Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication

Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication 2011156
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Determine the genetic etiology of a primary antibody deficiency in affected individuals.

See Related Tests for initial screening tests for immunodeficiency and mutation testing for a known familial pathogenic variant.

Primary antibody deficiency (PAD) syndromes are a group of rare genetic disorders affecting antibody (immunoglobulin) production. They include common variable immunodeficiency (CVID) disorders, agammaglobulinemia, and hyper-IgM syndrome. Molecular testing is used to determine the genetic etiology of PAD in affected individuals.

Disease Overview

Symptoms

  • Unusual, opportunistic, or severe infections
  • Infections typically affect multiple organs/organ systems:
    • Lungs
      • Pneumonia/empyema
    • Gastrointestinal
      • Intermittent or chronic diarrhea
    • Skin (infections)
    • Head and neck
      • Oral ulcers/gingivitis/stomatitis
      • Conjunctivitis
      • Otitis media
      • Lymphadenopathy
    • Central nervous system
      • Meningitis
  • Other signs
    • Sepsis
    • Failure to thrive
    • Splenomegaly
    • Autoimmune conditions
    • Neutropenia
    • Granulomatous disease
    • Lymphoid and nonlymphoid malignancies

Age of Onset

  • Agammaglobulinemia and hyper-IgM syndrome usually occur within the first 2 years of life.
  • CVID manifests at all ages, but most often in the second and third decade.

Incidence

Estimated at 4.6/100,000

Inheritance

X-linked, autosomal dominant, or autosomal recessive, depending on the causative gene

Test Interpretation

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

  • Agammaglobulinemia, 90%  (Conley, 1998)
  • Hyper-IgM syndrome, 75-80% (Conley, 2009)
  • CVID, 20% (Guillem, 2018)

Indications for Ordering

Determine the genetic etiology of a primary antibody deficiency in affected individuals.

Limitations

  • A negative result does not exclude a PAD syndrome.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in ADA2, ATP6AP1, CARD11, CD27, CD70, CDCA7, CTLA4, CXCR4, DNMT3B, GATA2, HELLS, IKBKG, IL21, IL21R, INO80, KDM6A, KMT2D, LRBA, LRRC8A, MALT1, MAP3K14, MOGS, NFKB1, PIK3CD, PIK3CG, PIK3R1, PLCG2, PRKCD, RNF168, SH2D1A, TCF3, TNFSF12, TRNT1, TTC37, XIAP, ZBTB24
    • Noncoding transcripts
    • Translocations
    • The following exon is not sequenced due to technical limitations of the assay:
      • CXCR4 (NM_001348056) 2
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1 kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
    • Gene Exon(s)

      ADA

      (NM_000022) 1

      AICDA

      (NM_020661) 5

      BTK

      (NM_000061) 11; (NM_001287344) 1

      CD79B

      (NM_000626) 2

      CR2

      (NM_001006658) 1

      DCLRE1C

      (NM_001033855) 4, 6, 8; (NM_001289076) 3

      IGLL1

      (NM_020070) 2, 3; (NM_152855) 2

      NFKB2

      (NM_001077494) 21

      RAC2

      (NM_002872) 2

      TNFRSF13B

      (NM_012452) 2

      TNFRSF13C

      (NM_052945) 1

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene MIM Number Disorder Inheritance

ADA

608958

SCID, T-cell/B-cell/NK-cell negative

AR

ADA2

607575

Polyarteritis nodosa

Vasculitis

Hypogammaglobulinemia

AR

AICDA

605257

Immunodeficiency with hyper-IgM, type 2

AR

ATM

607585

Ataxia-telangiectasia

AR

ATP6AP1

300197

Immunodeficiency 47

XL

BLNK

604515

Agammaglobulinemia

AR

BTK

300300

Xl agammaglobulinemia

XL

CARD11

607210

Immunodeficiency 11

AR

B-cell expansion with NFKB and T-cell energy

Immunodeficiency 11B with atopic dermatitis

AD

CD19

107265

CVID

AR

CD27

186711

Lymphoproliferative syndrome 2

AR

CD40

109535

Immunodeficiency with hyper-IgM, type 3

AR

CD40LG

300386

Immunodeficiency with hyper-IgM, type 1

XL

CD70

602840

Hypogammaglobulinemia

EBV susceptibility

AR

CD79A

112205

Agammaglobulinemia 3

AR

CD79B

147245

Agammaglobulinemia 6

AR

CD81

186845

CVID

AR

CDCA7

609937

Immunodeficiency-centromeric instability-facial anomalies syndrome

AR

CR2

120650

CVID

AR

CTLA4

123890

Autoimmune lymphoproliferative syndrome, type V

AD

CXCR4

162643

Whim syndrome

AD

DCLRE1C

605988

SCID with sensitivity to ionizing

Omenn syndrome

AR

DNMT3B

602900

Immunodeficiency-centromeric instability-facial anomalies syndrome

AR

GATA2

137295

Immunodeficiency 21

AD

HELLS

603946

Immunodeficiency-centromeric instability-facial anomalies syndrome

AR

ICOS

604558

CVID

AR

IGHM

147020

Agammaglobulinemia

AR

IGLL1

146770

Agammaglobulinemia

AR

IKBKG

300248

Ectodermal dysplasia, hypohidrotic, with immune deficiency

Ectodermal dysplasia, anhidrotic, with immunodeficiency,

Immunodeficiency without anhidrotic ectodermal dysplasia

Immunodeficiency 33

Invasive pneumococcal disease, recurrent isolated, 2

XL

IKZF1

603023

CVID

AD

IL21

605384

CVID

AR

IL21R

605383

IgE responsiveness, atopic

AD

Immunodeficiency 56 AR

INO80

610169

Hyper-IgM

AR

IRF2BP2

615332

CVID

AD

KDM6A

300128

Kabuki syndrome 1

AD

Kabuki syndrome 2 XL

KMT2D

602113

Kabuki syndrome 1

AD

LRBA

606453

CVID with autoimmunity

AR

LRRC8A

608360

Agammaglobulinemia

AD

MALT1

604860

Immunodeficiency 12

AR

MAP3K14

604655

Hypogammaglobulinemia

AR

MOGS

601336

Congenital disorder of glycosylation, type IIB

AR

MS4A1

112210

CVID

AR

NBN

602667

Nijmegen breakage syndrome

AR

NFKB1

164011

CVID

AD

NFKB2

164012

CVID

AD

NFKBIA

164008

Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency

AD

PIK3CD

602839

Immunodeficiency 14

AD

PIK3CG

601232

Hyper-IgM

AD

PIK3R1

171833

Agammaglobulinemia

AR
AD

PLCG2

600220

Autoinflammation, antibody deficiency, and immune dysregulation, PLCG2 associated

AD

PRKCD

176977

Autoimmune lymphoproliferative syndrome, type III

AR

RAC2

602049

Neutrophil immunodeficiency syndrome

AD

RAG1

179615

Combined cellular and humoral immune defects with granulomas

SCID, T-cell negative, B-cell negative, NK-cell positive

Omenn syndrome

Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe

AR

RAG2

179616

Combined cellular and humoral immune defects with granulomas

SCID, T-cell/B-cell negative, NK-cell positive

Omenn syndrome

AR

RNF168

612688

Riddle syndrome

AR

SH2D1A

300490

Lymphoproliferative syndrome, X-linked, 1

XL

STAT3

102582

Hyper-IgE recurrent infection syndrome

AD

TCF3

147141

Agammaglobulinemia 8

AD

TNFRSF13B

604907

CVID

Immunoglobulin A deficiency

AR

TNFRSF13C

606269

CVID

AR

TNFSF12

602695

Hypogammaglobulinemia

AD

TRNT1

612907

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers

AR

TTC37

614589

Trichohepatoenteric syndrome 1

AR

UNG

191525

Immunodeficiency with hyper-IgM syndrome

AR

VAV1

164875

CVID

AD

XIAP

300079

X-linked lymphoproliferative syndrome

XL

ZBTB24

614064

Immunodeficiency-centromeric instability-facial anomalies syndrome 2

AR

AD, autosomal dominant; AR, autosomal recessive; SCID, severe combined immunodeficiency; XL, X-linked

References 

Conley ME, Dobbs K, Farmer DM, Kilic S, Paris K, Grigoriadou S, Coustan-Smith E, Howard V, Campana D. Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol. 2009; 27: 199-227. PubMed

Conley ME, Mathias D, Treadaway J, Minegishi Y, Rohrer J. Mutations in btk in patients with presumed X-linked agammaglobulinemia. Am J Hum Genet. 1998; 62(5): 1034-43. PubMed

de Valles-Ibáñez G, Esteve-Solé A, Piquer M, González-Navarro A, Hernandez-Rodriguez J, Laayouni H, González-Roca E, Plaza-Martin AM, Deyà-Martínez A, Martín-Nalda A, Martínez-Gallo M, García-Prat M, Del Pino-Molina L, Cuscó I, Codina-Solà M, Batlle-Masó L, Solís-Moruno M, Marquès-Bonet T, Bosch E, López-Granados E, Aróstegui JI, Soler-Palacín P, Colobran R, Yagüe J, Alsina L, Juan M, Casals F. Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond. Front Immunol. 2018; 9: 636. PubMed

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Picard C, Gaspar B, Al-Herz W, Bousfiha A, Casanova J, Chatila T, Crow YJ, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Puck J, Tang ML, Tangye SG, Torgerson TR, Sullivan KE. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018; 38(1): 96-128. PubMed

Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012; 119(7): 1650-7. PubMed

Smith C, Berglof A. X-Linked Agammaglobulinemia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Aug 2016; Accessed: Nov 2018]

Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm R, Conley ME. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003; 82(6): 373-84. PubMed

Last Update: February 2019