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Neuromuscular Disorders 31 (2021) 1081–1089

www.elsevier.com/locate/nmd

Review
Genetic neuromuscular disorders: what is the best that we can do?
Nigel G Laing a,b,∗, Royston W. Ong a, Gianina Ravenscroft a,c
a QEIIMedical Centre, Neurogenetic Diseases Group, Harry Perkins Institute of Medical Research and University of Western Australia, 6 Verdun Street,
Nedlands, Western Australia 6009, Australia
b Neurogenetic Unit, Department of Diagnostic Genomics, PathWest Laboratory Medicine, West Australian Department of Health, QEII Medical Centre,

Nedlands, Western Australia 6009, Australia

c School of Biomedical Sciences, University of Western Australia, Nedlands, Western Australia 6009, Australia

Received 30 June 2021; accepted 12 July 2021

Abstract
The major advances in genetic neuromuscular disorders in the last 30 years have been: (a) identification of the genetic basis for hundreds
of these disorders, (b) through knowing the genes, understanding their pathobiology and (c) subsequent implementation of evidence-based
treatments for some of the disorders. New genomic technologies are providing precision diagnosis, mode of inheritance and likely prognosis
for more patients than ever before. Parents of children with a genetic diagnosis can then use preimplantation or prenatal diagnosis to avoid
having further affected children if they wish. But is this the best we can do for genetic neuromuscular disorders? Since the 1980s, it has
been argued it would be better to identify Duchenne muscular dystrophy carrier mothers, rather than diagnose their affected sons. Carrier
screening for recessive disorders can identify couples with a high chance of having affected children. It allows couples reproductive choice
and can prevent infant morbidity and mortality and significant distress for families. Professional bodies in many countries now recommend
prospective parents should be informed about carrier screening. Implementing and funding expensive therapies increases the cost-effectiveness
of carrier screening, increasing its attractiveness to governments. Best practice for genetic neuromuscular disorders should include equitable
access to carrier screening.
© 2021 Elsevier B.V. All rights reserved.

Keywords: Neuromuscular disorders; Genetics; Reproductive genetic carrier screening.

1. Introduction disorders. Although disease genes remain to be discovered,

A major advance in neuromuscular disorders in the
last 30 years has been the identification of the genetic
causes of many of the disorders. It can be argued that
the watershed event was the landmark sequencing of the
complete cDNA of the Duchenne muscular dystrophy gene
(DMD) in 1987 [1]. Now, hundreds of neuromuscular
disease genes have been identified, as catalogued in
the Neuromuscular Disorders Gene Table (http://www.
musclegenetable.fr/). This characterization of disease genes
has given enormous power over the genetics of neuromuscular
∗ Corresponding author at: QEII Medical Centre, Preventive Genetics
Group, Harry Perkins Institute of Medical Research and University of
Western Australia, 6 Verdun Street, Nedlands, Western Australia 6009,
Australia.
E-mail address: nigel.laing@perkins.uwa.edu.au (N.G. Laing).
and we do not recognize all pathogenic variants in known
disease genes, genomic diagnostics can perform analysis of
hundreds of neuromuscular disease genes simultaneously in
each patient. Targeted gene panels [2], exome sequencing
[3], whole genome sequencing [4] or transcriptome
sequencing [5] provide rapid, accurate molecular diagnosis
for neuromuscular disease patients for whom this was not
previously possible. This includes identification of variants in
the genes for the giant muscle proteins titin (TTN), nebulin
(NEB) (even their triplicated regions) and the ryanodine
receptor (RYR1), that were prohibitively expensive and thus
not practical to analyze using Sanger sequencing [2].
One of the most important aspects of genetic testing
is cascade testing from the proband in a family. This
is important in dominant neuromuscular diseases such as
myotonic dystrophy to identify family members who are at
risk from sudden cardiac death in order to be able to prevent

https://doi.org/10.1016/j.nmd.2021.07.007
0960-8966/© 2021 Elsevier B.V. All rights reserved.
N.G. Laing, R.W. Ong and G. Ravenscroft
that [6]. It is important in families with autosomal recessive
or X-linked recessive diseases to identify carriers so that the
carriers can avoid having affected children if they wish [7,
8].
The drive of couples who had already had an affected
child to avoid having further affected children was brought
home to one of us (NL) when the SMN1 deletions causing
spinal muscular atrophy were first identified. As previously
described [7], West Australian spinal muscular atrophy
families in those days before Twitter, somehow found out
before the SMN1 deletions were published, that “their gene
had been found” and within the shortest possible time after
the publication, we were performing prenatal diagnoses for
multiple families. The families had put off having any more
children until their gene had been found and they could avoid
causing more children to be affected.
Years before the DMD gene cDNA was sequenced in 1987,
researchers tried to find tests to identify which women in
the family of a boy with Duchenne muscular dystrophy were
carriers. One such researcher was Victor Dubowitz. Victor
published a paper in 1963 showing changes on muscle biopsy
and elevated serum creatine kinase (CK) and serum aldolase
in an obligate carrier in a Duchenne family [9]. The reason to
identify women who were carriers in Duchenne families was
so that they could know they were carriers and avoid having
affected sons if they wished to. Victor published on this in
1975 [10]. In the paper, Victor discusses using a mixture
of multiple CK measurements, light microscopy, electron
microscopy, and electromyography to identify carriers. Victor
also says in the paper “In our present ignorance of the
cause of muscular dystrophy and in the absence of any
available therapeutic measures, genetic counselling has an
important role in the prevention of the disease” and: “with
increasing public knowledge and awareness of the condition,
more female relatives are seeking advice and guidance”. We
think it is fair to say that even though we now know the
genetic cause of Duchenne muscular dystrophy and treatments
are available for some of the boys, cascade carrier screening
and genetic counselling still have a major role in prevention
of the disease. In addition, population awareness of Duchenne
muscular dystrophy and other genetic conditions has never
been higher.
While Victor was pursuing his research on identifying
carriers in London, on the other side of the world in
Perth, Western Australia, Byron Kakulas and Patricia Hurse,
starting in 1966, instituted a carrier screening program in
known Duchenne families. Their carrier diagnosis was based
on a mix of clinical assessment, CK measurements after
normal activity, after bedrest, and before and after strenuous
voluntary exercise, electromyography, light microscopy and
electron microscopy [11]. The program significantly reduced
the incidence of Duchenne muscular dystrophy in Western
Australia [11], one of the first places in the world where this
was achieved for known families. Western Australia thus has a
long history and legacy of carrier screening in neuromuscular
disorders. Years later, when we could precisely identify the
disease-causing variants in the DMD gene in the families, we
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were able to show that the determination of carrier status had
been largely correct [12]. We did change the status of some
women from carrier to non-carrier and vice versa [12], but
there was no way that the phenotypic determination of carrier
status was going to be 100% accurate. The reasons for this
were listed by Victor in his papers, including that: (1) carriers
may show nothing clinically, (2) CK declines in carriers
with age and (3) muscle biopsy and EMG may also show
no changes [10]. Identification of carriers based on knowing
the precise pathogenic variant(s) in a neuromuscular disease
family is always going to be more accurate than phenotypic
determinations. The accurate identification of carriers of the
family variant(s) for both dominant and recessive diseases
through cascade testing, gives couples shown to have a
high chance of having affected children, the opportunity to
use reproductive options such as preimplantation or prenatal
diagnosis to avoid having further affected children if they
wish to. This restores reproductive confidence [13]. The
identification of hundreds of neuromuscular disease genes has
made this possibility available for hundreds of diseases.
Identification of each disease gene has also opened the
door to understanding the pathobiology of the disease and
it has been possible to research evidence-based approaches
to therapy. This has resulted in the development of gene or
even variant-specific therapies that are being integrated into
clinical practice. These may be simple, inexpensive therapies,
such as high dose riboflavin for variants in SLC52A2 encoding
the riboflavin transporter [14], or repurposed drugs such as
salbutamol and others for DOK7 and other myasthenias [15].
At the other end of the spectrum of now available therapies
for neuromuscular disorders, there are extremely expensive
high-end antisense oligonucleotide treatments: for example,
Nusinersen for spinal muscular atrophy [16].
Current best practice in genetic neuromuscular disorders
is therefore molecular diagnosis for more diseases and genes
than previously possible, provision of reproductive options to
couples who have already had an affected child and their
family members and use of precision medicine treatments if
available for the gene/variant. But is this the best that we can
do?
2. Is this the best that we can do?
Current best practice still leads to extended diagnostic
odysseys for genetic diseases. For Duchenne muscular
dystrophy, despite the advances in molecular diagnostics, the
age at diagnosis has remained around four to five years of
age [17]. In a relatively recent population study in Italy, the
mean age at diagnosis was reduced to 41 months, but still
extended up to more than 11 years of age [17]. This means
that other boys who will become affected, are frequently
already born in a sibship before the first affected sib is
diagnosed. The end result is that everyone working in clinical
neuromuscular disorders knows families with multiple boys
affected by Duchenne muscular dystrophy.
Most children with autosomal or X-linked recessive
disorders have no previous family history. In a study of cystic
N.G. Laing, R.W. Ong and G. Ravenscroft
Fig. 1. Sanger sequencing confirmation.
(a) DMD gene nonsense variant in affected son and carrier mother. (b) Sanger sequencing of a family with a nonsense variant in KLHL40 associated with
Foetal akinesia nemaline myopathy. Both parents are carriers of the same variant, the affected child is homozygous for the variant.
fibrosis, fragile X and spinal muscular atrophy carriers in
Australia, 88% of identified carriers had no family history
[18]. The result of this therefore is that couples most often
have a child affected by a recessive genetic condition that
they did not know they were at risk for and therefore
had no pre-warning. This has been known to be the case
for Duchenne muscular dystrophy for a very long time.
In Western Australia, when molecular analysis first made
diagnosis of Duchenne muscular dystrophy carriers accurate,
75% of the Duchenne families had no family history [19].
What does this mean in practice in 2021? Time and
time again in the West Australian diagnostic Neurogenetic
Unit in PathWest (the laboratory arm of the West Australian
Department of Health), we show that the mother of a boy
we have molecularly diagnosed with Duchenne muscular
dystrophy is a carrier. However, she had no idea that she was a
carrier, because there was no family history. This is illustrated
for one Duchenne family in Fig. 1a. In this family, the mother
was 26 years old when she had her son who was diagnosed
eight years later with Duchenne muscular dystrophy. One way
of looking at this information is to say that there was a 26-
year window of opportunity in which the mother could have
been identified as a carrier and told she was a carrier. She
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could then have had the same reproductive options available
to her as a diagnosed carrier in a known Duchenne family.
The situation is similar for families with autosomal
recessive diseases. For one family with a child affected
by foetal akinesia because of homozygosity for a KLHL40
nonsense variant (Fig. 1b), the mother and father were both
30 years old when they had their affected child, who died
at seven days of age. For this couple there was a 30-
year window to determine that they were both carriers of a
KLHL40 pathogenic variant and therefore having as a couple
a one in four chance with every pregnancy of a child with a
lethal neuromuscular disorder. Once they had the molecular
diagnosis of KLHL40 they were able to have two unaffected
children through prenatal genetic diagnosis.
The big question is why, in 2021, does a woman have to
find out that she is a carrier of Duchenne muscular dystrophy
through having an affected son, or a couple find out they
are both carriers of the same severe autosomal recessive
genetic neuromuscular disorder by having an affected child?
For example, why does the KLHL40 couple described above
have to go through a whole precious pregnancy to have their
child die from a lethal neuromuscular disorder, which they
might feel they have inflicted on their child?
N.G. Laing, R.W. Ong and G. Ravenscroft
3. Every child is at risk from their parents’ genetics
It has been estimated that each one of us may be a carrier
of around 20 recessive diseases [8]. However, since most of
us have no idea what recessive diseases we and our chosen
reproductive partner are carrying, when most couples decide
to have children, that decision can be described as “playing
genetic roulette” [7].
How much of a genetic lottery having children is, was
illustrated by the presentation one of us (NL) gave at the first
meeting of the World Muscle Society in London in 1996.
The talk was on a case of spinal muscular atrophy that had
resulted when a sperm donor had been used to conceive the
child. At the end of the talk, hands went up from so many
of the neurologists in the audience, all saying that they had
similarly had patients with spinal muscular atrophy who had
been born following sperm donated pregnancy [20].
4. The health and health economic impacts of genetic
disease
It has long been recognized that a significant proportion
of infant mortality results from genetic disease. According
to Stevenson and Carey [21], 34% of all childhood deaths
(51% under age 1) result from malformations or genetic
disorders. This figure will include many neuromuscular
disorders such as foetal akinesias, congenital myopathies,
congenital muscular dystrophies and so on.
In 2017, Walker and colleagues [22] demonstrated that
rare diseases coded by only 467 orpha codes affected 2%
of the Western Australian population, but resulted in 9.9%
of hospitalizations and 10.5% of hospital inpatient costs,
equalling $395 m AUD a year. Since the Western Australian
population is one tenth of the Australian population, that
would equate to $3.95bn for the whole of Australia for a
year. These are just the hospitalization costs. These costs do
not include other financial costs for affected families such as
costs they have to pay themselves, which can be a sizeable
proportion of total costs [23]. They also do not include
the enormous psychosocial costs to a family living with a
child/children with severe neuromuscular disease.
5. Newborn screening for neuromuscular disorders
Newborn screening for Duchenne muscular dystrophy has
been implemented in the past notably in Wales [24]. There is
recent renewed interest in newborn screening for Duchenne
muscular dystrophy to allow early therapeutic intervention
[24]. There is similar current interest in newborn screening for
spinal muscular atrophy in order to make it possible to have
early intervention with the newly available spinal muscular
atrophy treatments and therefore the best outcomes from those
treatments-for example Nusinersen [25].
However, newborn screening still follows the medical
model of diagnosing an affected individual - even if the
diagnosis is very early in a newborn. It does not offer
the same opportunities of avoiding having an affected child
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available to couples identified in known pedigrees to be
carriers and at high chance of having an affected child.
6. Reproductive carrier screening
Reproductive carrier screening can give couples in the
general population the same options to have control over their
genetics as high chance couples identified in known pedigrees.
Reproductive carrier screening identifies individuals or, more
importantly, couples who are carriers of autosomal or X-
linked recessive conditions.
The primary aim of reproductive carrier screening,
according to the European Society of Human Genetics,
is “to facilitate informed reproductive decision making by
identifying those couples at risk of having an affected child
with an (autosomal or X-linked) recessive disorder” [26].
6.1. Historical reproductive carrier screening programs
Early reproductive carrier screening programs were
targeted at specific populations with particularly high
incidences of certain recessive diseases. Amongst the best-
known of these early programs would be those for Tay-
Sachs disease in Ashkenazi communities and for thalassaemia
in Mediterranean countries. For Tay-Sachs disease, carrier
screening programs were started in 1970, and in the USA
and Canada in a matter of years, the incidence of Tay-Sachs
disease was reduced by more than 90% [8]. Carrier screening
was started for thalassaemia in Mediterranean countries in the
late 1970s and led to similar decreases in disease incidence,
with programs later being instituted in many other parts of
the world [8].
6.2. History of discussion of reproductive carrier screening
for neuromuscular disorders
There has been discussion in the literature of the possible
role of reproductive carrier screening in neuromuscular
disorders for over 30 years. The early papers focus
on Duchenne muscular dystrophy, the only neuromuscular
disorder, along with the allelic Becker muscular dystrophy
whose gene had been identified. As early as 1988, Allen
Roses wrote: “Our goal is to shift ascertainment to carrier
females rather than ascertainment by the birth of an
affected male.” [27]. Later it was argued that multiple
parallel sequencing technologies could be used to take
reproductive carrier screening for neuromuscular disorders to
entire populations [7].
6.3. Current reproductive/preconception carrier screening
programs
Many current carrier screening programs remain targeted
at specific populations or communities. Few countries have
nationwide whole of population carrier screening programs.
Israel is one. The Israeli carrier screening program is
nationwide, panethnic and as far back as 2013, when
N.G. Laing, R.W. Ong and G. Ravenscroft
approximately 171,000 babies were born in Israel, around
62,000 individuals had carrier screening in the national
program [28]. The recent review by Delatycki et al.
[28] gives a snapshot of carrier screening in Australia, Cyprus,
Italy, Malaysia (and other South East Asian countries), the
Netherlands, Saudi Arabia, UK and USA in addition to Israel.
Carrier screening has to be implemented in each country
according to the particular attributes of its health system.
For example, commercial entities are not allowed to perform
carrier screening in the Netherlands [28].
6.4. Evolution of guidelines and opinions on carrier
screening
The guidelines on carrier screening put forward by
professional organizations in multiple countries have evolved
rapidly over recent years. One of the most pivotal publications
was Committee Opinion 690 of the American College of
Obstetricians and Gynecologists published in 2017 [29].
This Opinion had three principal statements:
(a) “The goal of genetic screening is to provide individuals
with meaningful information that they can use to guide
pregnancy planning based on their personal values.”
(b) “Ethnic-specific, panethnic, and expanded carrier
screening are acceptable strategies for prepregnancy and
prenatal carrier screening.”
(c) “Each obstetrician–gynaecologist or other health care
provider or practice should establish a standard
approach that is consistently offered to and discussed
with each patient, ideally before pregnancy.”
The crucial messages are: that multiple different methods
of carrier screening are acceptable, carrier screening should
be discussed with every patient, and that discussion is better
before a couple is pregnant. The most important message
is that carrier screening should be provided in accordance
with each individual’s personal values. This could include not
using carrier screening, if carrier screening clashes with an
individual’s values.
Professional organizations in other countries have followed
suit with similar recommendations. For example, in
Australia, the Royal Australian and New Zealand College
of Obstetricians and Gynaecologists (RANZCOG) and the
Royal Australian College of General Practitioners (RACGP)
have issued guidelines that all patients should be offered
reproductive carrier screening [30].
6.5. Ethical considerations in reproductive carrier screening
There have been many publications on the ethics of
reproductive carrier screening over the years. Perhaps one
of the most important was that by the UK Human Genetics
Commission in 2011, which said: “Having considered the
issues associated with preconception genetic testing, in
our view, there are no specific ethical, legal or social
principles that would make preconception genetic testing
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within the framework of a population screening programme
unacceptable” [31].
Customarily the generally accepted ethical framework of
carrier screening is of giving information to couples so that
they can make informed decisions about their reproductive
options [26], in other words, to enhance reproductive
autonomy [32]. The concepts of responsible parenthood and
procreative non-maleficence, that parents have responsibilities
for their future offspring, have also recently been introduced
and discussed as ethical considerations in carrier screening
[32].
Many have made the point that in order to be ethical,
there has to be equitable access to carrier screening. This
has included the European Society of Human Genetics [26].
Carrier screening to be ethical and equitable, then needs to be
funded by government and not funded on a user pays basis
where only the wealthy can afford it [33].
6.6. Implementation of carrier screening programs
As discussed above, carrier screening programs have to be
tailored to work in the health systems of each country. This
means that pilot studies have to be performed to research how
carrier screening might work in different countries. If a carrier
screening program is to be offered, there are many decisions
that need to be made. These include: which diseases or genes
to screen for, who is going to be tested, who is going to offer
the screening test to participants, what technologies are going
to be used, and, finally, what variants will be reported?
6.6.1. Which diseases or genes to screen for?
One decision that has to be made is which and how
many diseases or genes to screen for. In the early days of
screening, for example Tay-Sachs or sickle cell screening,
only one protein, gene or variant might be screened [8].
Other programs might screen for a small number of relatively
common conditions such as cystic fibrosis, fragile-X and
spinal muscular atrophy [18]. Expanded carrier screening
by definition tests for many recessive disorders, typically
more than a hundred gene or diseases, simultaneously [8].
Expanded carrier screening was made possible in the same
way multiple parallel sequencing made it possible to screen
hundreds of known disease genes to diagnose patients. The
seminal study was by Bell et al. in 2011 [34]. They screened
for 448 recessive childhood diseases/437 genes, including 122
neurological disorders. This study demonstrated that carrier
screening for hundreds of genes was feasible. Each proposed
carrier screening program or offering must then choose the
diseases that it will screen for. These are usually chosen based
on perceived severity and prevalence of the diseases [8, 35].
6.6.2. Will the program screen individuals or couples?
Classically carrier screening has been carried out mostly
for individuals [8]. However, more recently it has been argued
that couple-based screening, where the couple receive either
a high or low chance result as a couple, with no individual
results returned, is more appropriate for reproductive genetic
N.G. Laing, R.W. Ong and G. Ravenscroft
carrier screening programs. The basis of this argument is that
it is only the result as a couple that is relevant to reproductive
decision-making [36]. Doing the analysis on a couples-basis
considerably reduces the amount of counseling time that is
required, since only couples who have a pathogenic or likely
pathogenic variant in the same autosomal gene, or an X-linked
gene, need significant amounts of counseling time [8]. It also
cuts down on the amount of data analysis that needs to be
performed, since most variants identified in an individual can
be ignored because the partner does not also have a variant
in that gene [8].
6.6.3. Who is going to recruit the patients
Another consideration that has to be taken into account
in establishing a carrier screening program, is who is going
to recruit the individuals or couples into the program.
Surveys of target populations have consistently shown that
the major preferred option is to have carrier screening offered
through general practitioners [37, 38]. General practitioners
can include offering carrier screening as just another thing
they talk about with couples intending to start a family [30].
However, carrier screening also needs to be available through
many other types of health care professionals, such as genetic
services, obstetricians and gynaecologists, midwives, genetic
counselors, fertility specialists, etc. [38].
6.6.4. What technologies are to be used?
If the program is to be an expanded carrier screening
program screening for hundreds of genes and diseases, will
exome sequencing be performed with a selected panel of
genes analyzed bioinformatically, or will a targeted capture
and sequencing of a selected panel of genes be performed?
If spinal muscular atrophy and fragile X are to be screened,
separate tests will need to be established for those diseases
since standard multiple parallel sequencing is not good at
identifying those variants [18].
6.6.5. What variants will be reported?
In carrier screening, standard practice is to only report
variants that are classed as pathogenic or likely pathogenic
according to the American College of Medical Genetics
guidelines [39].
Once all these decisions have been made an overall
protocol can be generated for the proposed screening program
[39].
6.7. Considerations in relation to carrier screening
Carrier screening does not guarantee a child free of genetic
disease. It does not detect chromosomal rearrangements. It
does not replace non-invasive prenatal testing. It also does
not detect genetic disease that results from de novo variants.
In other words, it does not replace newborn screening [29],
which can detect disease caused by de novo variants.
There will be residual risk even for the diseases screened
for [29]. There will be false negatives and false positives [8].
False negatives may arise because the sequencing may not
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sequence parts of a gene well. However, most often false
negatives will arise because we do not know the pathogenicity
of all variants that will be identified by the sequencing.
Many variants identified in the participating individuals will
be classified as variants of unknown significance (VUS).
Identifying a VUS in one or both members of a couple
will mean the couple will not be classified as high-chance
couple. However, the VUS may later be reclassified as likely
pathogenic or pathogenic meaning the couple would be a false
negative couple. Conversely some variants which have been
classified in the literature as pathogenic or likely pathogenic
may be reclassified as benign causing a false positive [8].
There are flow on consequences if governments provide
free carrier screening. For example, governments will also
need to fund reproductive options, such as pre-implantation
genetic testing for couples identified as being at high chance
of having an affected child. (In Australia, Government
funding of preimplantation testing for couples with a high
chance of having a child with a genetic disease, was
announced in the Federal Budget of 2021.)
7. What are the factors that will decide whether carrier
screening programs are implemented?
There are probably three main factors that will determine
whether a country implements a reproductive genetic carrier
screening program: (1) public acceptance/appetite for carrier
screening, (2) health economics including cost-effectiveness,
and (3) political will
7.1. Public acceptance/appetite for carrier screening
There have been multiple surveys of the acceptability of
carrier screening to populations in a number of countries.
These surveys generally indicate high levels of acceptability
and appetite for carrier screening amongst the general
population [26, 37].
A 2018 survey of intention to use carrier screening in
the West Australian population indicated two thirds of West
Australians would use carrier screening if it was available to
them, 22% were undecided, while 10% said that they would
not use carrier screening if it was available [38]. The only
factor that correlated with not using carrier screening, was a
measure of religiosity [38]. This indicates a strong appetite
for the availability of carrier screening in Australia.
7.2. Health economics–cost effectiveness
Every intervention these days must be justified on the
basis of cost-effectiveness. Above we described how 467
orpha codes had been shown to correspond to $395 m AUD
hospitalization costs per annum in Western Australia [22].
There are ≈30,000 births a year in Western Australia.
The survey of West Australians we carried out suggested
67% would use carrier screening if it was available [38].
How many would use it in practice, we don’t know. If
implementing freely available carrier screening in Western
N.G. Laing, R.W. Ong and G. Ravenscroft
Australia allowed couples the choice to avoid having children
with severe genetic disorders and resulted in as little as a 10%
reduction in hospitalization costs, then implementing carrier
screening in Western Australia is likely to be cost-effective
on that basis alone.
Cost effectiveness does not however take into account the
humanity of any intervention. As Kakulas and Hurse wrote in
1977 in relation to health budget savings of detecting carriers:
“This is apart from the humane aspects such as relief of
suffering and social disruption in the affected families” [11].
One of the first people to express caution over the costs
of expensive therapies for genetic neuromuscular disorders,
was Professor Robert Griggs at the International Congress
of Neuromuscular Diseases, Naples in 2010. In his plenary
presentation he said: “If a therapy costs $500,000 per year
and you extend survival to a lifespan of 70 years, then the
therapy will total $35 m per patient. Health services simply
cannot afford this.” (Quoted with permission of Professor
Griggs). Funding expensive therapies in fact makes diseases
more expensive for governments [23]. Paradoxically then,
implementing expensive therapies will make reproductive
carrier screening more cost-effective and therefore more
attractive to governments
7.3. Political will
Even if members of a population of a country wish carrier
screening and it is shown to be cost-effective, if there is no
political will in that country to implement carrier screening,
it will not be implemented. Obviously, the political will
already exists in some countries that carrier screening should
be implemented and made available to the population, for
example Israel. Other countries are now exploring this, but in
some countries, such as the United States, the political will
may not exist [28].
8. Mackenzie’s mission
As we have seen above, there is appetite in the Australian
population for carrier screening to be available. At the
moment, there is also the political will.
Australia is currently carrying out a research project
to determine how to make carrier screening available free
across the whole of this vast country. This project is called
Mackenzie’s Mission (https://www.australiangenomics.org.au/
our- research/mackenzies- mission/). Mackenzie’s Mission is
named after Mackenzie Casella, a young girl who died from
spinal muscular atrophy at seven months of age in 2017.
Mackenzie’s parents Rachael and Jonathan Casella, lobbied
the Australian Federal Government to have carrier screening
put in place in Australia, so that no other couple would have
to go through what they went through. They were joined in
advocacy by many patient support groups and professional
organizations. [To find out more about the story of this
advocacy, read Rachael Casella’s book about their odyssey
from having Mackenzie diagnosed, to seeing Mackenzie’s
Mission in place [40].
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At the same time as the Casellas, patient groups and
professional bodies were advocating for carrier screening, a
group of researchers proposed a nationwide research project
on carrier screening to the Australian Federal Government.
These two approaches were rewarded in an announcement
by the Australian Federal Health Minister the Honourable
Greg Hunt on the 1st of March 2018, that he wanted to have
carrier screening available free to any couple in Australia who
wished to use carrier screening, and that he wished to see this
in place within 10 years. It was Health Minister Hunt who
named the research project “Mackenzie’s Mission”. The 1st
of March announcement was backed by funding of $20 m
AUD for Mackenzie’s Mission from the Australian Medical
Research Future Fund, Genomics Health Futures Mission in
the Federal Budget of May 2018.
Mackenzie’s Mission aims to recruit and screen 10,000
couples from across the full geographic spread of Australia
and couples of all socio-economic levels [30]. The couples
will be screened for ≈1300 genes associated with ≈750
diseases [35]. The aims of Mackenzie’s Mission are to see
how carrier screening can be made to work for all Australians
within the complexities of the multiple federal and state health
systems in Australia, determine its acceptability in practice,
likely uptake, and cost-effectiveness.
9. Conclusion
Carrier detection and screening for recessive disorders have
come a long way since Victor’s important work in the 1960s
to try to find ways to identify whether women in known
Duchenne muscular dystrophy families were or were not
carriers [9]. While many have discussed and advocated for
carrier screening for decades, in reality it is only recently that
the technology has been developed to make carrier screening
for hundreds of diseases possible at scale.
The best treatment for severe recessive neuromuscular and
other disorders may in fact be prevention. This would be
especially the case for severe recessive disorders with onset in
utero or that result in early demise. Carrier screening has the
potential to significantly reduce the morbidity and mortality
from genetic diseases. Carrier screening can give couples
power over their genetics [7], if using that power fits with
their personal values.
Carrier screening will only be implemented in a country
if the population wants it and there is political will to
make it available to the population. More countries are now
researching how such programs could be implemented in a
way that is consistent with their health systems [28].
Those of us who work in neuromuscular disorders can
carry on as we have done for centuries following the medical
model of treating the patient when the patient is there.
Alternatively, we can advocate for a change of paradigm
where we make available to the population, if they wish to
use it, the possibility of avoiding having the severely affected
children they otherwise might have.
In our opinion, future best practice for genetic
neuromuscular disorders should include successive layers of:
N.G. Laing, R.W. Ong and G. Ravenscroft
equitable access to reproductive genetic carrier screening,
non-invasive prenatal testing, newborn screening, ever more
accurate and rapid molecular diagnosis, and precision
medicine treatments.
Declaration of Competing Interest
None of the authors have any declarations of interest
Acknowledgments
This article is based on a presentation to the WMS2017
Annual Scientific Meeting in St Malo., France by N.L.
[41]. We would like to thank Victor Dubowitz and Thomas
Voit for requesting NL to make that presentation. We
would also like to thank members of the WMS who,
over the intervening years, have encouraged the write up
of that presentation – notably Basil Darras at the WMS
Copenhagen outing to Kronborg Castle. NL is supported
by an Australian National Health and Medical Research
Council Principal Research Fellowship (APP1117510). RO
was supported by an Australian Postgraduate Award and an
Australian Genomics (APP1113531) PhD top-up award. GR
is supported by an Australian National Health and Medical
Research Council Career Development Fellowship Level 1
(APP1122952). The Australian Reproductive Genetic Carrier
Screening Project (Mackenzie’s Mission) is funded by the
Australian Government’s Medical Research Future Fund as
part of the Genomics Health Futures Mission (GHFM), Grant
GHFM73390 (MRFF-G-MM). The grant is administered by
the Murdoch Children’s Research Institute through Australian
Genomics. We thank Padma Sivadorai and Joshua Clayton for
the Sanger sequencing figures. There was a restriction of 40
references for this article. Please forgive us therefore if we
have not referred to a publication of yours that you feel we
should have cited. We also have, instead of referencing the
original articles for a particular point frequently referenced
the truly comprehensive review of carrier screening published
by Antonarakis in 2019 [8].
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