Table 2.

Clinical presentation of patients with genes with pathogenic/likely pathogenic variants.

ID	Sex	Age at diagnosis	Relevant family history	Main clinical features	Panel/WES	Implicated gene	Variant classification (zygosity)	Accession numbers for pathogenicity scores	Diagnosis	Status	Medical interventions as indicated and/or substantiated by molecular diagnosis
Patients with likely pathogenic/pathogenic variants in genes previously associated with IEI (IUIS criteria)
001	F	2 years 5 months	None	Recurrent URTI; lymphadenitis; recurrent abscesses of lymph nodes; soft dysmorphism.	Panel1	PIK3R1 c.1425+1G>A (Splice donor)	Pathogenic (heterozygous)	rs587777709/VCV000372467.8	Autosomal dominant activated PI3K-delta syndrome	Alive	Prophylactic antibiotics.
											Annual surveillance for malignancy (Lymphoma).
											Regular surveillance for TB.
											Monthly Immune replacement therapy for life.
											Annual audiology screening.
002	M	8 months	Unknown	Recurrent and severe URTI requiring ICU admission in 1st year of life.	Panel1	CD40LG c.346G>T p.Gly116Cys	Likely pathogenic (hemizygous)	Invitae internal calling.	CD40 Ligand deficiency/X-linked Hyper IgM syndrome	Demised after molecular diagnosis	3 weekly immune replacement therapy.
											Regular neutrophil screening for indication of GCSF.
											Cotrimoxazole prophylaxis.
											Would have qualified for HSCT.
003	M	4 months	Unknown	Persistent hypoglycemia; eczema; recurrent fevers and infections with persistent neutropenia. Massive hepatosplenomegaly.	Panel1	SLC37A4 c.59G>A p.Gly20Asp; c.1047_1059delinsGGCTAT p.Phe349Leufs*52	Pathogenic (compound heterozygous)	rs193302881/VCV000551776.1 and Invitae internal calling.	Autosomal recessive glycogen storage disease type Ib	Alive	GCSF administration for neutropenia.
											High calorie diet to prevent hypoglycemic attacks.
											Regular infection screening.
											Endocrine surveillance.
											Organ transplant if needed.
004	M	10 months	Mom is a confirmed carrier	Septicaemia with empyema at 8/12, progressive neurodevelopmental delay and encephalopathy with persistent enteroviral shedding from stool, suspected to be oral Polio vaccine derived strain.	Panel2,3,4	BTK c.215dupA (p.Asn72Lysfs*13)	Pathogenic (hemizygous)	rs886041148/VCV000279713.4	X-linked Agammaglobulinemia	Demised after molecular diagnosis	Ig replacement therapy.
005	F	8 months	No	Recurrent URTI; flat diffuse warts; raised IgE levels.	Panel5	DOCK8 c.3803del (p.Phe1268Serfs*3)	Pathogenic (homozygous)	Invitae internal calling.	Autosomal recessive hyper-IgE syndrome with combined immunodeficiency	Alive	Prophylactic antibiotics.
											Malignancy surveillance of skin lesions.
											Qualifies for HSCT.
006	M	1 year 1 month	Affected maternal uncles (deceased) Mom is a confirmed carrier	Recurrent sepsis and shock; CMV induced LRTI; candida UTI; chronic gastroenteritis; FTT.	Panel6	CD40LG Deletion (Exon 3)	Pathogenic (hemizygous)	Invitae internal calling.	CD40 Ligand deficiency/X-linked Hyper IgM syndrome	Demised after molecular diagnosis	May have benefited from HSCT.
											Ig replacement therapy.
007	M	1 year 2 months	None	Progressive paralysis likely due disseminated oral polio vaccine; progressive weakness; nosocomial sepsis; reduced CD4 cells, with normal number of C8, C19 and CD16/CD56 cells.	Panel6	RFX5 c.367_368del (p.Leu124Cysfs*21)	Pathogenic (homozygous)	rs1228361094	Bare Lymphocyte syndrome 2	Demised before molecular diagnosis	May have benefited from HSCT.
008	M	2 months	Yes; brother died at 3 months from severe infection (suspected SCID)	SCID; lung disease; CMV; hepatitis.	Panel1	IL2RG c.116-1G>A (Splice acceptor)	Pathogenic (hemizygous)	rs104895462/VCV000004696.4	X-linked severe combined immunodeficiency	Demised after diagnosis	Ig replacement therapy.
											Did not meet criteria for HSCT due to disseminated persistent CMV infection).
009	F	1 year 8 months	No	PJP in early infancy, hypogammaglobulinemia with normal CD19, later onset neutropenia.	Panel1	MAP3K14 c.1033G>A p.Val345Met	Likely pathogenic (homozygous)	Invitae internal calling	MSMD	Alive	Ig replacement therapy.
											Prophylactic antibiotics.
											Live BCG vaccines avoided in sib at birth. Sibling vaccinated once results confirmed to be normal.
010	F	3 years 3 months	None	Boggy tenosynovitis of wrists and ankles; uveitis	Single gene screen	NOD2 c.1000C>T p.Arg334Trp	Pathogenic (heterozygous)	rs104895462/VCV000004696.4	Blau Syndrome	Alive	Methotrexate.
											Regular Follow up for uveitis progression.
011	F	2 years 1 month	None	Recurrent septicaemia, oral ulcers; congenital neutropenia; FTT.	Single gene screen	ELANE c.416C>T (p.Pro139Leu)	Pathogenic (heterozygous)	rs137854448/VCV000016743.4	Severe Congenital Neutropenia	Unknown Patient lost to follow up.	GCSF subcutaneous injections.
											Monitor for malignancies.
012	M	2 years 2 months	Mom is a confirmed obligate carrier	Agammaglobulinemia; absence of mature B-cells; recurrent pneumonias.	Single gene screen	BTK Partial Deletion (Exon 11)	Pathogenic (hemizygous)	Novel; Not reported in population databases; Not reported in literature.	X-linked Agammaglobulinemia	Alive	Ig replacement therapy.
											Eligible for gene therapy.
013	M	3 months	Yes: brother died from the same condition; further history of CID in cousins. Both parents are carriers	Multi-lobular pneumonia; low IgG; dysmorphism; diarrhoea.	WES	TTC37 c.4507 C>T p.R1503C	Pathogenic (homozygous)	rs200067423/VCV000287653.5	Trichohepatoenteric syndrome	Demised before molecular diagnosis	Parenteral nutrition.
											Ig replacement therapy.
											Surveillance for liver dysfunction.
014	F	9 years and 6 months	Yes, affected sibling	Central nervous system and skin; vasculitis, stroke with hemiparesis, seizures, progressive contractures of interphalangeal joints without bone resorption.	WES	SAMHD1 c.1681_1682del p.Ser561Phe fs*61)	Pathogenic (homozygous)	Novel; Not reported in population databases; Not reported in literature.	Aicardi-Goutières syndrome-5	Alive	Anticoagulant therapy.
											Immunomodulation therapy.
											Surveillance for unusual infections including TB.
											Surveillance for glaucoma.
015	F	14 years	Yes, affected sibling	Contractures of interphalangeal joints without bone resorption, severe glaucoma.	WES	SAMHD1 c.1681_1682del p.Ser561Phe fs*61	Pathogenic (homozygous)	Novel; Not reported in population databases; Not reported in literature.	Aicardi-Goutieres syndrome-5	Alive Follow up defaulter	Management of glaucoma.
											Surveillance for unusual infections including TB.
016	M	2 years 1 month	Unknown	Recurrent pneumonia and recurrent gastroenteritis. Chronic oral herpes lesions.	WES	TNFRSF13B c.236 A>G p.Tyr79Cys	Pathogenic (heterozygous)	rs72553876/VCV000281110.4	Common variable immunodeficiency-2 Normal B and T cells with Low IgG.	Alive	Ig replacement therapy for life.
017	F	9 years 5 months	No	Recurrent bacterial septicemias; pneumonias and herpes Labialis Molluscum; encephalitis; intellectual disability.	WES	LRBA c.3407 C>T p.Pro1136Leu	Pathogenic (homozygous)	rs113022115/VCV000287734.2	Common variable immunodeficiency-8 with autoimmunity	Demised before molecular dx. Molecular diagnosis made post mortem	Ig replacement therapy and immune modulation eg. CTLA-4 (Orencia) HSCT would have been indicated.
018	F	3 years 7 months	None	Initial cutaneous BCG abscess and later chronic CNS BCG dissemination, severe hypogammaglobulinemia.	WES	MAP3K14	Likely pathogenic (homozygous)	VCV000843423.2	CVID and Mendelian susceptibility to mycobacterial disease	Alive	TB surveillance.
						c.1033 G>A					Antibiotic prophylaxis.
						p.Val345Met					Ig replacement therapy.
						Avoid live vaccines.
019	M	Birth	Yes; male sibling with SCID died in early infancy prior to HSCT	Asymptomatic severe combined immunodeficiency T-B+NK-, identified on basis of positive family history.	WES	IL2RG c.443 T>G p.Leu148Arg	Pathogenic (hemizygous)	Novel; Not reported in population databases; Not reported in literature.	X-linked severe combined immunodeficiency	Alive	HSCT successful.
											Thriving requiring no further intervention.
020	M	4 months	Yes, brother died in early infancy from persistent diarrhea, thrombocytopenia (probable WAS)	Chronic diarrhoea, eczematous skin rashes, CMV pneumonitis, septic arthritis, Group B Streptococcal Septicaemia. Delayed onset thrombocytopaenia.	WES	WAS c.397 G>A p.Glu133Lys	Pathogenic (hemizygous)	VCV000870492.1	Wiskott–Aldrich syndrome	Alive	Immune replacement therapy.
											Prophylactic antibiotics
											Surveillance of autoimmunity and thrombocytopenia.
											Qualifies for HSCT but no consent.
021	F	6 years 4 months	None	Disseminated verrucae, chronic otitis media, Herpes Keratitis, bacterial pneumonias and suspected pulmonary tuberculosis.	WES	DOCK8 c.3912del p.N1267fs	Pathogenic (homozygous)	Novel; Not reported in population databases; Not reported in literature.	Autosomal recessive hyper-IgE syndrome with combined immunodeficiency	Alive	Screening for TB, malignancy (cervical and skin) & hepatic disorders.
											Ig replacement therapy.
											Qualifies for HSCT.
022	M	2 years 4 months	Yes; affected maternal uncle	Stable neutropenia, lymphopenia, hypogammaglobulinemia, pneumonias & upper respiratory infections in infancy and early childhood with spontaneous gradual improvement.	WES	MSN c.511C>T p.Arg171Trp	Pathogenic (hemizygous)	rs1057519074/VCV000372154.6	Immunodeficiency-50 (Mild phenotype)	Alive	Immune replacement therapy.
											Prophylactic antibiotics.
											HSCT not indicated because of mild phenotype.
023	F	5 years 4 months	None	Hypogammaglobulinemia, isolated ACTH deficiency, asymptomatic pulmonary infiltrates and canalicular liver function abnormalities.	WES	NFKB2 c.1288C>T p.Pro430Ser	Likely pathogenic (heterozygous)	rs202001697/VCV000474775.4	DAVID syndrome	Alive	Hormone replacement.
											Ig replacement therapy.
											Surveillance for Liver disease and other endocrine deficiencies.
024	F	7 years 6 months	None	Recurrent pneumonias with bronchiectasis, skin abscesses, scoliosis	WES	STAT1 c.802 G>T p.Glu268Ter	Likely pathogenic (heterozygous) VUS (heterozygous)	Novel; Not reported in population databases; Not reported in literature.	Hyper IgE syndrome	Alive	Immune replacement therapy.
											Prophylactic antibiotics.
											ZNF341 c.2167 A>C p.Thr723Pro

Panel¹, PR08100.02: Invitae Primary Immunodeficiency Panel; Panel², PR08111.02.1: Add-on Hypogammaglobulinemia Genes; Panel³, PR08111.02.2: Add-on Common Variable Immunodeficiency Genes; Panel⁴, PR08111.02:Invitae Agammaglobulinemia Panel; Panel⁵, PR08113.01:Invitae Hyper IgE Syndrome Panel; Panel⁶, PR08137.02: Invitae Combined Immunodeficiency (CID) Panel; Panel⁷, PR08143.02:Invitae Mendelian Susceptibility to Mycobacterial Disease Panel; Panel⁸, PR08112.01: Invitae Common Variable Immunodeficiency Panel; Panel⁹, PR08112.01.1: Add-on Genes for Primary Immunodeficiencies That Can Mimic Common Variable Immunodeficiency; Panel¹⁰, PR08114.01: Invitae Hyper IgM Syndrome Panel; Panel¹¹, PR08114.01.1: Add-on Clinically-overlapping Genes; Panel¹², PR08120.02.01: Add-on Autoimmunity Genes; Panel¹³, PR08120.02: Invitae Autoinflammatory Syndromes Panel; Panel¹⁴, PR08113.04:Invitae Hyper IgE Syndrome Panel; M, male; F, female; WES, whole exome sequencing; URTI, upper respiratory tract infections; FTT, failure to thrive; UTI, urinary tract infection; TBM, tuberculosis meningitis; ACTH, adrenocorticotropic hormone; LRTI, lower respiratory tract infections; ACTH, adrenocorticotropic hormone; LRTI, lower respiratory tract infections; CID, Combined Immunodeficiency; GIT, gastrointestinal tract; HSCT, haematopoietic stem cell transplant; GCSF, Granulocyte colony-stimulating factor; CMV, Cytomegalovirus; PJP, Pneumocystis jirovecii pneumonia; DAVID, Deficient anterior pituitary with variable immune deficiency; BCG, Bacillus Calmette Guérin; CNS, central nervous system; VUS, variant of unknown significance; ICU, intensive care unit.