CD3D, CD3E, CD3G, CD40, CD40LG, CD8A, CDCA7, CHD7, CIITA, CORO1A*, CRACR2A, CTC1, CTPS1, CXCR4, DCLRE1B, DCLRE1C*, DIAPH1, DKC1, DNMT3B, DOCK2, DOCK8, EPG5, ERBIN, ERCC6L2, EXTL3, FADD, FAT4, FCHO1, FOXI3, FOXN1, GINS1, HELLS, ICOS, ICOSLG, IKBKB, IKBKG*, IKZF1, IKZF3, IL21, IL21R, IL2RG, IL6R, IL6ST, IL7, IL7R, ITK, JAK3, KDM6A, KMT2D, LAT, LCK, LIG1, LIG4, LRBA, MAGT1, MALT1, MAP3K14, MCM4, MCM10, MSN, MTHFD1, MYSM1, NBN, NFE2L2, NFKBIA, NHEJ1, NHP2, NOP10, NSMCE3, OTULIN, ORAI1, PARN, PAX1, PGM3, PIK3CD, PIK3R1, PMS2, PNP, POLA1, POLD1, POLD2, POLE, POLE2, PRKDC, PTPRC, RAC2, RAG1, RAG2, RBCK1, REL, RELA, RELB, RFX5, RFXANK, RFXAP, RHOH, RMRP, RNF168, RNF31, RNU4ATAC, RTEL1, SEMA3E, SH2D1A, SKIC2/SKIV2L, SKIC3/TTC37, SLC46A1, SMARCAL1, SP110, SPINK5, STAT3, STAT5B, STIM1, STK4, STN1, TAP1, TAP2, TAPBP, TBX1, TCN2, TERC, TERT, TFRC, TINF2, TNFRSF4, TP63, TPP2, TRAC, TTC7A, WAS, WIPF1, ZAP70, ZBTB24, ZNF341

Autoimmune Lymphoproliferative Syndrome (ALPS) – 21 genes

BACH2, CASP10, CASP8, CD70, CTLA4, FADD, FAS, FASLG, ITCH, ITK, JAK1, MAGT1, OTULIN, PIK3CD, PIK3R1, PRKCD, RELA, STAT3, TET2, TNFRSF6B,TPP2

Familial Hemophagocytic Lymphohistiocytosis (FHLH) – 33 genes

AP3B1, BTK, CEBPE, CD27, CD40LG, CD70, CTPS1, FAAP24, ITK, LRBA, LYST, MAGT1, MCM4, MVK, NFKB1, NLRC4, PIK3CD, PIK3R1, PNP, PRF1, PRKCD, RAB27A, RAC2, RASGRP1, RHOG, SH2D1A, SLC7A7, STK4, STX11, STXBP2, UNC13D**, WAS, XIAP

Very Early Onset Inflammatory Bowel Disease (VEO-IBD)/Early Onset Enteropathy – 114 genes

ADA, ADAM17, AICDA, ALG6, ALPI, ANKZF1, AP3B1, AP3D1, ARPC1B, BACH2, BTK, CARD11, CARD8, CARMIL2, CASP8, CD3G, CD40, CD40LG, CD55, COL7A1, CTLA4, CYBA, CYBB, CYBC1, CYP27A1, DCLRE1C*, DEF6, DGAT1, DKC1, DOCK8, DUOX2, EGFR, EPCAM, FCHO1, FERMT1, FOXP3, G6PC3, GUCY2C, HPS1*, HPS3, HPS4, HPS5, HPS6, HRAS, ICOS, IKBKG*, IL10, IL10RA, IL10RB, IL21, IL2RA, IL2RB, IL2RG, ITCH, ITGB2, JAK1, LCT, LIG4, LIPA, LRBA, MALT1, MEFV, MVK, MYO5B, NCF1*, NCF2, NCF4, NEUROG3, NFAT5, NFKB1, NFKBIA, NLRC4, NLRP12, NOD2, NPC1, PIK3CD, PIK3R1, PLCG2, PLVAP, POLA1, PTEN, RAC2, RAG1, RAG2, RIPK1, RTEL1, SAR1B, SH2D1A, SI, SKIC2/SKIV2L, SKIC3/TTC37, SLC26A3, SLC37A4, SLC9A3, SLCO2A1, SPINT2, STAT1, STAT3, STAT5B, STIM1, STX3, STXBP2, TGFB1, TGFBR1, TGFBR2, TNFAIP3, TRIM22, TTC7A, UNC45A, WAS, XIAP, ZAP70, ZBTB24, ZNF341

Expanded – 738 genes

ABCB7, ABCG5, ABCG8, ACD, ACP5, ACTB*, ACTG1, ACTN1, ADA, ADA2, ADAM17, ADAMTS13, ADAMTS3, ADAR, ADIPOQ, ADIPOR1, ADIPOR2, AICDA, AIRE, AK2*, ALAS2, ALG6, ALPI, AMN, ANGPT1, ANKRD11, ANKRD26, ANKZF1, AP1S3, AP3B1, AP3D1, APOL1, ARHGEF1, ARPC1B, ASAH1, ATAD3A, ATG4A, ATM, ATP11C, ATP6AP1, ATR, ATRX, B2M, BACH1, BACH2, BANK1, BCL10, BCL11B, BCO1, BLK, BLM, BLNK, BLOC1S3, BLOC1S6, BRAF, BRCA1, BRCA2, BRIP1, BTK, C1QA, C1QB, C1QBP, C1QC, C1R, C1S, C2, C2orf69, C3, C3AR1, C4BPA, C4BPB, C5, C5AR1, C5AR2, C6, C7, C8A, C8B, C8G, C9, CARD11, CARD14, CARD8, CARD9, CARMIL2, CASP10, CASP8, CBL, CCBE1, CCDC103, CCDC39, CCDC40, CCDC65, CCNK, CCNO, CD19, CD247, CD27, CD28, CD3D, CD3E, CD3G, CD40, CD40LG, CD46, CD55, CD59, CD70, CD79A, CD79B, CD81, CD8A, CD93, CDAN1, CDC42*, CDCA7, CDK9, CDKN2A, CEBPA, CEBPE, CENPF, CFAP298, CFAP300, CFB, CFD, CFH*, CFI, CFP, CFTR*, CHD7, CHEK2*, CHUK, CIB1, CIITA, CLCN7, CLEC7A, CLPB, CLU, COG6, COL7A1, COLEC11, COPA, COPG1, CORO1A*, CPT2, CR2, CRACR2A, CREBBP, CRP, CSF2RA*, CSF2RB, CSF3R, CTC1, CTLA4, CTNNBL1, CTPS1, CTSC, CXCR2, CXCR4, CYBA, CYBB, CYBC1, CYCS*, CYP27A1, DBR1, DCLRE1B, DCLRE1C*, DDX11*, DDX41, DEF6, DGAT1, DGKE, DHFR*, DIAPH1, DKC1, DNAAF1, DNAAF11/LRRC6, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAAF6/PIH1D3, DNAH1, DNAH11, DNAH5, DNAH8, DNAH9, DNAI1, DNAI2, DNAJB13, DNAJC21, DNALI1, DNASE1L3, DNASE2, DNMT3B, DOCK11, DOCK2, DOCK8, DRC1, DSG1, DTNBP1, DUOX2, EFL1, EGFR, EIF2AK3, ELANE, ELF4, EPCAM, EPG5, EPO, ERBIN, ERCC2, ERCC3, ERCC4, ERCC6L2, ETV6, EXTL3, F12, FAAP100, FAAP24, FADD, FANCA, FANCB, FANCC, FANCD2*, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FAS, FASLG, FAT4, FCGR2A, FCGR2B*, FCGR3A, FCGR3B, FCHO1, FCN1, FCN2, FCN3, FERMT1, FERMT3, FLG, FLI1, FLNA, FNIP1, FOXI3, FOXN1, FOXP3, FPR1, FYB1, G6PC1/G6PC, G6PC3, G6PD, GAS2L2, GAS8, GATA1, GATA2, GBA1*, GFI1, GFI1B, GINS1, GLRX5, GNE, GP1BA, GP1BB, GP9, GTF2E2, GTF2H5, GUCY2C, HAVCR2, HAX1, HCK, HELLS, HMOX1, HNRNPK, HOXA11, HPS1*, HPS3, HPS4, HPS5, HPS6, HRAS, HSPA9, HTRA2, HYDIN*, HYOU1, ICOS, ICOSLG, IFIH1, IFNAR1, IFNAR2, IFNG, IFNGR1, IFNGR2, IGHM, IGKC, IGLL1, IKBKB, IKBKG*, IKZF1, IKZF2, IKZF3, IKZF5, IL10, IL10RA, IL10RB, IL12B, IL12RB1, IL12RB2, IL17F, IL17RA, IL17RC, IL18BP, IL18RAP, IL1RN, IL21, IL21R, IL23R, IL2RA, IL2RB, IL2RG, IL36RN, IL6R, IL6ST, IL7, IL7R, INO80, INSYN1, INVS, IRAK1, IRAK4, IRF2, IRF2BP2, IRF3, IRF4, IRF5, IRF7, IRF8, IRF9, ISG15, ITCH, ITGA2B, ITGAM, ITGB2, ITK, ITPKB, JAGN1, JAK1, JAK2, JAK3, KAT6A, KCNN4, KDM1A, KDM6A, KIF23, KLF1, KMT2A, KMT2D, KRAS, LAG3, LAMTOR2, LAT, LCK, LCP2, LCT, LIG1, LIG4, LIPA, LPIN2, LRBA, LRRC56, LRRC8A, LSM11, LYN, LYST, LZTR1, MAD2L2, MAGT1, MALT1, MAN2B1, MAN2B2, MANBA, MAP1LC3B2, MAP2K1, MAP2K2, MAP3K14, MAPK8, MASP1, MASP2, MASTL, MAT2A, MBL2, MCIDAS, MCM10, MCM4, MECOM, MEFV, MLH1, MLPH, MOGS, MPIG6B, MPL, MPLKIP, MPO, MRAS, MRE11, MRTFA, MS4A1, MSH2, MSH6, MSN, MTHFD1, MVK, MYD88, MYH9, MYO5A, MYO5B, MYSM1, NAF1, NBAS, NBEAL2, NBN, NCF1*, NCF2, NCF4, NCKAP1L, NCSTN, NEUROG3, NF1*, NFAT5, NFE2L2, NFIL3, NFKB1, NFKB2, NFKBIA, NHEJ1, NHP2, NLRC4, NLRP1*, NLRP12, NLRP3, NME8, NOD2, NOP10, NOS2, NPC1, NRAS, NSMCE3, NUP214, OAS1, ODAD1/CCDC114, ODAD2/ARMC4*, ODAD3/CCDC151, ODAD4/TTC25, OFD1, ORAI1, OSTM1, OTUD6B, OTULIN, PALB2, PARN, PAX1, PAX5, PDCD1, PEPD, PGM3, PIGA, PIK3CD, PIK3CG, PIK3R1, PLCG2, PLEKHM1*, PLG, PLVAP, PMM2*, PMS2, PNP, POLA1, POLD1, POLD2, POLE, POLE2, POLR3A, POLR3C, POLR3F, POMP, POT1, POU2AF1, PRF1, PRG4, PRKACG, PRKCD, PRKDC, PSEN1, PSENEN, PSMA3, PSMB10, PSMB4, PSMB8, PSMB9, PSMG2, PSTPIP1, PTEN, PTPN11, PTPRC, PTX3, PUS1, RAB27A, RAC2, RAD50, RAD51, RAD51C, RAF1, RAG1, RAG2, RANBP2, RAP1A, RAP1B, RASA2, RASGRP1, RBCK1, RBM8A*, RC3H1, RECQL4, REL, RELA, RELB, RFWD3, RFX5, RFXANK, RFXAP, RHOG, RHOH, RIGI/DDX58, RIPK1, RIT1, RMRP, RNASEH2A, RNASEH2B, RNASEH2C, RNF113A, RNF168, RNF31, RNU4ATAC, RORC, RPGR*, RPL10, RPL11, RPL15, RPL18, RPL19, RPL26, RPL27, RPL31, RPL35A, RPL36, RPL5, RPS10, RPS19*, RPS24, RPS26, RPS27A, RPS28, RPS29, RPS7, RPS9, RPSA, RRAS, RSPH1, RSPH3, RSPH4A, RSPH9, RTEL1, RUNX1, SAMD9, SAMD9L, SAMHD1, SAR1B, SASH3, SBDS*, SBF2, SCO2, SEC23B, SEC61A1, SEMA3E, SERPING1, SH2B3, SH2D1A, SH3BP2, SH3KBP1, SHOC2, SI, SIAE, SKIC2/SKIV2L, SKIC3/TTC37, SLC10A2, SLC19A2, SLC25A38, SLC26A3, SLC29A3, SLC35A1, SLC35C1, SLC37A4, SLC39A4, SLC39A7, SLC46A1, SLC5A1, SLC7A7, SLC9A3, SLCO2A1, SLFN14, SLX4, SMARCAL1, SMARCD2, SNORA31, SNX10, SOCS1, SOCS4, SOS1, SOS2, SP110, SPAG1, SPI1, SPINK5, SPINT2, SPPL2A, SRC, SRP54, SRP72, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, STIM1, STING1/TMEM173, STK36, STK4, STN1, STX11, STX3, STXBP2, STXBP3, SYK, TAFAZZIN/TAZ, TAOK2, TAP1, TAP2, TAPBP, TBK1, TBX1, TBX21, TBXAS1, TCF3, TCIRG1, TCN2, TERC, TERF2, TERF2IP, TERT, TET2, TFRC, TGFB1, TGFBR1, TGFBR2, THBD, THPO, THRA, THRB, TICAM1, TIMM50, TINF2, TIRAP, TLR3, TLR7, TLR8, TMC6, TMC8, TNFAIP3, TNFRSF11A, TNFRSF13B, TNFRSF13C, TNFRSF1A, TNFRSF4, TNFRSF6B, TNFRSF9, TNFSF11, TNFSF12, TNFSF13, TNFSF4, TOM1, TONSL, TOP2B, TP53, TP63, TPP2, TRAC, TRADD, TRAF3, TRAF3IP2, TREX1, TRIM22, TRNT1, TSR2, TTC7A, TUBB1, TYK2, UBA1, UBE2T, UNC119, UNC13D**, UNC45A, UNC93B1, UNG, USB1, USP18*, VAV1, VPS13B, VPS45, VSIG4, VTN, WAS, WDR1, WIPF1, WRAP53, XIAP, XRCC2, ZAP70, ZBTB24, ZCCHC8, ZMYND10, ZNF341, ZNFX1

Primary Ciliary Dyskinesia (PCD)  – 56 genes

CCDC103, CCDC39, CCDC40, CCDC65, CCNO, CFAP221, CFAP298, CFAP300, CFAP54, CFAP57, CFAP74, CFTR*, CLXN, DNAAF1, DNAAF11, DNAAF2, DNAAF3, DNAAF4, DNAAF5, DNAAF6, DNAH1, DNAH11, DNAH5, DNAH9, DNAI1, DNAI2, DNAJB13, DNAL1, DRC1, FOXJ1, GAS2L2, GAS8, HYDIN*, IFT74, LRRC56, MCIDAS, NEK10, NME5, NME8, ODAD1, ODAD2*, ODAD3, ODAD4, OFD1, RPGR*, RSPH1, RSPH3, RSPH4A, RSPH9, SPAG1, SPEF2, STK36, TP73, TTC12, TUBB4B, ZMYND10

*Gene with known pseudogenes that may impact ability to detect variants or have additional limitations resulting in low coverage.

**The UNC13D 253 kb inversion described in the literature (Meeths et al., 2011) is outside of the target region and will not be detected by this assay.

Reference Range

Interpretive report will be provided. Variants are classified using the ACMG/AMP guidelines (PMID: 25741868). Variants are that are considered neutral, risk alleles, or associated with carrier status for recessive disorders are not routinely reported.

Clinical Utility

While individually rare, immune disorders are a significant health burden. This is not a complete list, but genetic testing may be considered in individuals when the clinical differential diagnosis includes:

  • Dyskeratosis congenita
  • SCID
  • Bloom syndrome
  • CHARGE syndrome
  • Bone Marrow Failure
  • Roifman-Chitayat syndrome
  • SHORT syndrome
  • IMAGE-I syndrome
  • RIDDLE syndrome
  • Trichohepatoenteric syndrome
  • Wiskott-Aldrich syndrome

References

  • Zhang Q, et al. A pilot study of ruxolitinib as a front-line therapy for 12 children with secondary hemophagocytic lymphohistiocytosis. Haematologica. 2021 Jul 1;106(7):1892-1901, PMID: 32732367.
  • Canna SW and Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020 Apr 16;135(16):1332-1343, PMID: 32107531.
  • Janka G and zur Stadt U. Familial and acquired hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program. 2005:82-8, PMID: 16304363.
  • Meeths M, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood. 2011 Nov 24;118(22):5783-93, PMID: 21931115.

Requisition

Molecular Genetics

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