Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: CD46

I don't know

BIALLELIC CASES:
PMID: 40983966 Hu et al., 2025
Case of a 27-year-old Chinese male diagnosed with atypical Hemolytic Uremic Syndrome (aHUS) at the age of 8, who has experienced seven relapses over a span of 19 years. He was homozygous for a mutation in CD46: c.1127+2T>A (WES). CD46 mRNA and protein expression in the patient's peripheral blood were significantly reduced. Other modifier mutations may affect penetrance here.

PMID: 33238263 Bamhraz et al., 2020
Saudi Arabian aHUS cohort.
Patient 1 homozygous for CD46: c.736T>A (p.Phe246Ile) variant, as well as het for CFI c.540A>G (p.Glu180Glu) - both labelled VUS. Disease onset at 10yrs, complete recovery after eculizumab treatment.
Patient 5 - homozygous for CD46: c.769 C>A (p.Cys 256*) - LP, as well as heterozygous for CFI c.803 C>T (p.Ser268Leu) variant (LB). Disease onset at 2.5yrs, developed into ESRD and required a post-kidney transplant.
Patient 7 - homozygous for CD46: c.350-351dup AC (p.Glu11ThfsX17) - LP. Disease onset at 21 months. Patient responded to plasma therapy leading to full recovery.

PMID: 29644059 Khandelwal et al., 2018
Cohort of Indian children with aHUS.
Sibling pairs 2–3 and 7–8 with familial disease showed a homozygous c.286 + 2T > G splice-site mutation; in both families, the parents were consanguineous. Patient 9 had a homozygous c.104G > A, p.Cys35Tyr; his affected sibling had died before genetic evaluation. 3 unrelated families total.

PMID: 16762990 Fremeaux-Bacchi et al., 2006
3 homozygous aHUS patients (onset at 2, 5, and 27yrs).
Patient 1 - born with Pierre Robin sequence, presented with common variable immunodeficiency. Developed aHUS at 27yrs. Homozygous for CD46 R25X. MFI on granulocytes for CD46 expression was 0.
Patient 2 was homozygous for CD46 Y214X (no CD46 expression on granulocytes; Patient 3 homozygous for IVS2+2T>G - CD46 MFI level was 46 (normal range 600-1400). No mention of immunodeficiency in Patients 2 & 3.

PMID: 16621965 Caprioli et al., 2006
Family 099 - Sardinian origin, 2 individuals homozygous for CD46 IVS1-1G > C, and 1 heterozygous affected member (4 het carriers unaffected). The homozygous sibs developed aHUS early (before age 4 yrs); adult onset seen in heterozygous family members.
Family 024 - 2 comp het sibs CD46 variants c.218C>T, p.R25Stop & c.147G>A, p.C1Y - showed almost no MCP staining by FACS. Parents were carriers of 1 mutation each, unaffected.

PMID: 14566051 Richards et al., 2003
Family 3 - recessive aHUS, CD46 c.822T>C, p.Ser206Pro. Same mutation caused aHUS in Family 2 in a heterozygous state. Demonstrated that het patients had protein expression reduced by 50%, and it was absent in homozygotes.

Created: 24 Jun 2026, 10:17 a.m. | Last Modified: 26 Jun 2026, 11 a.m.

Panel Version: 9.18

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
{Hemolytic uremic syndrome, atypical, susceptibility to, 2}, OMIM:612922

Publications

• 14566051
• 16621965
• 16762990
• 29644059
• 33238263
• 40983966

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
atypical HUS

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): CD46 .PanelApp HGNC gene symbol check: CD46 . IUIS Disease: Membrane Cofactor Protein (CD46) deficiency . IUIS Inheritance: AD .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Atypical hemolytic-uremic syndrome, infections, preeclampsia. IUIS Major category: Complement Deficiencies. IUIS Subcategory: N/A

Created: 2 Jul 2018, 10:35 a.m.

Comment on list classification: Changed Amber to Green from external expert review and further publications to support gene-disease association

Created: 27 Jun 2018, 7:19 p.m.

Comment on publications: Added publications to support upgrading of the gene to Green

Created: 27 Jun 2018, 7:19 p.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: CD46, PanelApp HGNC gene symbol check: CD46, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Complement deficiencies / Complement deficiency / Membrane Cofactor Protein (CD46) deficiency

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: CD46, GRID_Gene_Symbol: CD46, GRID_Transcript_ENS_Community submitted: ENST00000322875, GRID_Transcript_RefSeq: NM_002389.4, GRID_Transcript_ENS_used_on_Production: ENST00000322875

Created: 17 Apr 2018, 12:12 p.m.