CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review

Case#: III:3, female, 45 years old, Italian

DiseaseAssertion: Celiac disease/IBD with immunodeficiency (CVID) and CNS demyelination

FamilyInfo: non-consanguineous Italian parents, history of autoimmune disorders (Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease and rheumatoid arthritis), see Figure 1 CasePresentingHPOs: HP:0002028, HP:0002721, HPO:0001888, HPO:0008897, HP000:6515, HP:0002110, HP:0011108, HP:0001878, HP:0001973, HP:0031688, HP:0007185, HP:0002140, HP:0001081, HP:0011097, HP:0001945, HP:0007305, HP:0000238, HP:0200063, HP:0004313, HP:0000939, HP:0030252

CasePreviousTesting: whole-exome sequencing on the proband and parental DNA samples (trio-WES) from peripheral blood

GenotypingMethod: Reads aligned against GRCh38/hg38, variant calling using in-house pipeline according to international guidelines, variants with a frequency of <5% in gnomAD v4.1.0 and an in-house database, virtual panel of 564 genes related to primary immunodeficiency and inflammatory bowel disease (PanelApp version 7.21), CNVs detected with Control-FREEC and EXCAVATOR tools

**Variant: ** NM_005214.5:c.436G>A; p.Gly146Arg

ClinVar: VCV000849622.11

gnomAD: 0.000001696 https://gnomad.broadinstitute.org/variant/2-203870912-G-A?dataset=gnomad_r4

Case#: Patient 5 (P5) is a 19-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patients mother, who harbors the same CTLA4 variant reported a history of chronic urticaria, alopecia areata, and intermittent diarrhea for over 10 years.

CasePresentingHPOs: HP:0001903 (Anemia), HP:0007418 (Alopecia totalis), HP:0002254 (Intermittent diarrhea), HP:0000964 (Eczematoid dermatitis), HP:0002716 (Lymphadenopathy), HP:0004818 (Paroxysmal nocturnal hemoglobinuria), HP:6000344 (Anti-intrinsic factor antibody positivity), HP:0000988 (Skin rash), HP:0004386 (Gastrointestinal inflammation), HP:0034839 (Lymphoid hyperplasia), HP:0040088 (Abnormal lymphocyte count), HP:0020062 Decreased hemoglobin concentration, HP:0025066 (Decreased mean corpuscular volume), HP:0025547 (Decreased mean corpuscular hemoglobin concentration)

CaseHPOFreeText: Patient's symptoms onset at age 10. Gastrointestinal endoscopy showed chronic inflammation and lymphoid hyperplasia. Patient has been treated with subcutaneous injections of abatacept (125mg) with notable clinical improvement. Fine white hair has started to regrow on her scalp, eyebrows, and eyelashes, and facial skin shows mild scaling.

CaseNotHPOs:

CaseNotHPOFreeText: Autoimmune screening including antinuclear antibodies were negative.

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.151C>T (p.Arg51Ter) variant.

ClinVar: 161109

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: There is no supplemental data.

[[AD_VCEP_Annotation_Protocol_Updated.pdf]]

Case#: 42 Chinese APDS1 patients (27 males and 15 females)

DiseaseAssertion: activated PI3Kδ syndrome 1(APDS1)

FamilyInfo: 42 patients from 41 different families in China (P3 and P11 were from one family)

CasePresentingHPOs: HP:0002205(Recurrent respiratory infections) HP:0002110(Bronchiectasis) HP:00027168(Lymphadenopathy) HP:0001744(Splenomegaly) HP:0002240(Hepatomegaly) HP:0002960(Autoimmunity) HP:0003496(Increased circulating IgM level) HP:0004315(Decreased circulating IgG level) HP:0003237(Increased circulating IgG level) HP:0003212(Increased circulating IgE level) HP:0002720(Decreased circulating IgA level) HP:0040218(Reduced natural killer cell count) HP:0005403(T lymphocytopenia) HP:0005407(Decreased proportion of CD4-positive helper T cells)

CaseHPOFreeText: Table 1 contains information of 42 patients. Immunological phenotype of cohort is summarized in Table 2.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole-exome sequencing

GenotypingMethod: Whole-exome sequencing

PreviouslyPublished: No

Variant: NM_005026.5:c.3061G>A p.E1021K

ClinVar: 88675

CAID: CA577192

gnomAD: 8.475e-7 https://gnomad.broadinstitute.org/variant/1-9726972-G-A?dataset=gnomad_r4

Variant: NM_005026.5(PIK3CD):c.3074A>G p.Glu1025Gly

ClinVar: 422410

CAID: CA16617216

gnomAD: Variant is not present in gnomAD data

Variant: NM_005026.5(PIK3CD):c.1574A>G (p.Glu525Gly)

ClinVar: 582515

CAID: CA338303813

gnomAD: Variant is not present in gnomAD data

Variant: NM_005026.5(PIK3CD):c.1570T>A p.Tyr524Asn

ClinVar: Not present in ClinVar

CAID: CA338303802

gnomAD: Variant is not present in gnomAD data

Case#: 20-year-old Spanish man

DiseaseAssertion: Immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation

FamilyInfo: Maternally inherited CTLA4 variant and paternally inherited CLEC7A variant. Patient's mother had been diagnosed with mild sarcoidosis, dysphagia with eosinophilic infiltrates of esophagus, low IgM, and decreased percentages of memory B cells.

CasePresentingHPOs: HP:0100651 (Type I diabetes mellitus) HP:0001045 (Vitiligo) HP:0001047 (Atopic dermatitis) HP:0002205 (Recurrent respiratory infections) HP:0001541 (Ascites) HP:0002014 (Diarrhea) HP:0410151 (Eosinophilic infiltration of the esophagus) HP:0410147 (Eosinophilic infiltration in the stomach mucosa) HP:0033351 (Candida esophagitis) HP:0100806 (Sepsis) HP:0032061 (Hypereosinophilia) HP:0032064 (Gastrointestinal eosinophilia)

CaseHPOFreeText: Type 1 diabetes was diagnosed at 15 months old. Patient has a history of severe enteritis. Investigations, which were undertaken due to hypereosinophilia and eosinophilic infiltration, revealed a clonal γδ T cell band, characterized as reactive, with subsequent exclusion of FIP1L1-FDGFRA and PDGFRB rearrangements, as well as any abnormal karyotype. Sepsis was due to Salmonella typhi and Clostridium difficile infection.

Article provides functional evidence of CLEC7A variant affecting phenotype of this patient. Their data suggest that partial loss of DECTIN-1 in a patient with CTLA-4h may enhance IDAIL penetrance and confer additional unique phenotypes, with persistent marked hypereosinophilia as the most remarkable uncommon clinical manifestation.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.

GenotypingMethod: Whole-genome sequencing was performed on the patient's whole blood sample. The variants were confirmed with Sanger sequencing. Presence of a somatic CTLA4 variant was ruled out with high-coverage WGS of sorted peripheral T cells.

PreviouslyPublished: No

Variant: NM_005214.5:c.208C>T p.Arg70Trp

ClinVar: 161114

CAID: CA173999

gnomAD: 0.000001313 https://gnomad.broadinstitute.org/variant/2-203870684-C-T?dataset=gnomad_r4

Variant: NM_197947.3:c.547C>T p.Leu183Phe

ClinVar: 717363

CAID: CA6443934

gnomAD: 0.01719 https://gnomad.broadinstitute.org/variant/12-10123309-G-A?dataset=gnomad_r4

SupplementalData: Detailed clinical info and and immunological test results can be found in Supplementary Materials.f

Case#: Schwab_2018_CaseVV.II.1, male, 7 .o. (onset) 13 y.o. (report), origin in Saudi Arabia, reported Caucasian ethnicity

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Same variant observed in the father. Consanguinity reported

CasePresentingHPOs: HP:0002086, HP:0005523, HP:0011024, HP:0004313, HP:0002720, HP:0001744, HP:0002240, HP:0011947, HP:0002090, HP:0002110, HP:0031035, HP:0002242 (respiratory involvement, lymphoproliferation, gastrointestinal involvement, hypogammaglobulinemia, low IgA, splenomegaly, hepatomegaly, upper and lower RTIs, pneumonia, bronchiectasis, chronic infection, enteropathy, cytopenia (ITP))

CaseHPOFreeText: low IgM, Lymphocytic or granulomatous organ infiltration (lung, liver, gut), GLILD

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

GenotypingMethod: unknown

PreviouslyPublished: no

Variant: c.359_359delG; p.A121fs*23

ClinVarID: not found

CAID: CA2573320362

gnomAD: not found

SupplementalData: extensive phenotype data in figure S1

Case#: Grammatikos_2021_Case2, female, 10 months (onset) 25 y.o. (report), origin not reported

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: Mother and brother are also affected. Extensive family history of autoimmune phenotypes in Figure S1.

CasePresentingHPOs: HP:0002315, HP:000340, HP:0003394, HP:0004313, HP:0012115, HP:0001878, HP:0007565, HP:0001744, HP:0004315, HP:0006577, HP:0002090, HP:0002829, HP:0005263, HP:0006532, HP:0033542, HP:0032174, HP:0002110, HP:0011473 (headache, peripheral paresthesia, muscle cramps, hypogammaglobulinemia, autoimmune hepatitis, hemolytic anaemia, cafe au lait spots, splenomegaly, low IgG, macronodular cirrhosis, fungal pneumonia, arthralgia, antral gastritis, recurrent bacterial pneumonias, bronchial wall thickening, diffuse tree-in-bud infiltrates, bronchiectasis, focal total villous atrophy)

CaseHPOFreeText: Severe lesion in right cerebellar hemisphere and left superior frontal gyrus. Evan's syndrome, bronchial associated lymphoid hyperplasia, intestinal metaplasia, intraepithelial lymphocytes

CaseNotHPOs: HP:0001369, HP:0012538 (artritis, response to gluten)

CaseNotHPOFreeText: n/a

CasePreviousTesting: 2 benign polymorphisms found in perforin gene. Other genes tested: Fas, Fas ligand, Caspase 10, Caspase 8, NRAS. Heterozygous VUS found in LRBA gene.

GenotypingMethod: not specified. It says, "Following her mother’s diagnosis of CTLA4 haploinsufficiency, she was confirmed to have the same genetic mutation." Mother was tested using NGS + Sanger

PreviouslyPublished: not reported

Variant: NM_005214.4(CTLA4):c.81_82insT (p.Leu28fs) heterozygous

ClinVarID: 644629

CAID: CA645516071

gnomAD: not found

SupplementalData: Figure S1 shows extensive family history

Case#: Collen_2022_Patient_2, female, <1 y.o. (onset) 14 y.o. (report), Ethnicity reported: Hispanic

DiseaseAssertion: CTLA4 haploinsufficiency

FamilyInfo: reported de novo, but no evidence

CasePresentingHPOs: HP:0002014, HP:0002013, HP:0001508, HP:0001508, HP:0001510, HP:0002018, HP:0002027, HP:0032249, HP:0031035, HP:0005263, HP:0010783, HP:0004313, (diarrhea, vomiting, failure to thrive, lack of growth, chronic nausea, abdominal pain, lung coccidiomycosis, persistent villous atrophy, diffuse stomach inflammation, erythema, mucus plaques, hypogammaglobulinemia)

CaseHPOFreeText: Patient is from an endemic coccidiomyosis region. Increased intra-epithelial lymphocytes, mucoid plaque, scalloping of the duodenum, lamina proprietor expansion, poor response to polysaccharide pneumoccal vaccine

CaseNotHPOs: HP:0002608 (celiac serologies)

CaseNotHPOFreeText: TTG, IgA, EMA, HLA, DQ2, and DQ8 were negative. Bowel wall thickening. abnormal ileocolonoscopy

CasePreviousTesting: Primary immunodeficiency gene panel testing by Invitae

GenotypingMethod: Primary immunodeficiency gene panel testing by Invitae

PreviouslyPublished: not reported

Variant: de novo heterozygous c.71_72del (p.Leu24Profs*35) in exon 1 (NM_005214.5:c.71_72del)

ClinVarID: 1439020

CAID: CA2573320555

gnomAD: not reported

SupplementalData: n/a

MultipleGeneVariants: A heterozygous variant in PLCG2 (c.802C>T, p.Arg268Trp) detected (ClinVarID:403319, CAID:CA8193460). It is not usually reported in the panel. The authors ruled it out because the variant was found in 5 of 66 patients with disseminated coccidiomycosis in PMID:PMC7776098. The variant has been associated with autoimmune diseases according to OMIM. It is present in gnomAD (MAF: 0.101, Ashkenazi Jewish). It has been classified as benign in ClinVar.

Case#: Collen_2022_Patient_1, female, infancy (onset) 23 y.o. (report), Ethnicity reported: white

DiseaseAssertion: CTLA4 haploinsifficiency

FamilyInfo: Mutation inherited from father, who had melanoma and was asymptomatic for autoimmunity. Paternal first cousin had type-1 diabetes. Mother and brother had no autoimmune symptoms to report.

CasePresentingHPOs: HP:0002014, HP:0001510, HP:0002608, HP:0003261, HP:0033637, HP:0011473, HP:0002900, HP:0001903, HP:0001944, HP:0002246, HP:0001973, HP:0000872, HP:0008207, HP:0003765, HP:0004315, HP:0410240, HP:0030374 (diarrhea, low growth, celiac disease, elevated TTG IgA, endomyosial antibody, absence of duodenal villi, secondary hypokalemia, anemia, dehydration, scalloping of duodenal folds, cytopenias, hashimoto thyroiditis, Addison disease, psoriasis, low IgG, low IgA, low memory B cells)

CaseHPOFreeText: possible lichen sclerosis, negative titers to varicella-zoster virus and mumps despite vaccination. Patient showed switched memory B cells 1.4%, unswitched memory B cells 4.9%, and intraepithelial lymphocytes. Additional diagnosis's: Celiac disease, Hashimoto thyroiditis, Addison disease, CVID

CaseNotHPOs: HP:0002718 (recurrent bacterial infections)

CaseNotHPOFreeText: abnormal stool culture

CasePreviousTesting: none

GenotypingMethod: Whole exome sequencing (research based)

PreviouslyPublished: not reported

Variant: NM_005214.5:c.457+2T>C

ClinVarID: not found

CAID: CA350138849

gnomAD: not found

SupplementalData: n/a

Note: Functional information present. Immunophenotyping using flow cytometery revealed diminished expression of CTLA4 on CD4+/Foxp3+/CD45RA− memory regulatory T cells (Tregs) (Figure 3A).

Case#: Patient 3 (P3) is a 20-year-old Chinese female.

DiseaseAssertion: Patients are asserted to have "CTLA4 haploinsufficiency (CTLA-4 h).

FamilyInfo: The patient's brother died at age 15 from pancytopenia. The patient's mother was diagnosed with large granular lymphocytic leukemia. Patient's mother (Patient 4) also harbors the same CTLA4 variant as the patient. Authors do not indicate if patient's brother had genetic testing.

CasePresentingHPOs: HP:0001744 (Splenomegaly), HP:0001369 (Arthritis), HP:0020062 (Decreased hemoglobin concentration), HP:0011873 (Abnormal platelet count), HP:0002254 (Intermittent diarrhea), HP:0001876 (Pancytopenia), HP:0020026 (Positive Coombs test)

CaseHPOFreeText: Patients symptoms onset at 9 years old with chronic eczema, Evans syndrome, and splenomegaly. Initially responded well to corticosteroids and IV Ig, but relapsed after steroid tapering. She developed polyarthritis at age 16, diagnosed as juvenile idiopathic arthritis. She also developed photosensitive rashes. She was hospitalized due to pancytopenia and heavy vaginal bleeding. Anti-kertain antibody (AKA) and antiperinuclear factor were negative. Treatment with subcutaneous abatacept injections (125mg) resolved joint pain and brought hemoglobin and platelet counts to normal range.

CaseNotHPOs: HP:0003493 (Antinuclear antibody positivity), HP:0034092 (Anti-cyclic citrullinated peptide antibody positivity), HP:0002923 (Rheumatoid factor positive),

CasePreviousTesting: None reported.

GenotypingMethod: Genotyping was performed via whole exome sequencing.

PreviouslyPublished: No prior article is known to contain information on the same proband.

Variant: The patient is heterozygous for the NM_005214.4 CTLA4):c.347T>A (p.Ile116Asn) variant.

ClinVar: 2430678

gnomAD: The variant was not found in gnomAD v4.1.1.

SupplementalData: There is no supplemental data.