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Astute Clinician Report: A Novel 10 bp Frameshift Deletion in Exon 2 of ICOS Causes a Combined Immunodeficiency Associated with an Enteritis and Hepatitis.

Robertson N, Engelhardt KR, Morgan NV, Barge D, Cant AJ, Hughes SM, Abinun M, Xu Y, Koref MS, Arkwright PD, Hambleton S - J. Clin. Immunol. (2015)

Bottom Line: Three pathogenic mutations in ICOS have been described to date in a total of 13 cases.Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6.Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.

View Article: PubMed Central - PubMed

Affiliation: Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

ABSTRACT
ICOS encodes the Inducible T-cell Co-Stimulator (ICOS). Deficiency of this receptor in humans causes a common variable immunodeficiency (CVID) characterised by an absence of class-switched memory B cells and hypogammaglobulinemia. Three pathogenic mutations in ICOS have been described to date in a total of 13 cases. Here we report a novel homozygous 10 base pair frameshift deletion in exon 2 discovered by whole exome sequencing of two siblings from a family of Pakistani origin. Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6. Activated patient CD3(+)CD4(+) T lymphocytes demonstrated a complete absence of ICOS expression and, consistent with previous reports, we detected a reduction in circulating T follicular helper cells. Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.

No MeSH data available.


Related in: MedlinePlus

10 base pair deletion in ICOS in two siblings. a Family tree. Diamonds represent healthy siblings whose gender is not disclosed to protect the family’s privacy. b Sanger sequencing of family members. Arrow indicates the start of the deletion. c Alignment of patient sequence with a parental sequence reconstructed by Poly Peak Parser to show reference and pathogenic alleles [10]
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Fig1: 10 base pair deletion in ICOS in two siblings. a Family tree. Diamonds represent healthy siblings whose gender is not disclosed to protect the family’s privacy. b Sanger sequencing of family members. Arrow indicates the start of the deletion. c Alignment of patient sequence with a parental sequence reconstructed by Poly Peak Parser to show reference and pathogenic alleles [10]

Mentions: The parents of the patients are from the same ethnic background and are not, to their knowledge, related (Fig. 1a). From the age of 2 years, their second child (patient 1) suffered from chronic loose watery stools associated with abdominal pain, fever, lethargy and weight loss. She was referred to immunology services aged 3.5 years and was noted to have absent class-switched memory B-cells (CD19 + CD27 + IgD-), hypogammaglobulinemia and impaired vaccine responses (Table 1). She was commenced on immunoglobulin replacement therapy but diarrhea persisted and she developed hepatomegaly associated with raised liver enzymes (alanine aminotransferase [ALT] of 2907 IU/L, normal range 10 to 40; gamma-glutamyl transferase [GGT] 152 IU/L, normal range 0–51). Stools were free of enteric pathogens with the exception of single samples positive for norovirus, adenovirus and Cryptosporidium.Fig. 1


Astute Clinician Report: A Novel 10 bp Frameshift Deletion in Exon 2 of ICOS Causes a Combined Immunodeficiency Associated with an Enteritis and Hepatitis.

Robertson N, Engelhardt KR, Morgan NV, Barge D, Cant AJ, Hughes SM, Abinun M, Xu Y, Koref MS, Arkwright PD, Hambleton S - J. Clin. Immunol. (2015)

10 base pair deletion in ICOS in two siblings. a Family tree. Diamonds represent healthy siblings whose gender is not disclosed to protect the family’s privacy. b Sanger sequencing of family members. Arrow indicates the start of the deletion. c Alignment of patient sequence with a parental sequence reconstructed by Poly Peak Parser to show reference and pathogenic alleles [10]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4628077&req=5

Fig1: 10 base pair deletion in ICOS in two siblings. a Family tree. Diamonds represent healthy siblings whose gender is not disclosed to protect the family’s privacy. b Sanger sequencing of family members. Arrow indicates the start of the deletion. c Alignment of patient sequence with a parental sequence reconstructed by Poly Peak Parser to show reference and pathogenic alleles [10]
Mentions: The parents of the patients are from the same ethnic background and are not, to their knowledge, related (Fig. 1a). From the age of 2 years, their second child (patient 1) suffered from chronic loose watery stools associated with abdominal pain, fever, lethargy and weight loss. She was referred to immunology services aged 3.5 years and was noted to have absent class-switched memory B-cells (CD19 + CD27 + IgD-), hypogammaglobulinemia and impaired vaccine responses (Table 1). She was commenced on immunoglobulin replacement therapy but diarrhea persisted and she developed hepatomegaly associated with raised liver enzymes (alanine aminotransferase [ALT] of 2907 IU/L, normal range 10 to 40; gamma-glutamyl transferase [GGT] 152 IU/L, normal range 0–51). Stools were free of enteric pathogens with the exception of single samples positive for norovirus, adenovirus and Cryptosporidium.Fig. 1

Bottom Line: Three pathogenic mutations in ICOS have been described to date in a total of 13 cases.Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6.Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.

View Article: PubMed Central - PubMed

Affiliation: Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

ABSTRACT
ICOS encodes the Inducible T-cell Co-Stimulator (ICOS). Deficiency of this receptor in humans causes a common variable immunodeficiency (CVID) characterised by an absence of class-switched memory B cells and hypogammaglobulinemia. Three pathogenic mutations in ICOS have been described to date in a total of 13 cases. Here we report a novel homozygous 10 base pair frameshift deletion in exon 2 discovered by whole exome sequencing of two siblings from a family of Pakistani origin. Both patients presented in early childhood with diarrhea, colitis and transaminitis and one showed defective handling of human herpesvirus 6. Activated patient CD3(+)CD4(+) T lymphocytes demonstrated a complete absence of ICOS expression and, consistent with previous reports, we detected a reduction in circulating T follicular helper cells. Findings in this kindred emphasise the phenotypic variability of ICOS deficiency and, in particular, the variably impaired antiviral immunity that is a poorly understood facet of this rare disorder.

No MeSH data available.


Related in: MedlinePlus