Preimplantation Genetic Testing for Human Leukocyte Antigens (PGT-HLA) provides patients with an option not only to avoid an inherited risk when combined with single gene testing (PGT-M), but also to establish a pregnancy with an exact HLA match to benefit an affected family member. HLA testing is done to enable stem cell transplantation treatment for an affected sibling. In our experience, the most common applications of PGT-HLA are for families with a child affected by hemoglobinopathy and congenital immunodeficiency. A total cure is possible when a compatible donor is made available through PGT-HLA. PGT-HLA can also be applied in cases that do not need preimplantation genetic testing for a monogenic disorder(s) (PGT-M), but need only an HLA-compatible donor. PGT-HLA without testing for a causative gene (PGT-M) was first performed by RGI for a patient with Diamond–Blackfan anemia (DBA) who required bone marrow transplantation.
PGT-HLA was first pioneered by Reproductive Genetic Innovations (RGI), world-wide, over twenty years ago. Our first case enabled a successful bone marrow transplantation treatment for a child with Fanconi Anemia (FA), an autosomal-recessive disorder causing bone marrow failure with increased predisposition to leukemia. Bone marrow transplantation is the only treatment, restoring hematopoiesis. Couples at risk for having a baby with FA are carriers of a pathogenic variant in the FANCC gene (FANCD2, FANCF, FANCI, FAMCCJ, and FANCA). However, an HLA-identical bone marrow match can result in the successful transplantation required for treatment of this disorder, namely by transfer of stem cells of an exact HLA match to the affected child. After the birth of a sibling baby who is HLA-matched, a sample of that normal baby’s bone marrow can save the life of its older affected sibling. This approach has been applied for an increasing number of congenital disorders that require an HLA-compatible donor for bone marrow transplantation. As with all PGT testing, PGT-HLA is performed in conjunction with an IVF cycle.
Many other disorders require HLA-compatible stem cell transplantation. Hemoglobinopathies — Sickle Cell and Thalassemias — are among the most common. Severe congenital immunodeficiency (SCID)* is another condition for which PGT-HLA and stem cell transplantation is required. Affected babies with SCID cannot survive, but again HLA-matched stem cell transplantation can replenish the immune system. Many other disorders RGI and our referring physicians have treated are listed in Table 1. In aggregate, 485 PGT-HLA cycles have been performed for 239 patients. A total of 424 HLA-matched embryos were identified for transfer into the uterus in 291 of 485 (68.6%) cycles. This resulted in 125 (43.0%) clinical pregnancies and the birth of 117 healthy HLA matched children, the result of availability of a normal sibling donating stem cells to their older affected sibling.
Table 1. Preimplantation HLA TESTING (PGT-HLA) WITH AND WITHOUT PGT-M
| Disease | Gene | # Patient | # Cycle | # Transfers | # Embryo transferred | Pregnancy | Birth |
| HLA genotyping | 60 | 119 | 73 | 108 | 25 | 22 | |
| HLA + ADADENOSINE DEAMINASE DEFICIENCY; ADA | ADA | 1 | 1 | 1 | 1 | 1 | 1 |
| HLA + ADRENOLEUKODYSTROPHY; ALD | ABCD1 | 3 | 7 | 2 | 2 | 1 | 2 |
| HLA + CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4; CMH4 | MYBPC3 | 1 | 1 | 1 | 1 | 1 | 1 |
| HLA + GRANULOMATOUS DISEASE, CHRONIC, AUTOSOMAL RECESSIVE; CDG1 | NCF1 | 1 | 3 | 2 | 2 | 1 | 1 |
| HLA + DIAMOND-BLACKFAN ANEMIA 1; DBA1 DIAMOND-BLACKFAN ANEMIA 2; DBA2 DIAMOND-BLACKFAN ANEMIA 3; DBA3 DIAMOND-BLACKFAN ANEMIA 5; DBA5 DIAMOND-BLACKFAN ANEMIA 9; DBA9 | RPS19, RPS20, RPS24, RPL35A, RPS10 | 10 | 17 | 14 | 20 | 8 | 8 |
| HLA + GLANZMANN THROMBASTHENIA; GT MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD | ITGA2B, DMD | 1 | 2 | 2 | 4 | 1 | 0 |
| HLA + MYOTONIC DYSTROPHY 1; DM1 | DMPK | 1 | 2 | 1 | 2 | 1 | 1 |
| HLA + ECTODERMAL DYSPLASIA AND IMMUNODEFICIENCY 1; EDAID1 | IKBKG | 3 | 10 | 8 | 10 | 3 | 4 |
| HLA + EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL DOMINANT; DDEB | COL7A1 | 1 | 1 | 1 | 1 | 1 | 1 |
| HLA + FANCONI ANEMIA, COMPLEMENTATION GROUP A; FANCA | FANCA | 18 | 56 | 29 | 42 | 14 | 13 |
| HLA + FANCONI ANEMIA, COMPLEMENTATION GROUP C; FANCC | FANCC | 3 | 6 | 6 | 9 | 2 | 2 |
| HLA + FANCONI ANEMIA, COMPLEMENTATION GROUP D2; FANCD2 | FANCD2 | 1 | 3 | 2 | 3 | 1 | 1 |
| HLA + FANCONI ANEMIA, COMPLEMENTATION GROUP F; FANCF | FANCF | 1 | 3 | 2 | 3 | 0 | 0 |
| HLA + FANCONI ANEMIA, COMPLEMENTATION GROUP G; FANCG | FANCG | 2 | 2 | 1 | 2 | 1 | 2 |
| HLA + FANCONI ANEMIA, COMPLEMENTATION GROUP I; FANCI | FANCI | 1 | 2 | 2 | 3 | 0 | 0 |
| HLA + FANCONI ANEMIA, COMPLEMENTATION GROUP J; FANCJ | BRIP1 | 2 | 4 | 4 | 3 | 1 | 1 |
| HLA + GRANULOMATOUS DISEASE, CHRONIC, X-LINKED; CDGX | CYBB | 11 | 16 | 12 | 15 | 7 | 6 |
| HLA + HBB SICKLE CELL ANEMIA; BETA-THALASSEMIA | HBB | 92 | 188 | 103 | 159 | 35 | 32 |
| HLA + IMMUNODEFICIENCY WITH HYPER-IgM, TYPE 1; HIGM1 | CD40LG | 11 | 16 | 10 | 15 | 9 | 8 |
| HLA + KRABBE DISEASE | GALC | 1 | 1 | 1 | 2 | 1 | 2 |
| HLA + MYELODYSPLASTIC SYNDROME; MDS | GATA2 | 1 | 2 | 1 | 1 | 1 | 1 |
| HLA + NEUTROPENIA, SEVERE CONGENITAL, 1, AUTOSOMAL DOMINANT; SCN1 | ELANE | 3 | 5 | 4 | 4 | 4 | 3 |
| HLA + SHWACHMAN-DIAMOND SYNDROME; SDS | SBDS | 4 | 9 | 3 | 3 | 2 | 2 |
| HLA + THROMBOTIC THROMBOCYTOPENIC PURPURA, CONGENITAL; TTP | ADAMTS13 | 1 | 2 | 2 | 4 | 1 | 1 |
| HLA + THROMBOCYTHEMIA 1; THCYT1 | SH2B3 | 1 | 2 | 2 | 2 | 2 | 1 |
| HLA + WISKOTT-ALDRICH SYNDROME; WAS | WAS | 1 | 1 | 0 | 0 | 0 | 0 |
| HLA + POLYCYSTIC KIDNEY DISEASE 1; PKD1 | PKD1 | 1 | 1 | 1 | 2 | 1 | 1 |
| HLA+ PYRUVATE KINASE DEFICIENCY OF RED CELLS | PKLR | 1 | 2 | 1 | 1 | 0 | 0 |
| HLA + HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL RECESSIVE | DOCK8 | 1 | 1 | 0 | 0 | 0 | 0 |
| TOTAL | 239 | 485 | 291 | 424 | 125 (43%) | 117 |
Technical limitations of PGT-HLA should be discussed with a genetic counselor, in order for couples to be fully informed about their options. Pivotal is that a relatively close HLA-match may be available but is not exact. Discussion with the referring pediatric hematologist is necessary to determine the feasibility of a successful transplantation.
Another limitation is the relatively advanced reproductive age of some couples or individuals requiring PGT-HLA. Two or more IVF cycles may be required to generate a sufficient number of embryos and assure HLA-identical and normal genotype. To maximize successful outcomes, PGT-A is recommended to exclude chromosomal abnormalities. In our experience reproductive outcome of PGT-HLA combined with PGT-A (Aneuploidy) is significantly higher than those PGT-HLA cycles without PGT-A.
To assist patients who cannot produce a sufficient number of oocytes required for PGT-HLA, RGI demonstrated that HLA matched donor oocytes (eggs) could potentially be used for PGT-HLA. This option was used in one of our PGT-HLA cases, the world’s first example using donor oocytes from a relative. This resulted in an unaffected HLA match for HLA stem cell transplantation, using a related adult as the oocyte donor.
Despite the above limitations, RGI’s overall experience of selection and transfer of HLA-matched and unaffected embryos was successful in 13.7% of the embryos tested. This rate reflects, in part, the small number of children per family. However, only less than one-third of eligible patients will have an HLA-identical family donor, so our experience summarized in the table 1 demonstrates the utility and reliability of PGT-HLA for families having affected children with bone marrow disorders who may wish to have another child.
Svetlana Rechitsky and Anver Kuliev*
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