Forty years of IVF

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding a peroxisomal ABC transporter. In this review, we compare estimates of incidence derived from different populations in order to provide an overview of the worldwide incidence of X-ALD. X-ALD presents with heterogeneous phenotypes ranging from adrenomyeloneuropathy (AMN) to inflammatory demyelinating cerebral ALD (CALD). A large number of different mutations has been described, providing a unique opportunity for analysis of functional domains within ABC transporters. Yet the molecular basis for the heterogeneity of clinical symptoms is still largely unresolved, as no correlation between genotype and phenotype exists in X-ALD. Beyond ABCD1, environmental triggers and other genetic factors have been suggested as modi- fiers of the disease course. Here, we summarize the findings of numerous reports that aimed at identifying modifier genes in X-ALD and discuss potential problems and future approaches to address this issue. Different options for prenatal diagnosis are summarized, and potential pitfalls when applying next-generation sequencing approaches are discussed. Recently, the measurement of very long-chain fatty acids in lysophosphatidylcholine for the identification of peroxisomal disorders was included in newborn screening programs.

https://dash.harvard.edu/bitstream/handle/1/16121005/4427263.pdf?sequence=1

The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis.

Designed to minimize chances of genetically abnormal embryos, preimplantation genetic diagnosis (PGD) involves in vitro fertilization (IVF), embryo biopsy, diagnosis and selective embryo transfer. Preimplantation genetic testing for aneuploidy (PGT-A) aims to avoid miscarriage and live born trisomic offspring and to improve IVF success. Diagnostic approaches include fluorescence in situ hybridization (FISH) and more contemporary comprehensive chromosome screening (CCS) including array comparative genomic hybridization (aCGH), quantitative polymerase chain reaction (PCR), next-generation sequencing (NGS) and karyomapping. NGS has an improved dynamic range, and karyomapping can detect chromosomal and monogenic disorders simultaneously. Mosaicism (commonplace in human embryos) can arise by several mechanisms; those arising initially meiotically (but with a subsequent post-zygotic 'trisomy rescue' event) usually lead to adverse outcomes, whereas the extent to which mosaics that are initially chromosomally normal (but then arise purely post-zygotically) can lead to unaffected live births is uncertain. Polar body (PB) biopsy is the least common sampling method, having drawbacks including cost and inability to detect any paternal contribution. Historically, cleavage-stage (blastomere) biopsy has been the most popular; however, higher abnormality levels, mosaicism and potential for embryo damage have led to it being superseded by blastocyst (trophectoderm - TE) biopsy, which provides more cells for analysis. Improved biopsy, diagnosis and freeze-all strategies collectively have the potential to revolutionize PGT-A, and there is increasing evidence of their combined efficacy. Nonetheless, PGT-A continues to attract criticism, prompting questions of when we consider the evidence base sufficient to justify routine PGT-A? Basic biological research is essential to address unanswered questions concerning the chromosome complement of human embryos, and we thus entreat companies, governments and charities to fund more. This will benefit both IVF patients and prospective parents at risk of aneuploid offspring following natural conception. The aim of this review is to appraise the 'state of the art' in terms of PGT-A, including the controversial areas, and to suggest a practical 'way forward' in terms of future diagnosis and applied research.

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Chromosomal analysis in IVF: just how useful is it?

Wiskott-Aldrich syndrome is a life-threatening primary immunodeficiency associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy. Stem cell transplantation offers the opportunity of cure for all these complications, and over the past 35 years there has been a remarkable improvement in survival following this treatment. Here, we review advances in management of clinical complications pre- and post-transplant, as well as discuss the morbidity Wiskott-Aldrich syndrome patients experience following treatment. For patients with a poorly matched stem cell donor, recent gene therapy trials demonstrate encouraging results and the potential of low-toxicity therapy for all patients.

Current and emerging treatment options for Wiskott-Aldrich syndrome.

Haematopoietic stem cell transplantation (HSCT) remains the best therapeutic option for many acquired and inherited paediatric haematological disorders. Unfortunately, the probability of finding an HLA matched donor is limited. An alternative technique is PGD combined with HLA matching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child, with the aim of possible use of stem cells from the resulting baby in future. Since the first successful report for Fanconi anaemia a decade ago, the therapeutic success of this technique was reported in a few cases and for a limited number of disorders. Here, we report full recovery of 44 sick children who received HSCT from healthy infants conceived after pre-implantation HLA matching for the following 10 indications; beta-thalassaemia, Wiskott–Aldrich syndrome, Fanconi anaemia, sickle cell anaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, Glanzmann's thrombasthaenia, Diamond–Blackfan anaemia, X-linked adrenoleukodystrophy and mucopolysaccharidosis type I. No serious complications were observed among recipients and donors. Graft failure occurred in four children with beta-thalassaemia where a second HSCT was planned. Preimplantation HLA matching is a reliable technique and provides a realistic option for couples seeking treatment for an affected child when no HLA-matched donor is available.

Shimon Slavin

Papers

Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching