Preimplantation diagnosis for Fanconi anemia combined with HLA matching.

CONTEXT The advent of single-cell polymerase chain reaction (PCR) has presented the opportunity for combined preimplantation genetic diagnosis (PGD) and HLA antigen testing. This is a novel and useful way to preselect a potential donor for an affected sibling requiring stem cell transplantation. OBJECTIVE To perform in vitro fertilization (IVF) and preimplantation HLA matching combined with PGD for Fanconi anemia (FA). DESIGN DNA analysis for the IVS 4 + 4 A-->T (adenine to thymine) mutation in the FA complement C (FANCC) gene in single blastomeres, obtained by biopsy of embryos, to identify genetic status and HLA markers of each embryo before intrauterine transfer. SETTING In vitro fertilization programs at large medical centers in Chicago, Ill, and Denver, Colo. PARTICIPANTS A couple, both carriers of the IVS 4 + 4 A-->T mutation in the FANCC gene with an affected child requiring an HLA-compatible donor for cord blood transplantation. MAIN OUTCOME MEASURES DNA analysis of single blastomeres to preselect unaffected embryos representing an HLA match for the affected sibling. RESULTS Of 30 embryos tested in 4 IVF attempts, 6 were homozygous affected and 24 were unaffected. Five of these embryos were also found to be HLA-compatible, of which 2 were transferred in the first and 1 in each of the other 3 cycles, resulting in a pregnancy and birth of an unaffected child in the last cycle. CONCLUSION To our knowledge, this is the first PGD with HLA matching, demonstrating feasibility of preselecting unaffected embryos that can also be an HLA-compatible source for stem cell transplantation for a sibling.

[1]  A. H. Handyside,et al.  Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification , 1990, Nature.

[2]  W. R. Shannon,et al.  Cloning of cDNAs for Fanconi's anaemia by functional complementation , 1992, Nature.

[3]  Z. Rosenwaks,et al.  First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia. , 1999, JAMA.

[4]  S. Seneca,et al.  Clinical application of preimplantation diagnosis for myotonic dystrophy , 1997, Prenatal diagnosis.

[5]  R. Berger,et al.  Bone Marrow Transplantation in Fanconi Anaemia , 1980, British journal of haematology.

[6]  M. Buchwald,et al.  Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9 , 1992, Nature Genetics.

[7]  R. Gibson,et al.  A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews , 1993, Nature Genetics.

[8]  K. Tadokoro,et al.  A nested PCR-RFLP method for high-resolution typing of HLA-A alleles. , 1998, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[9]  D. Cram An Atlas of Preimplantation Genetic Diagnosis , 2002 .

[10]  D. Huhn,et al.  Complete subtyping of the HLA-A locus by sequence-specific amplification followed by direct sequencing or single-strand conformation polymorphism analysis. , 1995, Tissue antigens.

[11]  J. Kurtzberg,et al.  Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. , 1989, The New England journal of medicine.

[12]  A. Cambon-Thomsen,et al.  Microsatellites in the HLA region: 1999 update. , 2000, Tissue antigens.

[13]  C. Mathew,et al.  Novel mutations and polymorphisms in the Fanconi anemia group C gene , 1996, Human mutation.

[14]  S. Rechitsky,et al.  Atlas of preimplantation genetic diagnosis , 2014 .

[15]  C. Strom,et al.  Prepregnancy testing for single-gene disorders by polar body analysis. , 1999, Genetic testing.

[16]  Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. , 1992 .

[17]  A. Kimura,et al.  Polymerase-chain-reaction-based analysis of polymorphism in the HLA-B gene. , 1992, Human immunology.

[18]  A. Cambon-Thomsen,et al.  Microsatellites in the HLA region: 1998 update. , 1998, Tissue antigens.

[19]  C. Strom,et al.  Analysis of the first polar body: preconception genetic diagnosis. , 1990, Human reproduction.

[20]  Z. Rosenwaks,et al.  Preimplantation diagnosis for p53 tumour suppressor gene mutations. , 2001, Reproductive biomedicine online.