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USIDNET 2024 Immunological Diseaes - Clarify MONDO codes #8090

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aslgraefe opened this issue Aug 21, 2024 · 12 comments
Open
48 tasks

USIDNET 2024 Immunological Diseaes - Clarify MONDO codes #8090

aslgraefe opened this issue Aug 21, 2024 · 12 comments
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aslgraefe commented Aug 21, 2024 •
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Dear all,

This issue compiles all the diseases from the unpublished USIDNET 2024 list for which MONDO codes have not yet been identified:

  • The diseases listed below correspond to those marked in yellow (n=37) in the Google Sheet 2024_CEIEN_Diseases_Codes, presented in the same order.
  • Prof. Beata Derflavi reviewed the diseases marked in green. Those listed below have associated MONDO codes but require validation or clarification to resolve assignment issues. Her comments are included below.
  • All diseases are provided with all additional information provided by the USIDNET-2024 Disease List that could aid in identification or clarification, such as inheritance patterns, gene names and codes, and associated features.

Table 1: Immunodeficiencies affecting cellular and humoral immunity

Subtable 2: T-B- SCID
  • NUDCD3 deficiency
    Gene: NUDCD3 (OMIM:610296)
    Inheritance: AR
    Associated Features: Omenn syndrome | T cell count & B cell count: very low
Subtable 3: Combined Immunodeficiencies Generally Less Profound than Severe Combined Immunodeficiency

Table 2: Combined immunodeficiencies with associated or syndromic features

Subtable 1: Immunodeficiency with Congenital Thrombocytopenia
  • IKZF2 DN
    Gene: IKZF2 (OMIM:606234)
    _Inheritance: AD & DN (Dominant-negative)
    Associated Features: CD4 and CD8 T cell lymphopenia with low TRECs; B-cell count normal to low; Developmental delay, hearing loss, cleft palate, abnormal teeth
Subtable 2: DNA Repair Defects other than those listed in Table 1
  • GINS4 deficiency
    Gene: GINS4 (OMIM:610611)
    Inheritance: AR
    Associated Features: Immunoglobulin levels normal or increased, Low NK cells, Herpes family viruses, growth delay
Subtable 3: Thymic Defects with Additional Congenital Anomalies
  • CHARGE syndrome due to SEMA3E deficiency
    Gene: SEMA3E (OMIM:608166)
    Inheritance: AD
    Related USIDNET2024 Disease: CHARGE syndrome due to CHD7 deficiency (MONDO:0008965)
    Associated Features: Coloboma, heart anomaly, choanal atresia, intellectual retardation, genital and ear anomalies, CNS malformation, some are SCID-like and have low TRECs; T cell count decreased or normal, response to PHA may be decreased; Immunoglobulin levels
    normal or decreased
Subtable 9 Other Combined immunodeficiencies with syndromic features

  • DIAPH1 deficiency
    Mondo Code: MONDO:0014714
    Immunology Comment (Prof. Beata Derfalvi): "PMID: 39120629, PMID: 33662367 Previously described disease with extended phenotype as combined immunodef. MONDO does not mention immune deficiency yet!"

  • FLT3L deficiency
    Gene: FLT3LG (OMIM:600007)
    Inheritance: AR
    Associated Features: Viral infections, diarrhoea; B cell count decreased; Immunoglobulin levels increased; Hypoplastic anaemia, monocytopenia, DC-penia, low/absence of dermal DCs

  • PTCRA deficiency
    Gene: PTCRA (OMIM:606817)
    Inheritance: AR
    Associated Features: Low T cell in infancy, Autoantibodies, norma patients are normal

  • CD28 Deficiency
    Gene: CD28 (OMIM:186760)
    Inheritance: AR
    Associated Features: Normal numbers of T and myeloid cells with decreased NK cells; Normal numbers of total B cells and subsets; Normal serum IgM, G, A; • intact levels of pathogen-spec IgG; HPV susceptibility

Table 3: Predominantly Antibody Deficiencies

Subtable 2 CVID Phenotype

  • **PTEN Deficiency (LOF)
    Gene: PTEN (OMIM:601728)
    Related MONDO Terms:
    MONDO:0011537 macrocephaly-autism syndrome
    MONDO:0008021 Cowden syndrome 1
    MONDO:0011789 familial meningioma
    MONDO:0013092 glioma susceptibility 2
    Immunologist Comment(Prof. Beata Derfalvi): I would NOT use these codes. suggest to develop a new MONDO code, based on PMID: 27426521, PMID: 37178059. PTEN def belongs to the APDS1 group (previously 2 cases were published with immunodeficiency, called "Cowden syndrome" , but immunologists do not use this syndrome name)

  • TWEAK deficiency
    Gene: TNFSF12 (OMIM:602695, one VUS variant: OMIM:602695.0001
    Inheritance: AD
    Associated Features: Low IgM and A, lack of anti-pneumococcal antibody, Pneumonia, bacterial infections, warts, thrombocytopenia.

Subtable 3: Severe Reduction in Serum IgG and IgA with Normal/Elevated IgM and Normal Numbers of B cells, Hyper IgM
  • INO80
    Gene: INO80 (OMIM:610169)
    Inheritance: AR
    Associated Features: Low IgG and IgA with normal or high IgM, Severe bacterial infections

Table 4 Diseases of Immune Dysregulation

Subtable 1: Familial Hemophagocytic Lymphohistiocytosis (FHL syndromes)
  • FAAP24 deficiency
    Gene: FAAP24 (OMIM:610884)
    Inheritance: AR
    Associated Features: Increased activated T cells, EBV infection-driven lymphoproliferative disease

Subtable 2: FHL Syndromes with Hypopigmentation

  • GIMAP6 deficiency
    Gene: GIMAP6 (OMIM:616960)
    Inheritance: AR
    Associated Features: Adenopathy, splenomegaly, vasculitis, autoantibodies, Decreased naïve T cells, High IgM, Reduced NK cytotoxicity

Subtable 4: Autoimmunity with or without Lymphoproliferation

  • PD-L1 deficiency
    Gene: CD274 (OMIM:605402)
    Inheritance: AR
    Associated Features: Low switched memory B cells, T cell count: Normal with high DR, Low MAITs, Neonatal onset autoimmunity

  • IRE1a deficiency
    Gene: ERN1 (OMIM:604033)
    Inheritance: AD
    Associated Features: Systemic autoimmunity, pleomorphic autoimmunity with autoantibodies

  • SH2B3 deficiency
    Gene: SH2B3 (OMIM:605093)
    related MONDO codes: MONDO:0007572 primary familial polycythemia due to EPO receptor mutation, MONDO:0008554 thrombocythemia 1, MONDO:0009692 primary myelofibrosis
    Immunologist Comment (Prof. Beata Derfalvi): I would NOT use these codes. I suggest to develop a new MONDO code, based on PMID: 37277724, the newly described SH2B3 deficiency is Interferon-gamma receptor 1 deficiency

Subtable 5: Immune Dysregulation with Colitis

  • NFAT5 haploinsufficiency
    Gene: NFAT5 (OMIM:604708)
    Inheritance: AD
    Associated Features: IBD, recurrent sinopulmonary infections

Subtable 6: Autoimmune Lymphoproliferative Syndrome (ALPS, Canale Smith syndrome)

  • ALPS-FASLG
    Gene: TNFSF6 (OMIM: 134638)
    related Mondo Term and USIDNET2024 disease: ALPS-FAS (AD / AR) (MONDO:0011158)
    _Immunologist Comment (Prof. Beata Derfalvi): "although this gene defect presents clinically as ALPS (similarly to the TNFRSF6 gene defect), since this is a separate gene, I would suggest to develop a new MONDO code"
Subtable 7: Susceptibility to EBV and Lymphoproliferative Conditions

  • IL-27RA deficiency
    Gene: (OMIM:605350)
    Inheritance: AR
    Associated Features: Severe primary EBV

  • CD137 deficiency (41BB) and 4-1 BBL Deficiency
    Gene: TNFRSF9 (OMIM:602250) and TNFSF9 (OMIM:620282)
    related MONDO term: MONDO:0859526 (immunodeficiency 109 with lymphoproliferative)
    comment by Prof. Beata Derfalvi:although this gene defect presents clinically similarly, since this is a separate gene, I would suggest to develop a new MONDO code PMID: 37144041
    although this gene defect presents clinically similarly, since this is a separate gene, I would suggest to develop a new MONDO code PMID: 35657354 (CD137 deficiency (41BB) and PMID: 35657354 (4-1 BBL Deficiency)

Table 5 Congenital defects of phagocyte number or function

Subtable 1 Congenital Neutropenias

  • DBF4 deficiency
    Gene: DBF4 (OMIM:604281)
    Inheritance: AR
    Associated Features: low Neutrophil count, Developmental delay

  • Schwachman Diamond syndrome due to DNAJC21 deficiency and ** ... due to SBDS deficiency**
    Genes: DNAJC21 (OMIM:617048) & SBDS (OMIM:607444)
    Related MONDO Term: Shwachman-Diamond syndrome 1 (MONDO:0044204)
    Comment Immunologist Prof. Beata Derfalvi: although this gene defect presents clinically similarly, since this is a separate gene, I would suggest to develop a new MONDO code

  • SRP19 deficiency
    Gene: SRP19
    Inheritance: AR
    Associated Features: Reduction in electron dense granules in PMN, Exocrine pancreatic insifficiency, poor growth, recurrent infections

  • SRPRA deficiency
    Gene: SRPRA (OMIM:182180)
    Inheritance: AR
    Associated Features: Reduction in electron dense granules in PMN, Exocrine pancreatic insifficiency, poor growth, recurrent infections

Table 6 Defects in intrinsic and innate immunity

Subtable 1 Mendelian Susceptibility to mycobacterial disease (MSMD)

  • IL-12Rb2 deficiency
    Gene: IL12Rb2 (OMIM:601642)
    Inheritance: AR
    Associated Features: Susceptibility to mycobacteria and Salmonella
    Related USIDNET2024 Diseases: IL-12p40 (IL-12 and IL-23) deficiency (MONDO:0013954) & IL-12 and IL-23 receptor b1 chain deficiency (MONDO:0013955)

  • IL-23R deficiency
    Gene: IL23R (OMIM:607562)
    Related Mondo Term: inflammatory bowel disease 17 (MONDO:0012840)
    Comment Prof. Beata Derfalvi: "This is a misleading MONDO code, recently described phenotype of this gene defect is Mendelian susceptibility to mycobacterial disease PMID: 36763636 (Although IL23R is implicated in the pathogenesis of inflammatory bowel diseases ,I cant find monogenic inflammatory bowel disease caused by IL23R)"

Subtable 3 Predisposition to Severe Viral Infection

  • NOS2 deficiency
    Gene: NOS2 (OMIM:163730)
    Inheritance: AR
    Associated Features: Low CD4 T cells, Low B cells,
    Related MONDO Disesae: cytomegalovirus pneumonia due to NOS2 deficiency (MONDO:0800143)

  • OAS2 deficiency
    Gene: OAS2 (OMIM:603350)
    Inheritance: AR
    Associated Features: MISC
    _Related USIDNET2024 Disease: OAS1 deficiency (MONDO:0020840)

  • RNA polymerase III deficiency due to POLR3C defects
    Gene: POLR3C (OMIM:617454)
    Inheritance: AD
    Associated Features: Severe VZV
    Related USIDNET2024 Diseases: RNA polymerase III deficiency due to POLR3A defects (MONDO:0009910) & RNA polymerase III deficiency due to POLR3F defects ([MONDO:0030813)

Subtable 4 Herpes Simplex Encephalitis (HSE)

  • ATG4A
    Gene: ATG4A (OMIM:300663)
    Inheritance: AD
    Associated Features: Mollaret's meningitis HSV2

  • GTF3A deficiency
    Gene: GTF3A (OMIM:600860)
    Inheritance: AR
    Associated Features: Fibroblasts affected, HSE

  • IKBKE deficiency
    Gene: IKBKE (OMIM:605048)
    Inheritance: AD
    Associated Features: Microglia affected, HSE

  • MAP1LC3B2
    Gene: MAP1LC3B2 (OMIM:620673)
    Inheritance: AD
    Associated Features: Mollaret's meningitis HSV2

  • RIPK3 deficiency
    Gene: RIPK3 (OMIM:605817)
    Inheritance: AR
    Associated Features: HSE, Neurons affected

Subtable 7 TLR Signaling Pathway Deficiency

  • TLR4 deficiency
    Gene: TLR4
    Inheritance: AR
    Associated Features: IBD
    Related MONDO Diseae: age related macular degeneration 10 (MONDO:0012674)

  • MD2 deficiency
    Gene: LY96 (OMIM:605243)
    Inheritance: AR
    Associated Features: IBD, infections, Myeloid cells affected

  • IRAK1 deficiency
    Gene: IRAK1
    Inheritance: XL (OMIM "not yet attributed")
    Associated Features: Bacterial infections, X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 | other affected cells: Lymphocytes + Granulocytes+ Monocytes

  • IRAK4 disorder
    Gene: IRAK4 (OMIM:606883)
    Inheritance: AR, GOF
    Associated Features: Neuroinflammation, fever, splenomegaly
    Related Disease USIDNET2024: IRAK4 deficiency (MONDO:0011888)

Subtable 9 Other inborn errors of immunity related to leukocytes

Table 7: Autoinflammatory Disorders

Subtable 1: Type 1 Interferonopathies

  • STING-like disease
    Gene: STING1
    Inheritance: AR, GOF
    Associated Features: Failure to thrive; early onset rash, fever, dyspnea, interstitial lung disease/pneumonitis, polyarthritis, autoAbs, clubbing. Increased inflammatory markers, IFN gene signature. Phenocopy of SAVI due to AD GOF TMEM173 variants. 2 patients succumbed; 4 successfully treated with JAK inhibitors | Immunoglobulin levels: Increased
    Related Disease USIDNET2024: STING--associated vasculopathy, infantile-onset (MONDO:0014405)

  • TREX1 deficiency, Aicardi-Goutieres syndrome 1 (AGS1) AD vs AR
    Gene: TREX1 (OMIM:225750)
    Related MONDO code: MONDO:0009165 Aicardi-Goutieres syndrome 1
    Comment Prof. Beata Derflavi: "Different presentation of het TREX-1 mutation: Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an autosomal-dominant disorder involving the cerebral, retinal, renal, and other systemic microvessels due to frameshift mutations in the TREX1 gene. PMID: 30561700 Please use different code in AR and AD form" --> However, no distinct MONDO codes exist for AD and AR

Subtable 3: Non-Inflammasome Related Conditions
  • Otulin haplosufficiency
    Gene: OTULIN (OMIM:615712)
    Inheritance: AD
    Associated Features: Inflammatory disease, Staphylococcus aureus infection
    Related Diseases USIDNET2024: Otulipenia/ORAS (MONDO:0014912) & Otulin deficiency (MONDO:0031030)

Table 8: Complement Deficiencies

  • Complete C4 Deficiency
    Gene: C4A & C4B (OMIM:120810) (Omim code provided by USIDNET2024, however this only refers to C4A)
    Related MONDO Diseases: MONDO:0013721 complement component 4a deficiency,
    MONDO:0013720 complement component 4b deficiency
    Associated Features: SLE, infections with encapsulated organisms , partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense
    Comment Prof. Beata Derflavi: although this gene defect presents clinically similarly, since this is a separate gene, I would suggest to develop individual MONDO code

  • C8g deficiency
    Gene: C8G (OMIM:120930)
    Inheritance: AR
    Associated Features: Disseminated neisserial infections

  • Factor H –related protein deficiencies
    Genes: CFHR2 (OMIM:600889) & CFHR4 (OMIM:605337)
    Inheritance: AR / AD
    Associated Features: Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections
@sabrinatoro sabrinatoro added the user request A request from an external user label Aug 30, 2024
@sabrinatoro sabrinatoro self-assigned this Aug 30, 2024
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cmungall commented Oct 9, 2024

@pnrobinson what is your recommendation for how to proceed here?

E.g. take "CHARGE syndrome due to SEMA3E deficiency". We have CHARGE as being due to CHD7 in Mondo, consistent with OMIM. We could make a grouping class a placeholder for a future phenotypic series, e.g.

  • CHARGE - new
    • CHARGE due to CHD7 - current
    • CHARGE due to SEMA3E - new
    • <others?>

this seems consistent with the literature, e.g
https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.1034
Besides common CHD7 gene variants, the mutations of elongation factor Tu GTP binding domain containing 2 (EFTUD2), lysine methyltransferase 2D (KMT2D), semaphorin 3E (SEMA3E) (OMIM# 214800) and arginine-glutamic acid dipeptide repeats (RERE) duplication could also cause CHARGE syndrome (Badalato et al., 2017; Jordan et al., 2018; Lehalle et al., 2014; Luquetti et al., 2013; Sanlaville & Verloes, 2007).

However I think we should coordinate with OMIM (and OMIM already have some notes about SEMA3E variants from a 2004 paper)

Also what do you think of prioritizing relevant papers like https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.1034 for phenopacket curation?

@pnrobinson
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There are several case reports that describe variants in SEMA3E in persons said to have CHARGE syndrome
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9143429/
https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.1034

I am not sure if the clinical diagnosis is really correct, because neither of the patients are said to have coloboma or choanal atresia.
It is hard to judge the validity of case reports like this where there is no statistics about the mutations and where the clinical match is only partial.

CHD7 is the major gene for CHARGE. https://omim.org/entry/214800?search=charge&highlight=charge
However, I believe that there are cases in which no molecular diagnosis can be made.

@ahamosh thoughts?

@aslgraefe
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@cmungall @pnrobinson I may have a suggestion. I am soon meeting Dr. Kathleen Sullivan soon in Philadelphia (Oct 29), who curated the USIDNET2024 list, and the Canadian Immunologists Beata Derfalvi and Nicola Wright (Nov 7-9). Also, Peter will have an HPO workshop with the European Immunologists in November. Perhaps we could curate the list as far as possible and coordinate with them to finish up on the clinical questions left. Perhaps we could bring all of this together somehow. I hope that may help and I am happy to coordinate if necessary.

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pnrobinson commented Oct 10, 2024 via email

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pnrobinson commented Oct 10, 2024 via email

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pnrobinson commented Oct 10, 2024 via email

@cmungall
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We should be able to bring any kind of spreadsheet it. But it would be good to have an SOP for things such as naming conventions and placement.

It sounds like in this case calling the disease "CHARGE syndrome due to SEMA3E deficiency" would not be correct. Would the appropriate name be something like:

  • CHARGE-like syndrome due to SEMA3E deficiency
  • SEMA3E deficiency
  • SEMA3E deficiency based immunological disease

(of course we can retain any number of additional synonyms)

For terms like:

name: NUDCD3 deficiency
Gene: NUDCD3 ([OMIM:610296](https://omim.org/entry/610296))
Inheritance: AR
Associated Features: Omenn syndrome | T cell count & B cell count: very low

We likely wouldn't want to call this disease "NUDCD3 deficiency" in Mondo (there may be non immune diseases associated eg with lissencephaly). Is there a naming convention we prefer?

  • NUDCD3 deficiency based immunological disease

or more specific to its placement

  • T-B- SCID NUDCD3 deficiency?

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pnrobinson commented Oct 11, 2024 via email

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pnrobinson commented Oct 11, 2024 via email

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pnrobinson commented Oct 11, 2024 via email

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pnrobinson commented Oct 11, 2024 via email

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This issue is currently waiting for feedback on this PR
@cmungall could you please let me know how to proceed on this. If we decide to drop the logic for these terms (and keep up to date manually), then I can go ahead with the issue here.

Note: Once I have the information above, the creation of these terms will be very quick.

Thank you for your patience.

@sabrinatoro sabrinatoro mentioned this issue Nov 19, 2024
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