Activating de novo monoallelic variants causing inborn errors of immunity in two unrelated children born of HIV-seroconcordant couples

Abstract

Introduction: Around 20% of all inborn errors of immunity (IEI) are autosomal dominant or monoallelic, either by haploinsufficiency, negative dominance, or gain of function (GOF). GOF phenotypes usually include autoinflammation, autoimmunity, lymphoproliferation, allergies, and some infections. Case series: We describe the cases of two unrelated patients born of HIV-seroconcordant parents. Both patients are HIV-negative but carry de novo GOF missense variants that resulted in inflammatory lymphoproliferative IEI diseases: signal transducer and activator of transcription 3 (STAT3)-GOF and phosphatidylinositol 3-kinase, catalytic delta (PIK3CD)-GOF. Both variants were found through whole-exome sequencing and confirmed by Sanger. An 11-year-old male with recurrent sinopulmonary infections, dysmorphism, growth delay, bronchiectasis, and mild mental retardation, as well as lymphopenia, thrombocytopenia, and high immunoglobulin M. Both his parents were known to be HIV-positive under anti-retroviral treatment. HIV infection was repeatedly ruled out in the patient, whom through whole-exome sequencing was found to have a heterozygous missense variant in exon 24 of PIK3CD, a hotspot transition, and the most reported variant in PIK3CD-GOF patients. A 6-year-old male with autoimmune hemolytic anemia, lymphoproliferation, short stature, and intractable diarrhea. Both his parents were found to be HIV-positive. HIV was repeatedly ruled out in the patient by ELISA and viral load. He was found to have a heterozygous missense/splice variant in exon 22 of STAT3, a hotspot transition, and the most reported variant in STAT3-GOF patients. Discussion: The AID/APOBEC3 A-H family of proteins are cytidine deaminases that induce G>A hypermutation in both the invading viral DNA and the host genome, which results in stop codons inside the endogenized retroviral sequence. Both variants found in our patients are G to A transitions. Retroviral infection might thus have resulted in host genome instability, and our patients’ rare congenital diseases are the unfortunate consequence of somatic hypermutation in one of their parents’ gametes.

Potential HIV/ART-mediated germline mutations causing congenital inborn errors of immunity in children born to HIV+ couples: an alarming spectre

“…In conclusion, the study by Reyes et al [1] has raised an alarming spectre. They have highlighted an important avenue of investigations in the biology of HIV infection.…”

“…In the two cases reported by Reyes et al [1], it is very likely that APOBECs have induced the mutations in fathers' gametes. Unlike ova from women which are resistant to HIV entry and infection, early stage testicular germ cells (spermatogonia) can be infected with HIV via cell to cell spread, but not by cell-free virus as they do not express CD4 þ on their surface [6].…”

“…In this issue of AIDS, Reyes et al [1] describe two HIV-negative children, born to two HIV-1 infected non-consanguineous parents, with mono-allelic inborn errors of immunity (IEI): a 6 year-old boy with heterozygous missense/splice variant in exon 22 of signal transducer and activator of transcription-3 (STAT-3) in a hotspot for gain of function (GOF) mutations in this gene, and a 13 year-old boy with heterozygous missense variant in exon 24 of phosphatidylinositol-2,4-biphosphate kinase-3 catalytic domain delta (PIK3CD), also a GOF mutation in a known mutational hotspot for this gene. Both the mutations involved G>A/C>T transitions.…”

“…Interestingly, one member of the APOBEC family (A4) is predominantly expressed in the testes, though it lacks cytidine deaminase activity and increases HIV replication [10]. Thus, it is biological plausible that the two cases of IEI, reported by Reyes et al [1], resulted from mutations induced by APOBEC family members in germ cells of the affected children's fathers.…”