Retrospective Genetic Molecular Diagnosis for Inborn Errors of Immunity in Patients with Autoimmunity: Experience from a Single Center

Mora, Gabriela F.; Valdez, Rita; Lotersztein, Vanesa

doi:10.70962/LASID2025abstract.67

Adults diagnosed with inborn errors of immunity (IEI) frequently lack a history of recurrent infections, but often present a myriad of autoimmune or inflammatory manifestations. Suspicion for an underlying IEI in patients with autoimmunity should be accounted for those patients with poly-autoimmunity (endocrinal or systemic or both), atypical course of disease, refractory immune cytopenias, and concurrent neoplasia or history of it. A recent work from Riviere et al. tested retrospectively a scoring system for diagnosis of IEI in a cohort of pediatric and adult patients. The most frequent warning sign among adults identified as high risk was bronchiectasia in the absence of cystic fibrosis, followed by systemic and endocrine autoimmune diseases, cytopenias, and more than 3 pneumonias.

Case Patients

Here, we present a case series of seven patients that were selected for molecular genetic testing. Among these patients, poly-autoimmunity, recalcitrant eczema, autoinflammatory clinical traits, immune cytopenias, atypical course and refractory disease were the main criteria for testing (Sanger, next-generation sequencing, whole exome sequencing).

Results

All seven patients presented IEI genetic variants of genes congruent with their disease profile. Patient characteristics and genetic results are depicted in Tables 1, 2. The most frequently diagnosed defect was common variable immune deficiency and immune dysregulation and autoinflammatory syndromes. Most of the variants found were not previously reported, of uncertain significance, and autosomal dominant in heritance. One patient had compound heterozygous likely pathogenic variants of AIRE gene, and one patient had a pathogenic variant of NOD2 gene. No patient had a history of recurrent infections.

Table 1.

Genetic testing of the seven patients.

Patient	Gene	Variant (cDNA)	Effect	Zygocity	Variant type	Methodology	Reported	ACMG classification
1	AIRE	1. c.1095+6G>A	1. -	Compound heterozygous	Germinal	Sanger	1. Yes	1. LP
1	AIRE	2. c.834C>G	2. p.S278_R	Compound heterozygous	Germinal	Sanger	2. No	2. VUS
2	1. *CR2*	1. c763C>T	1. p.Arg255Trp	Heterozygous	Germinal	Targeted NGS	1. No	1. VUS
2	2. *JAK3*	2. c478G>T	2. Gli160cis	Heterozygous	Germinal	Targeted NGS	2. No	2. VUS
3	1. *NOD2*	1. C.2104C>T	1. p.Arg702Trp	Heterozygous	Germinal	Targeted NGS	1. Yes	1. P
	2. IL6ST	2. c.371-3T>A	2. Intrónica	Heterozygous			2. No	2. VUS
	3. MSN	3. c.1304G>C	3. p.Arg435Pro	Heterozygous			3. No	3. VUS
	4. PRKDC	4. c9071C>T	4. p.Pro3024Leu	Heterozygous			4. No	4. VUS
4	*CASP10*	c.738C>A	p.Asp246Glu	Heterozygous	Germinal	Targeted NGS	No	VUS
5	*NCKAP1L*	c.2189C>T	p.Thr730Met	Heterozygous	Germinal	Targeted NGS	No	VUS
6	1. ATP6AP1	1. c1219GzA	1. p.Val407Ile	Heterozygous	Germinal	Targeted NGS	1. No	1. VUS
	2. LYST	2. c4313C>G	2. p.Ala1438Gly	Heterozygous	Germinal	Targeted NGS	2. No	2. VUS
	3. TRFC	3. c.1575C>G	3. p.Asp525Glu	Heterozygous	Germinal	Targeted NGS	3. No	3. VUS
	4. IKZF3	4. c.707C>T	4. p.Thr236Ile	Heterozygous	Germinal	Whole exome sequencing	4. No	4. VUS
7	*PIK3CD*	c.707C>T	p.Pro236Leu	Heterozygous	Germinal	Whole exome sequencing	No	VUS

Patient	Gene	Variant (cDNA)	Effect	Zygocity	Variant type	Methodology	Reported	ACMG classification
1	AIRE	1. c.1095+6G>A	1. -	Compound heterozygous	Germinal	Sanger	1. Yes	1. LP
1	AIRE	2. c.834C>G	2. p.S278_R	Compound heterozygous	Germinal	Sanger	2. No	2. VUS
2	1. *CR2*	1. c763C>T	1. p.Arg255Trp	Heterozygous	Germinal	Targeted NGS	1. No	1. VUS
2	2. *JAK3*	2. c478G>T	2. Gli160cis	Heterozygous	Germinal	Targeted NGS	2. No	2. VUS
3	1. *NOD2*	1. C.2104C>T	1. p.Arg702Trp	Heterozygous	Germinal	Targeted NGS	1. Yes	1. P
	2. IL6ST	2. c.371-3T>A	2. Intrónica	Heterozygous			2. No	2. VUS
	3. MSN	3. c.1304G>C	3. p.Arg435Pro	Heterozygous			3. No	3. VUS
	4. PRKDC	4. c9071C>T	4. p.Pro3024Leu	Heterozygous			4. No	4. VUS
4	*CASP10*	c.738C>A	p.Asp246Glu	Heterozygous	Germinal	Targeted NGS	No	VUS
5	*NCKAP1L*	c.2189C>T	p.Thr730Met	Heterozygous	Germinal	Targeted NGS	No	VUS
6	1. ATP6AP1	1. c1219GzA	1. p.Val407Ile	Heterozygous	Germinal	Targeted NGS	1. No	1. VUS
	2. LYST	2. c4313C>G	2. p.Ala1438Gly	Heterozygous	Germinal	Targeted NGS	2. No	2. VUS
	3. TRFC	3. c.1575C>G	3. p.Asp525Glu	Heterozygous	Germinal	Targeted NGS	3. No	3. VUS
	4. IKZF3	4. c.707C>T	4. p.Thr236Ile	Heterozygous	Germinal	Whole exome sequencing	4. No	4. VUS
7	*PIK3CD*	c.707C>T	p.Pro236Leu	Heterozygous	Germinal	Whole exome sequencing	No	VUS

In bold, the genes mainly related to the patient’s phenotype. NGS: next-generation sequencing; LP: likely pathogenic; VUS: variant of uncertain significance; P: pathogenic.

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Table 2.

Genetic, clinical, and phenotypical characteristics of the tested patients.

Patient	Sex	Age	Gene	Zygocity	Heritance	Family affected	Clinical phenotype	T-B lymphocytes phenotype	IEI phenotype
1	F	60	AIRE	Compound heterozygous	AR	No	Polyendocrinopathy + autoimmune hepatitis + celiac disease + undifferentiated spondyloarthropathy.	CD4 - CD8 naive lymphopenia.	Atypical autoimmune polyglandular syndrome
1	F	60	AIRE	Compound heterozygous	AR	No		B1a lymphopenia.	Atypical autoimmune polyglandular syndrome
2	F	62	1. *CR2*	Heterozygous	AD	No	Lung granulomas. Bronchiectasia.	CD4 - CD8 naive lymphopenia. NK deficit.	CVID
2	F	62	2. *JAK3*	Heterozygous	AD	No	Lung granulomas. Bronchiectasia.	CD4 - CD8 naive lymphopenia. NK deficit.	CVID
3	F	21	1. *NOD2*	Heterozygous	AD	No	Recurrent fever. Lymphoproliferation. Rash.	Normal.	Yao Syndrome
			2. IL6ST	Heterozygous	AD
			3. MSN	Heterozygous	LX
			4. PRKDC	Heterozygous	AR
4	M	30	*CASP10*	Heterozygous	AD	No	ALPS + psoriasis.	CD4 - CD8 naive lymphopenia. CD8 early effectors elevated. B naive -pre-switch memory lymphopenia.	ALPS
5	F	65	*NCKAP1L*	Heterozygous	AR?	No	Autoimmune hepatitis + Sjögren’s syndrome.	CD4 - CD8 naive lymphopenia. NK deficit. B lymphopenia: transitional, pre-post switch memory.	CVID
6	F	56	*IKZF3*	Heterozygous	AD	Yes (daughter)	Panuveitis + IgA nephropathy.	CD4 - CD8 naive lymphopenia. NK deficit. B lymphopenia: transitional.	AIOLOS haploinsufficiency
7	M	48	*PIK3CD*	Heterozygous	Variable	No	Behcet’s disease (skin, oral, neurological). Anti-phospholipid syndrome atypical epilepsy.	Normal.	Activated PIK3CD syndrome

Patient	Sex	Age	Gene	Zygocity	Heritance	Family affected	Clinical phenotype	T-B lymphocytes phenotype	IEI phenotype
1	F	60	AIRE	Compound heterozygous	AR	No	Polyendocrinopathy + autoimmune hepatitis + celiac disease + undifferentiated spondyloarthropathy.	CD4 - CD8 naive lymphopenia.	Atypical autoimmune polyglandular syndrome
1	F	60	AIRE	Compound heterozygous	AR	No		B1a lymphopenia.	Atypical autoimmune polyglandular syndrome
2	F	62	1. *CR2*	Heterozygous	AD	No	Lung granulomas. Bronchiectasia.	CD4 - CD8 naive lymphopenia. NK deficit.	CVID
2	F	62	2. *JAK3*	Heterozygous	AD	No	Lung granulomas. Bronchiectasia.	CD4 - CD8 naive lymphopenia. NK deficit.	CVID
3	F	21	1. *NOD2*	Heterozygous	AD	No	Recurrent fever. Lymphoproliferation. Rash.	Normal.	Yao Syndrome
			2. IL6ST	Heterozygous	AD
			3. MSN	Heterozygous	LX
			4. PRKDC	Heterozygous	AR
4	M	30	*CASP10*	Heterozygous	AD	No	ALPS + psoriasis.	CD4 - CD8 naive lymphopenia. CD8 early effectors elevated. B naive -pre-switch memory lymphopenia.	ALPS
5	F	65	*NCKAP1L*	Heterozygous	AR?	No	Autoimmune hepatitis + Sjögren’s syndrome.	CD4 - CD8 naive lymphopenia. NK deficit. B lymphopenia: transitional, pre-post switch memory.	CVID
6	F	56	*IKZF3*	Heterozygous	AD	Yes (daughter)	Panuveitis + IgA nephropathy.	CD4 - CD8 naive lymphopenia. NK deficit. B lymphopenia: transitional.	AIOLOS haploinsufficiency
7	M	48	*PIK3CD*	Heterozygous	Variable	No	Behcet’s disease (skin, oral, neurological). Anti-phospholipid syndrome atypical epilepsy.	Normal.	Activated PIK3CD syndrome

In bold, the genes mainly related to the patient’s phenotype. F: female; M: male; AR: autosomal recessive; AD: autosomal dominant; ALPS: autoimmune lymphoproliferative syndrome; CVID: common variable immune deficiency.

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Conclusion

Testing for IEI should be taken into account in patients with poly-autoimmunity, atypical manifestations, or refractory disease. A proper diagnosis of underlying IEI in this group could facilitate management and result in less morbidity for these patients.