PMID: 34694545

Gene: ICOSLG

Disease: Combined Immunodeficiency

MonDO: MONDO:0015131

InheritancePattern: Autosomal recessive

Notes:

Case#: 77 yo Female. French Canadian

Demographics: French-Canadian. Parents from an isolated island Quebec, Canada.

CasePresentingHPOs: HP:0033166, HP:0002090, HP:0200043, HP:0001875, HP:0032247, HP:0002205, HP:0006532,HP:0033005, HP:0040167, HP:0032215, HP:0003139, HP:0032155, HP:0002014, HP:0025085, HP:0001824, HP:0033431, HP:0032247, HP:0001875

CaseFreetextHPOs: Beginning at age 14 proband was hospitalized for pneumonia. Started at age 14- 62 developed pneumonia several times. Had immunoglobulin replacement therapy. Has finger and forehead warts. Multiple episodes of Bowen's Disease of cheek. Due to worsening CMV colitis she underwent total abdominal colectomy with end ileostomy at age 77.. CMV viral load was 8641 copies/mL. IgG 11.32(g/L), IgA .28(g/L), IgM.2 (g/L). IgA and IgM are below the reference range. Neutropenia occurred only while on (val)ganciclovir for CMV.

Person first evaluated at age 74. Colonic diseases No known consanguinity Proband was hospitalized as early as 14 years of age for pneumonia

CasePreviousTesting: Near-absence of ICOSL in plasma. Cell surface expression of ICOSL by flow cytometry-based evaluation of PBMC from whole blood revealed severely diminished levels on CD19+ B cells.

CaseMethod1: WES

CaseMethod2:

CaseGenotypingMethod: Whole exome sequencing (WES) was performed on whole blood DNA from the patient.

Variant: NM_015259.6:c.657C > G (p.N219K)

ClinVar: Not registered

CAID: CA321497070

gnomAD: 0.00006424

VariantEvidence: Proband was homozygous for the missense variant in ICOSLG, p.N219K. Similar to the previous paper this individual is also French Canadian. No known consanguinity. p.N219K variant is reported at the highest frequency of 0.00006424 (4/62262 non Finnish European alleles in gnomAD 2.1.1.

CaseAddInfo: Sibling of proband died of unknown cause or blood disorders

CasePMIDs:

Case#: 38 yo Male. Canadian

Demographics: French-Canadian. Parents from an isolated island Quebec, Canada.

CasePresentingHPOs: HP:0000246, HP:0032301, HP:0033004, HP:0002205, HP:0001875, HP:0004313, HP:0001888, HP:0000403, HP:0011108, HP:0012387, HP:0002090, HP:0200043, HP:0032215, HP:0032076, HP:0410028, HP:0100825, HP:0011107,

CasePresentingHPOsFreeText: Had recurrent sinusitis approximately once per year as a youth. Age 21 was hospitalized for pneumonia. Had genital warts at age 16. Absent cell-surface expression determines functional consequence of mutation on the T-cell. At age 35 IgG 10.9-17.6 (g/L), IgA .16-0.3(g/L), IgM 0.66-0.76 (g/L). IgA are below the reference range. At age 38 CD3+ T cells: 387; CD4+ T cells: 281 CD8+ T cells: 92 all below the reference range. Started intravenous immunoglobulin replacement which helped with his respiratory tract infection.

CaseNotHPOs HP:0002718, HP:0410295, HP:0410303, HP:0003453, HP:0031160, HP:0002863

CaseNotHPOsFreetext: Diphtheria

CasePreviousTesting: Flow cytometric analysis, using two different antibodies recognizing distinct epitopes of ICOSL, showed that its cell-surface expression was absent in P1. Confocal microscopy likewise demonstrated decreased cell-surface expression. Both showed that ICOSL was absent. Sequencing of CXCR4 identified no mutation.

CaseMethod1:WES

CaseMethod2:Sanger Sequencing

CaseGenotypingMethod: Whole-exome sequencing was performed on genomic DNA. Sanger Sequencing confirmed that he is homozygous for the variant.

Variant: NM_015259.6:c.657C>G(p.Asn219Lys)

ClinVar:

CAID: CA321497070

gnomAD: 0.00006424

​​VariantEvidence: No known direct consanguinity. RT PCR to compare the ICOSLG mRNA levels and it showed that there was not significant decay in the mRNA. We observed a similar phenomenon following transient transfection of HEK293T cells, which lack endogenous ICOSL, with either WT or p.N219K ICOSL protein. Western Blot analysis of whole cell lysates.p.N219K variant is reported at the highest frequency of 0.00006424 (4/62262 non Finnish European alleles in gnomAD 2.1.1.

CaseAddInfo: French ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. His parents were heterozygous and his healthy brother was homozygous for the WT allele

PMID: 30498080

Gene: ICOSLG

Disease: Combined Immunodeficiency

MonDO: MONDO:0015131

InheritancePattern: Autosomal recessive pattern