Description
A- or hypo-gammaglobulinaemia eligibility statement:

Relevant diseases:

- A- or hypo-gammaglobulinaemia 
- Agranulocytosis
- Congenital neutropaenia
- SCID
- Combined B and T cell defect

Primary immunodeficiency disorders inclusion criteria (29434)
- Suspected primary immunodeficiency diagnosed by a consultant immunologist, particularly if familial.
- Appropriate available diagnostic tests should have ruled out mutations in relevant known genes.
- All cases must be discussed and approved by the PID-MDT at the recruiting GMC

Primary immunodeficiency disorders exclusion criteria (29434)
- Known genetic cause already identified in proband or family member with similar phenotype.
- Secondary immunodeficiency likely

Prior genetic testing guidance (29434)
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. 
- Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.  

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Closing statement (29434)
These requirements will be kept under continual review during the main programme and may be subject to change.

15 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • Richard Scott (North Thames GMC/UCL)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Tracy Briggs (Manchester Genomic Medicine Centre)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Peter Arkwright (Royal Manchester Foundation Trust)

    Group: GeCIP domain
    Workplace: NHS clinical service

  • Sophie Hambleton (Newcastle University)

    Group: GeCIP domain
    Workplace: Research lab

  • William Rae (University Hospital Southampton NHS Foundation Trust)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Christopher Duncan (Newcastle University)

    Group: GeCIP domain
    Workplace: Research lab

  • emma baple (South West GMC)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Ellen Thomas (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Olivia Niblock (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Rebecca Foulger (Genomics England curator)

    Group: Other
    Workplace: Other

  • Louise Daugherty (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Owen Siggs (Flinders University)

    Group: Other
    Workplace: Research lab

  • Adrian Shields (Oxford University NHS Foundation Trust and University of Oxford)

    Group: Other NHS organisation
    Workplace: NHS clinical service

28 Entities

28 reviewed, 12 green

List Entity Reviews Mode of inheritance Details
28 Entitiess
Green Green List (high evidence)
AICDA
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Hyper IgM syndrome with lymphoid hyperplasia
  • Immunodeficiency with hyper-IgM, type 2, 605258
  • Primary Immune Deficiencies
Tags
Green Green List (high evidence)
BLNK
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Agammaglobulinemia 4, 613502
  • agammaglobulinaemia with absent B cells
Tags
Green Green List (high evidence)
BTK
7 reviews
6 green
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Agammaglobulinemia, X-linked
  • Agammaglobulinemia, X-linked 1, 300755Agammaglobulinemia and isolated hormone deficiency, 307200
Tags
Green Green List (high evidence)
CD19
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Immunodeficiency, common variable, 3 613493
  • hypogammaglobulinemia
Tags
Green Green List (high evidence)
CTLA4
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • CVID
  • hypogammaglobulinaemia
  • lymphadenopathy
  • T cell lymphopenia
  • enteropathy
  • interstitual lung disease
  • autoimmunity
  • Autoimmune lymphoproliferative syndrome, type V 616100
Tags
Green Green List (high evidence)
DNMT3B
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • IMMUNODEFICIENCY-CENTROMERIC INSTABILITY-FACIAL ANOMALIES SYNDROME 1 242860
Tags
Green Green List (high evidence)
EXTL3
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Immunoskeletal dysplasia with neurodevelopmental abnormalities 617425
Tags
Green Green List (high evidence)
IGHM
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Agammaglobulinemia 1 601495
Tags
Green Green List (high evidence)
IKZF1
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Immunodeficiency, common variable, 13 616873
Tags
Green Green List (high evidence)
PIK3CD
4 reviews
3 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Immunodeficiency 14 615513
Tags
Green Green List (high evidence)
PIK3R1
6 reviews
5 green
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Agammaglobulinemia 7, autosomal recessive, 615214
  • SHORT syndrome, 269880
  • Immunodeficiency 36 616005
Tags
Green Green List (high evidence)
TCN2
4 reviews
3 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Transcobalamin II deficiency
  • can have a presentation similar to severe combined immunodeficiency
  • pancytopenia
  • neutropenic colitis
  • Agammaglobulinemia
  • megaloblastic bone marrow
  • thrombocytopenia
  • neutropenia
  • failure to thrive
  • hypotonia, myoclonic like movements, pallor, purpura, anaemia, thrombocytopenia, megaloblastosis, aplastic bone marrow. 275350
Tags
  • treatable
Amber Amber List (moderate evidence)
LAT
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Other
Phenotypes
  • Immunodeficiency 52, 617514
Tags
  • watchlist
Amber Amber List (moderate evidence)
MYD88
4 reviews
1 green 1 red
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Pyogenic bacterial infections, recurrent, due to MYD88 deficiency, 612260
  • Macroglobulinemia, Waldenstrom, somatic, 153600
Tags
Amber Amber List (moderate evidence)
NFKB2
3 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Amber
Phenotypes
  • hypogammaglobuliaemia
  • immune dysregulation
  • central adrenal insufficiency
Tags
Amber Amber List (moderate evidence)
PLCG2
4 reviews
2 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
  • Expert Review Amber
  • Literature
  • Other
Phenotypes
  • Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory
  • Autoinflammation, antibody deficiency, and immune dysregulation syndrome
  • Familial cold autoinflammatory syndrome 3
Tags
Amber Amber List (moderate evidence)
TCF3
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Agammaglobulinemia
  • Agammaglobulinemia 8, autosomal dominant, 616941
  • Primary immunodeficiency
Tags
Amber Amber List (moderate evidence)
TNFRSF13B
4 reviews
3 red
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Immunoglobulin A deficiency 2, 609529
  • Immunodeficiency, common variable, 2, 240500
Tags
Amber Amber List (moderate evidence)
TTC37
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Amber
Phenotypes
  • intrauterine growth retardation, woolly hair
  • facial dysmorphism
  • intractable diarrhoea in infancy requiring total parenteral nutrition
  • hypogammaglobulinaemia
Tags
Amber Amber List (moderate evidence)
UNG
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Amber
Phenotypes
  • Hyper IgM syndrome with lymphoid hyperplasia
Tags
Red Red List (low evidence)
CD79A
5 reviews
3 green 1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Agammaglobulinemia 3, 613501
Tags
Red Red List (low evidence)
CD79B
4 reviews
2 green 1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Agammaglobulinemia 6, 612692
Tags
Red Red List (low evidence)
CR2
3 reviews
1 green 1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Immunodeficiency, common variable, 7 614699
Tags
Red Red List (low evidence)
ELF4
4 reviews
3 red
Unknown
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • X-linked hypogammaglobulinemia with isolated growth hormone deficiency (pmid 16264330)
Tags
Red Red List (low evidence)
GAD1
4 reviews
3 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
Phenotypes
  • Immunoglobulin A deficiency (2)
Tags
Red Red List (low evidence)
ICOS
3 reviews
2 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Literature
Phenotypes
  • Immunodeficiency, common variable, 1 607594
Tags
Red Red List (low evidence)
IGLL1
4 reviews
2 green 1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Agammaglobulinemia 2, 613500
Tags
Red Red List (low evidence)
LRRC8A
4 reviews
3 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Agammaglobulinemia 5, 613506
Tags

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