cmungall
commented
1 month ago @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
aslgraefe
sabrinatoro
Dear all,
This issue compiles all the diseases from the unpublished USIDNET 2024 list for which MONDO codes have not yet been identified:
Table 1: Immunodeficiencies affecting cellular and humoral immunity
Subtable 2: T-B- SCID
Subtable 3: Combined Immunodeficiencies Generally Less Profound than Severe Combined Immunodeficiency
[ ] IRF4 multimorphic R95T Gene: IRF4 (OMIM:601900) Inheritance: AD Associated Features: PJP, viral, T cell count normal except low Th17 and TFH, B cell count reduced, Agammaglobulinemia Related Disease in MONDO: diffuse large B-cell lymphoma activated B-cell type
[ ] NFATC1 deficiency Gene: NFATC1 Inheritance: AR Associated Features: Hypogammaglobulinemia, Sinopulmonary infections, warts | B-cell count: Low switched memory
[ ] Already opened Issue: Polymerase d 2 deficiency & Polymerase d 3 deficiency
Table 2: Combined immunodeficiencies with associated or syndromic features
Subtable 1: Immunodeficiency with Congenital Thrombocytopenia
Subtable 2: DNA Repair Defects other than those listed in Table 1
Subtable 3: Thymic Defects with Additional Congenital Anomalies
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
Table 4 Diseases of Immune Dysregulation
Subtable 1: Familial Hemophagocytic Lymphohistiocytosis (FHL syndromes)
Subtable 2: FHL Syndromes with Hypopigmentation
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
Subtable 6: Autoimmune Lymphoproliferative Syndrome (ALPS, Canale Smith syndrome)
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
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