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various genetic testing options throughout pregnancy.
Boys conceived by IVF / ICSI from fathers with severely reduced sperm count or motility, generally have sperm profiles similar to males who were not conceived through assisted reproductive technologies. 14 While sperm abnormalities often have a genetic component, the inheritance patterns are not necessarily straightforward. The direct transmission of these conditions from fathers to male offspring is not common and genetic factors are only one contributory element.
Reproductive management for hereditary disorders
In recent years, an increasing number of couples are seeking advice on safe reproduction to minimise the risk of their children inheriting a known genetic disorder. This can be due to various scenarios, including those outlined in box 1.
Genetic counselling is required given the nuances regarding different inheritance patterns and residual reproductive risks for different conditions. Medicare rebates are now available for preimplantation genetic testing( PGT) to avoid passing on known chromosomal or single-gene disorders. Eligibility requirements for these rebates include referral of the couple to a clinical geneticist, usually by their IVF specialist.
PGT may be performed for chromosome aneuploidies( PGT-A), structural rearrangements such as translocation( PGT-SR) or monogenic( single-gene) disorders( PGT-M).
PGT-A is often utilised in the context of increasing aneuploidy rates that occur with increasing maternal age. The couple undertakes a conventional IVF cycle, and embryos are biopsied at blastocyst stage( day 5 / 6). Next-generation sequencing identifies chromosomal aneuploidy with 95-98 % accuracy,
There are many genetic influences that affect human reproduction.
Box 1. When couples may seek advice about genetic disorders
• A family history of genetic illness, even if the parents are currently unaffected.
• One parent may have a known condition or carrier status of a gene.
• A child may have been born with a paediatric diagnosis indicating parental carrier status.
• A previous in-utero diagnosis of an abnormality leading to pregnancy termination.
• Shared carrier status by a couple identified through preconception reproductive carrier screening.
and euploid embryos are transferred in a subsequent frozen embryo transfer cycle. PGT-A is commonly used in routine IVF to reduce implantation failure, miscarriage rate and fetal abnormality risk due to aneuploidies such as trisomy 21. PGT-SR will screen for chromosome aneuploidies similarly to PGT-A, with additional specific testing to detect both balanced and unbalanced forms of chromosomal rearrangements known to be present in the parents.
PGT for a monogenic disorder is more complicated and requires the gene variant to be‘ fingerprinted’ in a process called karyomapping. DNA samples are collected from the pro-
The timing of genetic counselling and / or genetic testing is important.
spective parents and several other‘ reference’ individuals, such as an affected child or the couple’ s parents. The gene sequence of interest is then mapped to each sample, a process which usually takes several weeks. IVF with ICSI is required to minimise DNA contamination, and the blastocyst biopsy is compared to the previously mapped samples. PGT-M provides both monogenic disorder and aneuploidy results. A non-affected embryo will be preferentially transferred, but carrier embryos are also suitable for transfer. Sometimes, the IVF cycle may not yield any embryos suitable for biopsy, or PGT-M results will identify that all embryos are affected. This latter scenario requires significant genetic counselling around the possibility and implications of utilising affected embryos.
PGT-M offers the potential to essentially eliminate continued inheritance of a monogenic disorder from a family lineage. Of course, this is not a guarantee against all other genetic conditions.
Utilising IVF with PGT may also identify embryos that are mosaic for various genetic changes. Whether or not these embryos are suitable for transfer requires careful assessment and genetic counselling.
The role of genetic counselling
Specialist genetic counselling has become an essential component of reproductive healthcare, providing invaluable support to individuals and couples navigating the complexities of genetic tests and results. Available through fertility clinics, pathology units and private genetic clinics, these services are often integrated into multidisciplinary teams that include geneticists, IVF specialists and other healthcare professionals.
Genetic counsellors hold advanced degrees in both genetics and psychosocial counselling, and are trained to assess family and medical histories, educate patients about inheritance patterns and advise on appropriate genetic testing options. They interpret test results and facilitate informed decision-making regarding reproductive choices. This includes in guiding patients through the wide range of reproductive carrier screening options that are becoming commonplace in fertility.
Panels range from the Medicare-rebated three-gene screen( CFTR, SMA and FMR1) to extended panels with many hundreds of genes, and decision-making in this context should take family history, ancestry and personal values into account.
The study that ascertained how best to deliver reproductive genetic carrier screening in Australia at scale was Mackenzie’ s Mission. This research project was named after Mackenzie Casella, who died at age seven months from spinal muscular atrophy. 15 Mackenzie’ s Mission paved the way in determining that reproductive carrier screening was possible in Australia and helped create today’ s national reproductive screening program.
The timing of genetic counselling and / or genetic testing is important in the fertility journey. It is generally advisable for couples to engage in this before initiating fertility treatments, to allow for the return of test results and for couples to attain a proper understanding of the potential genetic risks. Delaying treatment until after receiving genetic test results can empower couples to make informed decisions about their reproductive options.
Genetic counselling can provide valuable psychosocial support to couples navigating the significant emotional challenges associated with navigating infertility and the implications of hereditary conditions.
References on request from kate. kelso @ adg. com. au