Hemophagocytic Lymphohistiocytosis (HLH) Extended Genetic Panel (41 genes and UNC13D inversion) (2 Day STAT TAT) - Clinical Genetic Test - GTR

Hemophagocytic Lymphohistiocytosis (HLH) Extended Genetic Panel (41 genes and UNC13D … see more Hemophagocytic Lymphohistiocytosis (HLH) Extended Genetic Panel (41 genes and UNC13D inversion) (2 Day STAT TAT) see less

Clinical Genetic Test

offered by

Machaon Diagnostics

View lab's test page

GTR Test Accession: GTR000613186.2

CAP

IMMUNOLOGYINHERITED DISEASESYNDROMIC DISEASE ... View more

Last updated in GTR: 2024-03-07

Last annual review date for the lab: 2024-04-04

At a Glance

Test purpose:

Diagnosis

Conditions (7):

X-linked lymphoproliferative disease due to XIAP deficiency; Familial hemophagocytic lymphohistiocytosis 2; Familial hemophagocytic lymphohistiocytosis 3 more...

Genes (41):

ADA (20q13.12); AP3B1 (5q14.1); AP3D1 (19p13.3); CD27 (12p13.31); CD70 (19p13.3) more...

Methods (1):

Molecular Genetics - Sequence analysis of select exons: Next-Generation (NGS)/Massively parallel sequencing (MPS)

Target population:

Not provided

Clinical validity:

Clinical sensitivity: Because the conditions targeted here are mostly ultra-rare, …

Clinical utility:

Not provided

Ordering Information

Offered by:

Machaon Diagnostics
View lab's website
View lab's test page

Specimen Source:

Buccal swab
Peripheral (whole) blood
View specimen requirements

Who can order:

Health Care Provider
Licensed Physician

Test Order Code:

P1237

How to Order:

Order URL

Test service:

Custom Sequence Analysis
Result interpretation

Test development:

Test developed by laboratory but exempt from FDA oversight (eg. NYS CLEP approved, offered within a hospital or clinic)

Informed consent required:

Decline to answer

Pre-test genetic counseling required:

Decline to answer

Post-test genetic counseling required:

Decline to answer

Recommended fields not provided:

Lab contact for this test, Contact policy, Test strategy

Conditions

Total conditions: 7

Condition/Phenotype	Identifier

Test Targets

Genes

Total genes: 41

Gene	Associated Condition	Germline or Somatic	Allele (Lab-provided)	Variant in NCBI

Methodology

Total methods: 1

Method Category

Test method

Instrument *

Sequence analysis of select exons

Next-Generation (NGS)/Massively parallel sequencing (MPS)

* Instrument: Not provided

Clinical Information

Test purpose:

Diagnosis

Clinical validity:

Clinical sensitivity: Because the conditions targeted here are mostly ultra-rare, potentially under-diagnosed, and in need of more research, the clinical sensitivity is unknown. Mutations in the genes covered in our panel may account for 90% of the cases of primary/familial HLH; the cause of the remaining 10% is unknown. Nevertheless, … View more

View citations (1)

Côte M, Ménager MM, Burgess A, Mahlaoui N, Picard C, Schaffner C, Al-Manjomi F, Al-Harbi M, Alangari A, Le Deist F, Gennery AR, Prince N, Cariou A, Nitschke P, Blank U, El-Ghazali G, Ménasché G, Latour S, Fischer A, de Saint Basile G. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest. 2009;119(12):3765-73. doi:10.1172/JCI40732. Epub 2009 Nov 02. PMID: 19884660.

Recommended fields not provided:

Clinical utility, Target population, What is the protocol for interpreting a variation as a VUS?, Is research allowed on the sample after clinical testing is complete?, Sample negative report, Sample positive report

Technical Information

Test Comments:

This test sequences the exons plus 5bp of the flanking introns of (41 genes) ADA, AP3B1, AP3D1, CD27, CD70, CDC42, CTPS1, CYBA, CYBB, CYBC1, GATA2, HAVCR2, IL2RG, ITK, LIPA, LYST, MAGT1, NCF2, NCF4, NCKAP1L, NLRC4, PRF1, RAB27A, RASGRP1, RC3H1, RHOG, SH2D1A, SLC7A7, STX11, STXBP2, UNC13D, XIAP, UNC13D 253-kb inversion, FADD, … This test sequences the exons plus 5bp of the flanking introns of (41 genes) ADA, AP3B1, AP3D1, CD27, CD70, CDC42, CTPS1, CYBA, CYBB, CYBC1, GATA2, HAVCR2, IL2RG, ITK, LIPA, LYST, MAGT1, NCF2, NCF4, NCKAP1L, NLRC4, PRF1, RAB27A, RASGRP1, RC3H1, RHOG, SH2D1A, SLC7A7, STX11, STXBP2, UNC13D, XIAP, UNC13D 253-kb inversion, FADD, FAS, FASLG, MEFV, MVK, NLRP3, STAT1, TNFRSF1A and WAS. Additionally, several known mutations that reside in deep intronic or promoter elements are also included. Sanger sequencing may be used to confirm variants as needed. This test also includes a PCR-based assay to detect the recurrent pathogenic UNC13D inversion. Hemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive hyperinflammatory disorder. In rare circumstances, it can instead show autosomal dominant or X-linked inheritance. This life-threatening disorder is characterized by unremitting fever, hepatosplenomegaly, hyperferritinemia, cytopenia, and sometimes hemophagocytosis. It involves the aberrant activation of lymphocytes and macrophages, leading to excessive cytokine production, and engulfment of the hematopoietic cells by these macrophages. The genetic causes of HLH can be categorized as either familial HLH (FHL) or secondary, depending on family history or presence of triggers such as infection or malignancy or autoimmune disorder. A true epidemiology of the condition is unavailable although it is estimated that it is found in approximately 1 in 100,000 children less than 18 years of age. Several disorders share clinical manifestations immune deficiencies such as Griscelli syndrome, X-linked lymphoproliferative syndrome (XLP), Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, and autoimmune-associated macrophage activation syndrome (MAS). Early and correct treatment in critical to patient outcome. MAS is a usually fatal complication of rheumatic diseases that is found in Juvenile Idiopathic Arthritis (JIA) and rarely also in systemic lupus erythematosus and Kawasaki disease. MAS is clinically similar to certain forms of hemophagocytic lymphohistiocytosis (HLH), making diagnosis challenging unless the genetic cause is known. Median survival of HLH without treatment is less than two months. Timely diagnosis has been a major challenge; some patients must start receiving aggressive therapies or be admitted to the ICU before final diagnostic results are available. Different underlying genetic causes of HLH and syndromes that present with HLH require different treatments; for example, mutations in familial HLH genes require bone marrow transplantation. View more

Availability:

Tests performed
Entire test performed in-house

Analytical Validity:

The analytic specificity and sensitivity of the NGS panel are greater than 99%.

Assay limitations:

This test will not detect variants located outside of the targeted DNA regions. This test is not optimized to detect chimerism or somatic mosaicism. This test will detect small indels but may miss larger deletions or duplications. Balanced structural variants will not be detected unless specifically targeted by a custom … View more

View citations (1)

Tesi B, Lagerstedt-Robinson K, Chiang SC, Ben Bdira E, Abboud M, Belen B, Devecioglu O, Fadoo Z, Yeoh AE, Erichsen HC, Möttönen M, Akar HH, Hästbacka J, Kaya Z, Nunes S, Patiroglu T, Sabel M, Saribeyoglu ET, Tvedt TH, Unal E, Unal S, Unuvar A, Meeths M, Henter JI, Nordenskjöld M, Bryceson YT. Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis. Genome Med. 2015;7:130. doi:10.1186/s13073-015-0244-1. Epub 2015 Dec 18. PMID: 26684649.

Proficiency testing (PT):

Is proficiency testing performed for this test?
Yes

Method used for proficiency testing:
Formal PT program

PT Provider:
College of American Pathologists, CAP

Recommended fields not provided:

Test Confirmation, Description of internal test validation method, Citations for Analytical validity, Description of PT method, Major CAP category, CAP category, CAP test list

Regulatory Approval

FDA Review:

Not provided

Additional Information

Reviews:

Genereviews

PubMed Clinical Queries

Clinical resources:

Molecular resources:

View XIAP variations in ClinVar

RefSeqGene

Coriell Institute for Medical Research

Consumer resources:

Genetic Alliance

MalaCards

MedlinePlusGenetics (GHR)

NCATS Office of Rare Diseases Research (GARD)

MedlinePlus

IMPORTANT NOTE: NIH does not independently verify information submitted to GTR; it relies on submitters to provide information that is accurate and not misleading. NIH makes no endorsements of tests or laboratories listed in GTR. GTR is not a substitute for medical advice. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.