20 JUNE 2025 ausdoc. com. au

Therapy Update

Genetics

Dr Kym Mina is a consultant genetic pathologist based in Western Australia and is chair of the Royal College of Pathologists of Australasia’ s Genetics Advisory Committee.

Genetic carrier screening for couples planning pregnancy is an important step to allow informed reproductive decision-making.

NEED TO KNOW

Reproductive genetic carrier screening( RGCS) should be offered to all women planning pregnancy or in the early stages of pregnancy, if not already conducted.

Timely identification of couples who are carriers allows for discussion of options to reduce the risk of having a child affected, or to optimise neonatal and postnatal care.

Three-gene RGCS alone is not appropriate for couples with a family history of a known genetic disorder( unless that disorder is one of the three included tests), who require specific genetic testing to identify the genetic disorder or variants in the family.

Professional bodies recommend that RGCS be offered to all women planning pregnancy, or in the early stages of pregnancy. To support this, MBS items for three-gene RGCS for cystic fibrosis( CF), spinal muscular atrophy( SMA) and fragile X syndrome( FXS) were introduced in November 2023.

This article focuses on the principles and utility of RGCS, MBS-funded testing performed so far, and practical tips for using the three-gene screen.

To clearly describe the utility and application of RGCS, the following terms are used throughout this article: reproductive couple, reproductive partner and carrier couple to describe those contributing genetically to a pregnancy, and male and female to refer to chromosomal sex( XY or XX).

What is RGCS?

The purpose of RGCS is to identify reproductive couples with a high chance of having children with severe autosomal recessive( AR) or X-linked( XL) inherited genetic disorders.

RGCS may focus on genetic disorders prevalent in a specific ethnic group, or be offered more broadly to all individuals of reproductive age as either a screen for the most common genetic disorders in the general population, or as an expanded screen that includes additional( typically hundreds) of rare genetic disorders. 1

Three-gene RGCS for identification of carriers for CF, SMA and FXS is MBSfunded for individuals of reproductive age, regardless of ethnic background or family history. These disorders are included in screening because they all have significant population carrier frequencies in

Australia, can have devastating effects on life expectancy and quality of life( see table 1), and most carriers have no personal or family history. Published Australian data indicates that about one in 20 adults are expected to be carriers for CF, SMA or FXS, and one in 240 couples have a high chance of having an affected child. 2

Screening aims to identify carrier couples with a reproductive risk of at least one in four of having a child affected with AR disease( CF or SMA) due to both partners being carriers, or a risk of at least one in two of having a child affected with XL disease( FXS) because the female partner is a carrier. Identification of carrier couples enables couple-specific reproductive decision-making that can include options to reduce the chance of having an affected child, or optimise neonatal and postnatal care.

RGCS can be offered either prior to conception or in early pregnancy. However,

preconception RGCS allows more time for decision-making, access to sufficient genetic counselling, and consideration of the widest range of reproductive options including pre-implantation genetic diagnosis or gamete donation. 3, 4

Earlier identification of carrier couples also maximises understanding of anticipated postnatal outcomes, and preparation for critical perinatal and neonatal management, including timely access to disease-specific drug therapies. 3, 5

In the laboratory

Genetic testing is the only way to confirm that an individual is a carrier for CF, SMA and FXS. The three-gene RGCS test involves the detection of genetic variants in the CFTR, SMN1 and FMR1 genes that, when passed onto children, can cause these disorders. The testing is performed on DNA extracted from a peripheral blood or buccal / saliva sample using three different gene tests that are combined to generate a result.

The characteristics of the genetic variants in the CFTR, SMN1 and FMR1 genes are well understood. 6-8 This means that laboratories offering this testing in Australia use well-established methods with high accuracy and sensitivity to identify most genetic carriers for CF, SMA and FXS. Therefore, when a disease-causing genetic variant is detected in any of the genes tested, it indicates with high confidence that the person tested is a carrier, and that this information can be used to determine next steps in management.

When no variants are identified— that is, the individual tested is not identified as a carrier— this result provides reassurance that they have a low chance of having children with CF, SMA or FXS. Note

Professional bodies recommend that RGCS be offered to all women planning pregnancy, or in the early stages of pregnancy.

that as the sensitivity of RGCS is less than 100 %, the possibility of being a carrier is not completely excluded by this result.

While there is some variation in the appearance of laboratory reports from different pathology providers, most follow a common format that includes a clear statement as to whether the individual tested has been identified as a carrier for each of the disorders screened, a description of any genetic variants detected, and guidance on next steps, including the need for testing of the reproductive partner or referral for genetic counselling.

Quantification of residual reproductive risk( remaining chance of having an affected child when RGCS does not identify a disease-causing variant) may also be provided in the laboratory report or on request. This is best calculated knowing

Expanded RGCS may be more appropriate for screening couples of non-European or disparate backgrounds or consanguinity.

Three-gene RGCS is MBS-funded. Australian data on the uptake of three-gene RGCS suggests there may be incomplete uptake of testing for male partners of confirmed female carriers, which is an area for potential improved practice.

the ethnicity of both reproductive partners, the sensitivity of the screen used, and any family history of the disorders included in the screen.

Basic principles of using RGCS

There is universal agreement among local and international professional societies that the following should apply to RGCS. 9-12

Firstly, it should be performed as early as possible, preferably prior to conception, to allow for the widest range of reproductive options, and to enable testing, counselling and decision-making to occur without time pressures.

Secondly, it should be offered to all, but as an opt-in, as determined by the individual or couple based on their personal circumstances.

Thirdly, RGCS should be offered with appropriate pre-test and post-test counselling, delivered by a medical practitioner or qualified genetic counsellor.

Table 1. Clinical and molecular features of CF, SMA and FXS Disorder Carrier frequency * Inheritance Testing approach for RGCS Clinical features