Criterion 1: The condition is a serious health problem

PWS clearly meets this criterion. PWS is more common than several other rare genetic disorders, such as SCID and X-ALD, which are currently included in the Australian NBS program (Ref. 16). Globally, PWS affects an estimated 1 in 10,000 to 1 in 30,000 live births, with similar frequency between sexes and across different races (Refs Reference Szabadi, Sila, Dewey, Rowland, Penugonda and Ergun-Longmire6, Reference Shaikh, Barrett, Bridges, Chung, Gevers, Goldstone, Holland, Kanumakala, Krone, Kyriakou and Livesey19, Reference Muscogiuri, Formoso, Pugliese, Ruggeri, Scarano, Colao and Restare36, Reference Yang, Choi, Kang, Hong and Chung37). In Australia, epidemiological data suggest that approximately 20–30 infants are born with PWS each year (Refs Reference Lionti, Reid, White and Rowell20, 38). A population-based study using the Victorian PWS Register identified 160 individuals, with a birth prevalence of 1 in 15,830 during 2003–2012 (Ref. Reference Lionti, Reid, White and Rowell20). Another Australian newborn screening study of 16,579 infants from the general population identified two cases of PWS, corresponding to a prevalence of approximately 1 in 8,300 (Ref. Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26).

PWS is a lifelong, multisystem neurogenetic disorder associated with substantial medical, developmental and behavioural morbidity from infancy through adulthood (Ref. Reference Lionti, Reid, White and Rowell20). PWS presents with a range of symptoms that start early in life and worsen over time, imposing severe health challenges for affected individuals. Early presentation typically involves severe neonatal hypotonia and feeding difficulties, often necessitating nasogastric or gastrostomy feeding. Over time, this evolves into hyperphagia and insatiable appetite, resulting in life-threatening obesity if uncontrolled. Obesity-related complications, including type 2 diabetes, cardiovascular disease, thromboembolic events, sleep-disordered breathing and respiratory failure are the leading causes of premature death in Australian cohorts, with Victorian PWS registry data estimating survival of only ~87% to 35 years and documenting deaths in early childhood and adolescence (Ref. Reference Lionti, Reid and Rowell39). Australian clinical reports also highlight high rates of intellectual disability, developmental delay, behavioural and psychiatric difficulties, and endocrine dysfunction such as growth hormone deficiency and hypogonadism, all of which generate high healthcare utilisation and long-term support needs for families and services (Refs Reference Lionti, Reid, White and Rowell20, Reference Smith, Egan, Ridley, Haan, Montgomery, Williams and Elliott40). Because these morbidities are predictable, progressive and, in part, modifiable when identified early (e.g., early growth hormone therapy (GHT), weight management programs, respiratory surveillance), PWS aligns with the Framework’s intent to prioritise conditions that cause ‘serious, life-threatening disease’.

Criterion 2: Benefit of newborn screening

In routine care, infants with pronounced neonatal hypotonia are often recognised and tested early, but milder presentations, infants born outside tertiary centres, or those whose hypotonia is transient or is accounted to other more common causes such as preterm birth, can be missed or diagnosed late. Newborn screening could address this gap by standardising diagnosis at birth, reducing reliance on clinical vigilance and ensuring equitable detection across care settings.

Although no published studies have directly compared ‘screen-detected’ versus ‘clinically detected’ PWS, strong indirect evidence supports the clinical value of early identification. Early initiation of GHT within the first year of life, compared with initiation after 15 months or later childhood, was associated with improved height, earlier walking (median 18 vs 36.6 months) and a lower peak body mass index (BMI) (2.2 vs 3.7) over follow-up (Refs Reference Kodytková, Amaratunga, el-Lababidi, Čermáková, Černá, Dvořáková, Kalvachová, Koloušková, Kotvalová, Magnová, Neumann, Novotná, Obermannová, Pomahačová, Průhová, Strnadel, Škvor, Šnajderová, Šumník, Zapletalová, Zemková, Kusalová, Šilar and Lebl8, Reference Corripio, Tubau, Calvo, Brun, Capdevila, Larramona and Gabau21). Early recognition also enables family-centred dietary and environmental controls before hyperphagia emerges, proactive respiratory and sleep surveillance, and access to early developmental and behavioural services (Refs Reference Lionti, Reid, White and Rowell20, Reference Scheermeyer41). While most PWS-related morbidities can be managed with supportive care rather than emergency treatment (Ref. Reference Butler, Miller and Forster42), respiratory failure represents a critical early risk in infancy, accounting for 31%–50% of deaths in individuals with PWS (Refs Reference Com, Santhanam and Ergun-Longmire3, Reference Pacoricona Alfaro, Lemoine, Ehlinger, Molinas, Diene, Valette, Pinto, Coupaye, Poitou-Bernert, Thuilleaux, Arnaud and Tauber43, Reference Butler, Manzardo, Heinemann, Loker and Loker44). During infancy, respiratory compromise is primarily related to impaired central respiratory control, severe hypotonia and sleep-disordered breathing. Many neonates with PWS exhibit central hypoventilation and nocturnal hypoxia without overt signs of respiratory distress, likely reflecting impaired ventilatory control and hypersomnolence (Ref. Reference Duis, Pullen, Picone, Friedman, Hawkins, Sannar, Pfalzer, Shelton, Singh, Zee, Glaze and Revana45). Infants with PWS demonstrate absent or markedly blunted ventilatory and arousal responses to hypoxic challenge, so that even mild hypoxia acts as a depressant of respiratory control rather than a stimulus to arousal. Hypersomnolence, a recognised feature of PWS from infancy, driven by hypothalamic dysfunction and an abnormal rapid eye movement sleep pattern, further increases this vulnerability (Refs Reference Duis, Pullen, Picone, Friedman, Hawkins, Sannar, Pfalzer, Shelton, Singh, Zee, Glaze and Revana45, Reference Kempen, Boon, Dereymaeker, Rochtus, Proost, Lemmens and Jansen46). In older children and adults, respiratory failure is more commonly associated with obesity-related hypoventilation, obstructive sleep apnoea, recurrent respiratory infections and progressive respiratory muscle weakness (Ref. Reference Com, Santhanam and Ergun-Longmire3). Consequently, although respiratory complications may occur throughout life, respiratory failure is a leading cause of death, particularly during adulthood (Ref. Reference Urquhart, Gulliver, Williams, Harris, Nyunt and Suresh10). Thus, early diagnosis enables prompt respiratory monitoring, including pulse oximetry and polysomnography, allowing initiation of supportive measures such as home low-flow supplemental oxygen or non-invasive respiratory support for infants with clinically significant hypoxia (Refs Reference Urquhart, Gulliver, Williams, Harris, Nyunt and Suresh10, Reference Fishman, Wen, Massicotte, Narang, Chiang, Bola, Ambreen, Zweerink and Amin47).

Early identification of PWS during the neonatal period (before 2 months of life) and multidisciplinary care have been shown to shorten hospital stays (from 30 to 21 days), prevent growth delays, reduce the need for gastric tube feeding (from 30.5 to 15 days) and delay the onset of obesity (Ref. Reference Bacheré, Diene, Delagnes, Molinas, Moulin and Tauber48). Children diagnosed earlier also tended not to gain excess weight later: around age 10 if diagnosed before 1 year, age 6 if between 1–3 years and age 4 if diagnosed after 3 years (Ref. Reference Kimonis, Tamura, Gold, Patel, Surampalli, Manazir, Miller, Roof, Dykens, Butler and Driscoll9). Furthermore, early diagnosis allows families to access essential resources, reducing the emotional and financial strain associated with delayed diagnosis of PWS. However, newborn screening for PWS presents a number of potential challenges, including the psychological impacts on families, leading to stress, anxiety or stigma from a positive diagnosis (Refs Reference Chien and Hwu49, Reference Feighan, Hughes, Maunder, Roche and Gallagher50). A survey of 33 families with genetically confirmed PWS found that primary caregivers experienced significantly higher rates of depression and caregiver burden compared with non-primary caregivers (Ref. Reference González Ruiz, Gerk and Stegmann51). Nevertheless, these potential harms can be mitigated through appropriate counselling and confirmatory diagnostic pathways currently available. In addition, similar psychosocial challenges are already experienced by families whose infants are diagnosed clinically, most commonly following presentation with neonatal hypotonia, and these issues are routinely managed within existing care pathways. These impacts, while similar, are less significant than those associated with a diagnostic odyssey for those families who receive delay in diagnosis (Ref. Reference Wheeler, Gantz, Cope, Strong, Bohonowych, Moore and Vogel-Farley22).

Based on data from the UK and USA, approximately 66%–71% of individuals with PWS are diagnosed by 1 month of age and 85% by 1 year, through clinical suspicion and targeted molecular testing (Refs Reference Wheeler, Gantz, Cope, Strong, Bohonowych, Moore and Vogel-Farley22, Reference Sritharan, Lodge, Tadros, Menzies and Gevers23). Consequently, an estimated 15% of infants have been reported to not be diagnosed early and may experience delays in accessing key interventions. For this subgroup, NBS would offer a clear and non-incremental benefit by enabling prompt diagnosis, earlier initiation of GHT and coordinated multidisciplinary care during a critical developmental window. While the relatively high rate of early clinical diagnosis may limit the incremental benefit of NBS for the majority of infants, screening has the potential to improve outcomes for those who would otherwise experience delayed diagnosis. Nevertheless, while immediate postnatal intervention is not essential for survival in PWS, earlier confirmation through NBS could confer benefits by enabling prompt initiation of multidisciplinary care and psychosocial preparedness for families. On balance, this criterion is partially fulfilled: existing evidence demonstrates benefits from early identification, yet PWS lacks a distinct presymptomatic phase in most cases where intervention unequivocally prevents irreversible or fatal outcomes.

Criterion 3: The natural history of PWS

The natural history of PWS is well characterised and follows recognised nutritional phases described by Miller et al. (Ref. Reference Miller, Lynn, Driscoll, Goldstone, Gold, Kimonis, Dykens, Butler, Shuster and Driscoll4). Infants initially present with hypotonia, poor suck, feeding difficulties and failure to thrive (Phase 1a), followed by improved feeding and normal growth (Phase 1b). During early childhood, children typically progress to Phase 2a, characterised by excessive weight gain without increasing appetite, before developing Phase 2b, when appetite progressively increases. Phase 3 is characterised by hyperphagia and lack of satiety, usually during later childhood. Some adults subsequently enter Phase 4, in which appetite may become less intense in a subset of individuals (Ref. Reference Miller, Lynn, Driscoll, Goldstone, Gold, Kimonis, Dykens, Butler, Shuster and Driscoll4). Understanding these predictable nutritional phases provides an important framework for early monitoring and anticipatory management. Behavioural manifestations, including temper outbursts, compulsive behaviours and anxiety, typically become more prominent during childhood and adolescence, while musculoskeletal complications such as progressive scoliosis may also develop. Clinical manifestations of PWS in Australia align with the global trend, where longitudinal studies and registry data from Victoria have shown that PWS follows a highly predictable sequence: neonatal hypotonia, poor suck and feeding difficulties, followed by a transition to hyperphagia and rapid weight gain in early childhood. These early features evolve into obesity-related, endocrine and behavioural complications in later life, including type 2 diabetes, hypogonadism, short stature, sleep-disordered breathing and respiratory issues which may lead to sudden death if not managed (Refs Reference Shepherd, Vos, Reid, Godler, Guzys, Moreno-Betancur and Amor5, Reference Lionti, Reid, White and Rowell20, Reference Lionti, Reid and Rowell39). This staged progression is concordant with international literature that define ‘nutritional phases’ and recognise PWS as a hypothalamic disorder with predictable endocrinological, cognitive and behavioural trajectories (Refs Reference Cassidy, Schwartz, Miller and Driscoll52, Reference Tauber and Hoybye53). Because these features unfold in an orderly manner and early manifestations (hypotonia, feeding difficulty) are qualitatively different from later, more hazardous manifestations (hyperphagia, obesity, respiratory compromise), PWS fits well with the Framework’s requirement that the transition from latent to clinically declared disease be understood.

In terms of age at clinical detection, Australian reports indicate that many children are diagnosed in infancy, especially when severe neonatal hypotonia and feeding difficulties trigger genetic testing, but a measurable minority are diagnosed later in childhood when hyperphagia, obesity or developmental delay become obvious (Refs Reference Lionti, Reid and Rowell39, Reference Mackay, McCallum, Ambler, Vora, Nixon, Bergman, Shields, Milner, Kapur, Crock, Caudri, Curran, Verge, Seton, Tai, Tham, Musthaffa, Lafferty, Blecher, Harper, Schofield, Nielsen, Wilson, Leonard, Choong and Downs54). While advances in molecular diagnostics and clinical guidelines have improved timing and rates of diagnosis, multiple studies indicate that a proportion of individuals with PWS remain undiagnosed until later stages of life (Refs Reference Lionti, Reid, White and Rowell20, Reference Wheeler, Gantz, Cope, Strong, Bohonowych, Moore and Vogel-Farley22, Reference Smith, Egan, Ridley, Haan, Montgomery, Williams and Elliott40, Reference Thomson, Glasson and Bittles55, Reference Sritharan, Morrogh, Allen, Tadros and Menzies56). For example, in a Victorian cohort, the mean age at molecular confirmation improved from approximately 1.3 years (for those born 1993–2002) to around 8.6 ± 17.4 weeks for individuals born between 2003 and 2012 (Ref. Reference Lionti, Reid, White and Rowell20); however, these data are largely historical, and no Australian published studies have reported diagnostic age trends for children born within the past 10 years.

This pattern mirrors international experience, where diagnosis has shifted earlier over the last two decades as methylation testing became routine, yet still depends on clinical suspicion and service access. Historically, diagnoses of PWS were delayed, with children often identified between 7 and 9 years of age (Ref. Reference Mahmoud, Singh, Weiss, Lakatos, Oakes, Hossain, Butler and Kimonis24). However, current diagnostic ages range from as early as 18 days to approximately 4.9 years (Refs Reference Mahmoud, Singh, Weiss, Lakatos, Oakes, Hossain, Butler and Kimonis24, Reference Bar, Diene, Molinas, Bieth, Casper and Tauber25, Reference Fricke57, Reference Gold, Mahmoud, Cassidy and Kimonis58). The median age of diagnosis for PWS in the USA is now around 1 month (Ref. Reference Wheeler, Gantz, Cope, Strong, Bohonowych, Moore and Vogel-Farley22). However, delays still occur, especially in cases with mild or atypical symptoms or when the baby is born in rural settings where referral to testing may not occur as quickly as in metropolitan areas with better medical infrastructure (Ref. Reference Sritharan, Lodge, Tadros, Menzies and Gevers23). A French study of 38 infants with PWS born in 2013 reported a median age at diagnosis of 18 days; however, diagnosis was delayed beyond 2 months of age in five cases (13%) (Ref. Reference Bar, Diene, Molinas, Bieth, Casper and Tauber25). Another study from the UK, conducted in a health system similar to Australia’s, reported that 27% (254/945) of individuals with PWS diagnosed between 1968 and 2023 were identified after 1 year of age, with recent data (2019–2022), showed that among 28 positive cases, 71% were diagnosed before 1 month of age, while the remaining cases were diagnosed later, including 7% at 1–24 months, 3.5% at 2–5 years and 18% after 5 years (Ref. Reference Sritharan, Lodge, Tadros, Menzies and Gevers23). Another US study reported that 66% of individuals with PWS are diagnosed within 1 month of birth and 85% by 1 year (Ref. Reference Wheeler, Gantz, Cope, Strong, Bohonowych, Moore and Vogel-Farley22). A recent nationwide cohort study from South Korea analysed data for individuals with PWS diagnosed between 2005 and 2021 and reported a median age at diagnosis of 1.0 year, further demonstrating that despite improvements in clinical recognition, a proportion of individuals with PWS continue to experience delayed diagnosis (Ref. Reference Yang, Choi, Kang, Hong and Chung37). Together, these data highlight that a considerable proportion of PWS cases continue to be diagnosed after the first year of life. In cases where diagnosis is delayed, confirmation is often made later during early childhood or adolescence, when more distinctive features emerge (Refs Reference Butler59, Reference Vears, Savulescu, Christodoulou, Wall and Newson60, Reference Kahane, Metivier, Bahm and Hamilton61). Early detection of PWS, especially in asymptomatic or mildly symptomatic infants, offers clinical benefits (Refs Reference Shepherd, Vos, Reid, Godler, Guzys, Moreno-Betancur and Amor5, Reference Butler59).

Regarding penetrance and phenotypic breadth, classical PWS due to 15q11–q13 deletion or mUPD shows very high penetrance for the core phenotype: neonatal hypotonia, developmental delay, evolving hyperphagia and characteristic endocrine dysfunction (Ref. Reference Cassidy, Schwartz, Miller and Driscoll52). While phenotypic variability exists, such as patients with mUPD or imprinting-centre defects may exhibit milder dysmorphism but greater psychiatric or autistic features in adolescence (Ref. Reference Ogata, Ihara, Murakami, Gito, Kido and Nagai62), truly benign or asymptomatic forms have not been described (Ref. Reference Ogata, Ihara, Murakami, Gito, Kido and Nagai62). Importantly, there is no evidence of a hidden population of undiagnosed, benign or adult-onset PWS cases that could lead to over-diagnosis through newborn screening. On this basis, Criterion 3 is fully fulfilled for PWS: the condition has a well-characterised, stepwise natural history; the typical age of clinical detection is known; and penetrance for the core phenotype in recognised molecular subtypes is high. Remaining uncertainties relate to rare, atypical or mosaic cases and to long-term adult outcomes, rather than to the core paediatric course that is most relevant to newborn screening decisions.

Criterion 4: Feasibility and reliability of test protocol

The gold standard for diagnosing PWS is DNA methylation testing of the SNRPN promoter, which detects over 99% of cases (Refs Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26, Reference Smith and Hung63). Common first-tier methylation protocols include methylation-specific PCR (mPCR) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) (Ref. Reference Mahmoud, Singh, Weiss, Lakatos, Oakes, Hossain, Butler and Kimonis24). Additional testing, such as single nucleotide polymorphism (SNP) microarray or microsatellite analysis, is typically used to determine the specific genetic subtype (paternal 15q11–q13 deletions, mUPD or imprinting defects), particularly when heterodisomy or other atypical presentations are suspected. While multiple testing workflows exist, DNA methylation testing remains the most reliable and widely accepted first-tier diagnostic approach (Ref. Reference Godler, Singh and Butler64). However, combining whole-exome sequencing (WES) combined with DNA methylation has been described as an enhanced approach for determining both disease diagnosis and genetic mechanism, which could potentially be applied to newborn screening (Ref. Reference Strom, Hossain, Grigorian, Li, Fierro, Scaringe, Yen, Teguh, Liu, Gao and Butler65).

A number of recent studies have demonstrated that DNA methylation analysis is a feasible first-tier test to detect PWS as part of standard-of-care newborn screening (Refs Reference Mahmoud, Singh, Weiss, Lakatos, Oakes, Hossain, Butler and Kimonis24, Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26, Reference Ferreira, Costa, Gomes, dos Santos Cunha, Tyszler, Freitas, Llerena Junior, de Vasconcelos, Nicholls and Guida27). Godler et al. validated a novel DNA methylation assay called methylation-specific quantitative melt analysis (MS-QMA) on 1,356 samples, showing high sensitivity, specificity and predictive values. Feasibility of the method was further evaluated in a large-scale screening of 16,579 newborn blood spots from the general population, successfully identifying two cases of PWS, two of Angelman syndrome and one of Dup15q syndrome (Ref. Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26). This workflow is currently being scaled to 100,000 Victorian infants through Epi-Genomic Newborn screening (EpiGNs) program (Ref. Reference Alshawsh, Wake, Gecz, Corbett, Saffery, Pitt, Greaves, Williams, Field, Cheong, Bui, Arora, Sadedin, Lunke, Wall, Amor and Godler66). This assay is compatible with DBS in terms of material requirements (only one 3.2 mm punch per blood spot, automation) and low reagent cost, positive predictive value (PPV), as well as minimal training as it uses equipment already in place for SCID and SMA testing (Ref. Reference Cartagena, Alshawsh, Bui, Gamage, Thakor, Pitt, Greaves, Wall, Saffery, Amor and Godler67). Moreover, in an earlier study has been combined with use of genomics as part of second-tier testing to define genetic aetiology of PWS (Ref. Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26). However, its performance (with and without use of genomics) and feasibility remain to be tested in a clinical environment at population scale, as would occur if implemented within standard-of-care newborn screening workflows. Similarly, methylation-sensitive high-resolution melting (MS-HRM) analysis on DBS was shown to provide a promising approach for PWS screening (Ref. Reference Ferreira, Costa, Gomes, dos Santos Cunha, Tyszler, Freitas, Llerena Junior, de Vasconcelos, Nicholls and Guida27). However, this method was only tested on high-quality DNA extracted from blood of 43 individuals suspected of having PWS and not the limited amount of dried blood spot material (a single 3.2 mm punch) used for NBS.

Key performance metrics for screening tests include sensitivity, specificity, PPV, negative predictive value (NPV), false positive rate (FPR) and false negative rate (FNR) on limited blood spot material (one to two 3.2 mm punches per infant) typically used for NBS. DNA methylation testing for PWS shows high sensitivity and specificity, providing reliable results across varied genetic backgrounds of PWS (Refs Reference Mahmoud, Singh, Weiss, Lakatos, Oakes, Hossain, Butler and Kimonis24, Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26, Reference Buchholz, Jackson, Robson and Smith68, Reference White, Durston, Harvey and Cross69, Reference Martínez, León, Monfort, Oltra, Roselló and Orellana70). Its high PPV and NPV reflect its precision in detecting the shared methylation signature among all PWS molecular classes (paternal deletion, mUPD, ICD), making false negatives extremely rare (Refs Reference Buchholz, Jackson, Robson and Smith68, Reference White, Hall and Cross71). False positives are also rare but can occur in cases with ambiguous methylation patterns. This aligns well with the Framework’s requirements for test accuracy and low false-positive rates in rare disorders.

Although DNA methylation testing serves as an effective first-tier screening tool, confirmatory second-tier diagnostics, such as droplet digital PCR (ddPCR), MLPA or low-coverage whole genome sequencing (WGS), may be required to identify the specific deletions on chromosome 15. The workflow described by Godler et al. (Ref. Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26) efficiently integrates these steps by performing methylation and copy number variation (CNV) analyses on a second NBS punch by ddPCR and WGS for the cases identified to have a positive methylation result by the first-tier methylation screen. This approach takes into account results from different NBS punches with the potential to lead to PPV approaching 100% for PWS.

Advances in genomic sequencing technologies may provide future opportunities for incorporating PWS into expanded newborn screening approaches, including use as a second-tier approach for detecting multiple genetic conditions to complement newborn screening (Ref. Reference Kingsmore, Smith, Kunard, Bainbridge, Batalov, Benson, Blincow, Caylor, Chambers, del Angel, Dimmock, Ding, Ellsworth, Feigenbaum, Frise, Green, Guidugli, Hall, Hansen, Hobbs, Kahn, Kiel, van der Kraan, Krilow, Kwon, Madhavrao, le, Lefebvre, Mardach, Mowrey, Oh, Owen, Powley, Scharer, Shelnutt, Tokita, Mehtalia, Oriol, Papadopoulos, Perry, Rosales, Sanford, Schwartz, Tran, Reese, Wright, Veeraraghavan, Wigby, Willis, Wolen and Defay72). While short-read WGS can identify up to 75% of individuals with PWS from diagnostic testing (Ref. Reference Gao, Zhong, Dai, Jiang and Zou73), these figures are not available for asymptomatic newborns from the general population. While long-read sequencing technologies, including Oxford Nanopore Technology and PacBio single-molecule sequencing, have the potential to detect methylation and DNA sequence changes in one test (Ref. Reference Sigurpalsdottir, Stefansson, Holley, Beyter, Zink, Hardarson, Sverrisson, Kristinsdottir, Magnusdottir, Magnusson, Gudbjartsson, Halldorsson and Stefansson74), they have not yet been adopted into routine clinical practice. Importantly, there is no evidence to show that these approaches can detect methylation and DNA sequence changes to identify PWS or any other condition using limited material typically extracted from a single 3.2 mm punch from dried blood spots utilised by most newborn screening programs. As such, high quantity and quality DNA requirements and relatively high cost are currently prohibitive for their widespread use in population-scale newborn screening programs. Other methods, such as fluorescence in situ hybridisation (FISH), Southern blot analysis and short-read WGS, although precise, are less suitable for large-scale first-tier newborn screening due to cost, complexity and sample requirements (Ref. Reference Monaghan, Wiktor and Van Dyke75). In contrast, DNA methylation test stands out as a feasible option for large-scale screening, providing a balance between efficiency, affordability, ethical consideration and diagnostic capability in population-wide screening (Refs Reference Mahmoud, Singh, Weiss, Lakatos, Oakes, Hossain, Butler and Kimonis24, Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26, Reference Buchholz, Jackson, Robson and Smith68, Reference Monaghan, Wiktor and Van Dyke75). Implementing DNA methylation testing for PWS using DBS provides a simpler and less resource-intensive alternative to more complex sequencing methods. Utilising a single 3.2 mm punch from an existing newborn DBS or materials remaining after SMA and SCID screening minimises additional collection and processing costs, aligning with current public health cost structures for population-wide newborn screening. Furthermore, advanced methods like MS-QMA have been shown to be highly sensitive for PWS on limited blood spot material (Ref. Reference Cartagena, Alshawsh, Bui, Gamage, Thakor, Pitt, Greaves, Wall, Saffery, Amor and Godler67). Overall, SNRPN promoter DNA methylation analysis as a first-tier screening test meets key technical, ethical and logistical requirements for potential inclusion of PWS in newborn screening programs in Australia.

Criterion 5: Social and ethical acceptability of test protocol

Public and stakeholder studies in Australian settings report high parental interest and conditional support for expanded NBS, provided that screening focuses on treatable, early-onset disorders, information is delivered clearly, and robust consent and counselling pathways are in place (Refs Reference Lynch, Best, Gaff, Downie, Archibald, Gyngell, Goranitis, Peters, Savulescu, Lunke, Stark and Vears76, Reference Scarfe, Turner, Meagher, Farrar, Bhattacharya, Paguinto, Millis, Watson, Kariyawasam and Norris77, Reference Lunke, Downie, Caruana, Kugenthiran, De Fazio, Hollizeck, Bouffler, Amor, Archibald, Bombard and Christodoulou78). The SNRPN methylation protocol used for PWS does not identify carriers and primarily detects clinically significant imprinting disorders (PWS, Angelman syndrome, and Dup15q), with second-tier testing then refining the molecular subtype, which limits uncertainty and mitigates variant-of-unknown-significance issues associated with use of WGS for newborn screening (Ref. Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26).

Newborn screening for conditions like PWS offers potential clinical benefits but also poses psychosocial and ethical challenges for families. Studies indicate that parents value early diagnosis because it facilitates timely intervention, reduces diagnostic uncertainty and allows families to prepare for care requirements (Refs Reference Mahmoud, Singh, Weiss, Lakatos, Oakes, Hossain, Butler and Kimonis24, Reference Boychuk, Kelly, Goldenberg and Wasserstein79). However, ethical concerns arise from the stigma associated with early diagnoses, anxiety and the emotional burden of receiving such information shortly after birth. Parents often struggle with uncertainty about their child’s future and may have difficulty understanding complex medical information (Refs Reference Mazaheri, Rae-Seebach, Preston, Schmidt, Kountz-Edwards, Field, Cassidy and Packman28, Reference Thomson, Glasson, Roberts and Bittles80, Reference Micallef Pulè and Hughes81). While these may be significant issues to address for other rare disorders, they are less pronounced for PWS, given the existing experience and infrastructure to provide appropriate counselling and support. Early identification through newborn screening can further ensure that all children have equitable access to timely interventions, follow-up care and psychosocial support, helping to alleviate parental distress and improve both short- and long-term outcomes for affected infants and their families (Ref. Reference Thomson, Glasson, Roberts and Bittles80).

For genomic NBS to be considered as a first-tier test, practical and technical challenges have been identified, including the need for appropriate parental consent and an opt-out process, pre- and post-test counselling, bioinformatic interpretation and managing potentially large genomic data (Refs Reference Levy82, Reference White, Mossfield, Fleming, Barlow-Stewart, Ghedia, Dickson, Richards, Bombard and Wiley83). Studies emphasise the importance of careful, ethical implementation of genomic NBS, prioritising patient and family interests (Refs Reference Ji, Farrar, Norris, Bhattacharya, Bennetts, Newson, Healy, Millis and Kariyawasam13, Reference Lynch, Best, Gaff, Downie, Archibald, Gyngell, Goranitis, Peters, Savulescu, Lunke, Stark and Vears76, Reference Cao, Notini, Ayres and Vears84). While it is critical to establish stringent guidelines regarding informed consent, data management and privacy protection for all conditions screened, PWS would follow workflows already established for SCID and SMA, making the required processes familiar and feasible within Australian NBS programs. Within current Australian opt-out NBS practice and with explicit information, the balance of benefit over psychosocial risk for a methylation-first, two-tier protocol appears favourable. Thus, Criterion 5 is partially fulfilled, contingent upon standardised consent materials, culturally safe counselling and clear policies for storage and use of residual blood spots, as outlined in the Framework.

Criterion 6: Healthcare services for diagnosis and management

Australia has a strong, well-established healthcare infrastructure supporting the diagnosis and management of genetic and rare disorders, including PWS, with services largely coordinated through tertiary paediatric hospitals and multidisciplinary clinics (Ref. 85). Diagnostic services using genetic testing, including DNA methylation and SNP arrays, are accessible via clinical genetics services, such as Victorian Clinical Genetics Services (VCGS) and NSW Health Pathology, and are often initiated when characteristic signs such as hypotonia and feeding difficulties are observed in infancy. Non-invasive prenatal testing (NIPT) for PWS is also available from 9 to 10 weeks gestation, indicating advanced diagnostic capabilities (Ref. Reference Poulton and Hui86). Hence, diagnostic capacity is readily available and technically robust, meeting the Framework’s standards for post-screening confirmatory testing and support.

Management services for PWS are delivered through multidisciplinary models of care involving genetics, paediatric endocrinology, dietetics, psychology, respiratory and sleep medicine, speech and occupational therapy, and physiotherapy to address the syndrome’s multifaceted challenges of PWS. GH therapy is initiated through paediatric endocrinology services in major hospitals and has been subsidised for all children with PWS in Australia under the Pharmaceutical Benefits Scheme (PBS) since 2009. Organisations such as the Prader-Willi Research Foundation Australia (PWRFA) and Prader-Willi Syndrome Australia (PWSA) offer resources and guidance to families and healthcare professionals to ensure comprehensive care (Ref. 87). Though Australia offers well-equipped facilities and comprehensive services for managing PWS, disparities persist, particularly in remote areas where access to genetic testing and specialist care is constrained (Refs Reference Casauria, Collins, White, Konings, Wallis, Pachter, McGaughran, Barnett and Best88, Reference Bourke, Harper, Johnson, Green, Anish, Muduwa and Jones89). Overall, Criterion 6 is fully fulfilled, as high-quality diagnostic and management services for PWS in Australia are already available, reliable and adaptable to accommodate additional screen-detected cases.

Criterion 7: Availability of effective intervention for diagnosed cases

Management of PWS focuses on symptom alleviation rather than cure; however, several well-established interventions significantly improve health outcomes and quality of life when initiated early. The treatment pathways for PWS incorporate recombinant human growth hormone (rhGH) therapy, nutritional and behavioural interventions, sleep-disordered breathing surveillance, endocrine therapies and family-centred developmental supports (Ref. Reference Deal, Tony, Höybye, Allen, Tauber and Christiansen29). rhGH is an FDA-approved therapy for growth failure in PWS and provides the greatest benefit when initiated early, typically between 4 and 24 months of age (Refs Reference Wheeler, Gantz, Cope, Strong, Bohonowych, Moore and Vogel-Farley22, Reference Grootjen, Trueba-Timmermans, Damen, Mahabier, Kerkhof and Hokken-Koelega90). In Australia, the TGA has approved rhGH for use in paediatric patients with PWS to improve body composition and address short stature associated with this condition. A number of studies have shown that rhGH treatment improves body composition, linear growth and muscle mass, reduces fat mass, benefits motor development in the long term and enhances quality of life, especially if initiated early during infancy or early childhood (Refs Reference Jin and Luo91–Reference Ferruzzi, Vrech, Pietrobelli, Cavarzere, Zerman, Guzzo, Flodmark, Piacentini and Antoniazzi96). Potential adverse events of rhGH therapy such as worsening of sleep apnoea, intracranial hypertension, or scoliosis are well recognised and mitigated by standard pre-treatment and follow-up protocols, including polysomnography and multidisciplinary monitoring (Refs Reference Caudri, Nixon, Nielsen, Mai, Hafekost, Kapur, Seton, Tai, Blecher, Ambler, Bergman, Vora, Crock, Verge, Tham, Musthaffa, Lafferty, Jacoby, Wilson, Downs and Choong30, Reference Tauber and Diene92, Reference Tauber, Diene and Molinas97, Reference Salvatoni, Squillace and Calcaterra98). In a cohort study of 235 individuals with PWS, outcomes during 3 years of rhGH treatment were compared with participants’ pre-treatment baseline measurements, demonstrating significant improvement in height, with treatment-related adverse events reported in 16.6% of participants, most commonly sleep apnoea (4.7%) and tonsillar hypertrophy (1.7%) (Ref. Reference Lämmer, Backeljauw, Tauber, Kanumakala, Loche, Otfried Schwab, Pfäffle, Höybye, Lundberg, Dahlgren, Ek, Battelino, Kriström, Esmael and Zabransky99).

The available evidence for cognitive and motor benefits of rhGH is promising but still emerging (Refs Reference Deal, Tony, Höybye, Allen, Tauber and Christiansen29, Reference Siemensma, Tummers-de Lind van Wijngaarden, Festen, Troeman, van Alfen-van der Velden, Otten, Rotteveel, Odink, Bindels-de Heus, van Leeuwen, Haring, Oostdijk, Bocca, Mieke Houdijk, van Trotsenburg, Hoorweg-Nijman, van Wieringen, Vreuls, Jira, Schroor, van Pinxteren-Nagler, Willem Pilon, Lunshof and Hokken-Koelega100–Reference Osório103). A meta-analysis of 10 RCTs found that growth hormone treatment significantly improved motor development in children with PWS but showed no consistent cognitive effects (Ref. Reference Luo, Zheng, Yang, Bai, Yang, Zhu, Pan and Chen104). However, findings from a 52-week phase 3 single-arm study suggest that early rhGH treatment in infants and young children with PWS may improve growth, BMI and aspects of mental development, with greater cognitive benefits observed in those treated before 9 months of age. Intervention was also reported to slow motor decline (Ref. Reference Cheng, Ying, Qiu, Fu, Gong, Yang, Shi, Li, Ma, Wang, Liu, Chen, Su, Luo, Luo and Lu93). While not as robust as RCTs, such findings may indicate potential age-related benefits that warrant further investigation in controlled studies. Other longitudinal studies report improvements in mobility, motor skills and language functions within the first year of therapy, although the quality of evidence is moderate and findings are not entirely consistent across studies (Refs Reference Deal, Tony, Höybye, Allen, Tauber and Christiansen29, Reference Jin and Luo91, Reference Myers, Whitman, Carrel, Moerchen, Bekx and Allen105, Reference Donze, Damen, Mahabier and Hokken-Koelega106).

Sleep-disordered breathing, nocturnal hypoxia and respiratory abnormalities are highly prevalent in PWS and are associated with an increased risk of sudden death from infancy if not managed (Refs Reference Gillett and Perez107, Reference Abushahin, al-Naimi, Abu-Hasan, Arar, Lina Hayati, Belavendra and Janahi108). These complications can be effectively managed through established interventions such as home low-flow supplemental oxygen for infants with persistent hypoxemia related to central hypoventilation, positive airway pressure and ongoing sleep and respiratory monitoring (Refs Reference Urquhart, Gulliver, Williams, Harris, Nyunt and Suresh10, Reference Cohen, Hamilton and Narang109). Cohen et al. demonstrated that low-flow oxygen significantly (p = 0.008) reduced the median central apnoea index from 14.0 to 1.0 events/hour and improved oxygen saturation nadirs in PWS infants with confirmed central sleep apnoea, obviating the need for positive pressure ventilation in all treated infants (Refs Reference Cohen, Hamilton and Narang109). A 2025 proof-of-concept RCT confirmed that therapeutic oxygen significantly (p = 0.048) reduced the central apnoea–hypopnoea index compared with medical air (mean difference –7.7 events/hour) without inducing hypercapnia (Ref. Reference Fishman, Wen, Massicotte, Narang, Chiang, Bola, Ambreen, Zweerink and Amin47). This treatment is usually required for only a few months during infancy, after which central apnoea resolves and obstructive patterns predominate (Ref. Reference Cohen, Hamilton and Narang109). Regular polysomnography before and after growth hormone initiation allows early detection and management of airway obstruction or hypoventilation, which further enhances safety and treatment effectiveness (Refs Reference Miller, Silverstein, Shuster, Driscoll and Wagner110, Reference Berini, Spica Russotto, Castelnuovo, di Candia, Gargantini, Grugni, Iughetti, Nespoli, Nosetti, Padoan, Pilotta, Trifirò, Chiumello and Salvatoni111). Importantly, because NBS-identified infants will receive the diagnosis before symptoms are apparent, respiratory surveillance and home oxygen therapy can be arranged in advance of any clinical deterioration, representing a clear benefit of the early detection window that NBS enables. Early diagnosis facilitates timely implementation of these supportive measures during the neonatal period before more severe respiratory complications develop. Regular polysomnography before and after rhGH initiation allows early detection and management of airway obstruction or hypoventilation, which further enhances safety and treatment effectiveness (Refs Reference Miller, Silverstein, Shuster, Driscoll and Wagner110, Reference Berini, Spica Russotto, Castelnuovo, di Candia, Gargantini, Grugni, Iughetti, Nespoli, Nosetti, Padoan, Pilotta, Trifirò, Chiumello and Salvatoni111). Endocrine management for addressing hypothyroidism, adrenal insufficiency and hypogonadism further reduces morbidity across childhood and adolescence, while early diagnosis ensures timely referral and monitoring (Refs Reference Goldstone, Holland, Hauffa, Hokken-Koelega and Tauber31, Reference Alves and Franco112).

Emerging pharmacological agents targeting hyperphagia, such as beloranib and oxytocin, have shown potential in reducing appetite and improving food-related behaviours (Refs Reference Tan, Orsso, Deehan, Triador, Field, Tun, Han, Müller and Haqq113, Reference Miller, Tamura, Butler, Kimonis, Sulsona, Gold and Driscoll114), although they remain experimental and their long-term safety profiles are yet to be fully understood (Refs Reference Tan, Orsso, Deehan, Triador, Field, Tun, Han, Müller and Haqq113, Reference Mahmoud, Kimonis and Butler115). For example, experimental treatments like beloranib were associated with venous thromboembolic events, including fatalities during clinical trials (Ref. Reference Mahmoud, Kimonis and Butler115). Oxytocin treatments have yielded inconsistent results, with improvements in social and eating behaviours in some individuals but no significant effects in others. Recently, diazoxide choline controlled release (DCCR), marketed as Vykat XR, was approved by the FDA for the treatment of hyperphagia in individuals with PWS from 4 years of age (Refs Reference Miller, Gevers, Bridges, Yanovski, Salehi, Obrynba, Felner, Bird, Shoemaker, Angulo, Butler, Stevenson, Goldstone, Wilding, Lah, Shaikh, Littlejohn, Abuzzahab, Fleischman, Hirano, Yen, Cowen and Bhatnagar32, Reference Butler116, Reference Miller, Gevers, Bridges, Yanovski, Salehi, Obrynba, Felner, Bird, Shoemaker, Angulo, Butler, Stevenson, Abuzzahab, Barrett, Lah, Littlejohn, Mathew, Cowen, Bhatnagar, das, Fleischman, Goldstone, Harwood, Holland, Kimonis, McCandless, Schillaci, Shaikh, Shea, Viskochil and Wilding117). Despite advancements, pharmacological interventions remain inadequate in reducing hyperphagia and obesity, which require lifelong management.

Beyond medical therapies, multidisciplinary nutritional, behavioural and developmental interventions, including structured dietary management, physiotherapy, behavioural therapies, speech and language support and early-intervention developmental services, are effective in addressing hyperphagia, obesity, communication challenges and cognitive delays associated with PWS (Refs Reference Dykens and Shah118, Reference Salvatoni, Nosetti, Salvatore and Agosti119, Reference Erhardt and Molnár120). These interventions mitigate hypotonia, support normal growth patterns, delay the onset of severe hyperphagia, improve developmental and social outcomes, and significantly enhance the quality of life for individuals with PWS and their families (Refs Reference Jin and Luo91, Reference Tauber and Diene92, Reference Mahmoud, Kimonis and Butler115, Reference Qiu, Chang, Ma, Strong, Okun, Foote, Wexler, Gunduz, Miller and Halpern121).

In summary, there is consensus and robust evidence supporting early multidisciplinary interventions for PWS, which improve physical, motor and metabolic outcomes. While the urgency of treatment is moderate and immediate postnatal therapy is not required, timely intervention is critical when respiratory episodes occur, as these can be life-threatening if not appropriately managed. Early initiation of care is also important to prevent irreversible physical and developmental delays. Our assessment of Criterion 7 as partially fulfilled reflects the current evidence base rather than the effectiveness of available interventions. Although several interventions, including GHT, nutritional management, respiratory support, developmental therapies and multidisciplinary care, have demonstrated clear clinical benefits for individuals with PWS, there remains limited direct evidence from newborn screening programs demonstrating the incremental long-term benefits of screening compared with early clinical diagnosis. Additional prospective studies evaluating health outcomes following newborn screening would further strengthen fulfilment of this criterion.

Criterion 8: Screening benefits outweigh its impact on the program

Screening for PWS could be technically integrated into the existing Australian NBS pathway. PWS screening could potentially utilise existing newborn screening laboratory workflows and equipment established for conditions such as SMA and SCID; the molecular targets and assays differ. Specifically, SMA screening detects SMN1 gene deletions, whereas SCID screening quantifies T-cell receptor excision circles (TRECs) by real-time PCR (Ref. Reference Bzdok, Czibere, Burggraf, Pauly, Maier, Röschinger, Becker and Durner122). In contrast, PWS screening would require detection of abnormal DNA methylation, which could be achieved using the same equipment that is used for SMA and SCID screening (Ref. Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26). Screening methods that utilise equipment already used in routine practice are feasible and comparable to current standard-of-care testing, with the potential of adding additional conditions with rationale for inclusion, like Angelman syndrome and Dup15q syndrome, at little added cost (Refs Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26, Reference Ferreira, Costa, Gomes, dos Santos Cunha, Tyszler, Freitas, Llerena Junior, de Vasconcelos, Nicholls and Guida27). This approach would not require changes to sample collection, transport or reporting processes, with minimal training required as it relies on equipment already used in routine newborn screening. Overall, this supports the operational feasibility of incorporating DNA methylation-based screening within the current program structure, with no evidence suggesting that such an addition would undermine public trust or participation in NBS.

At present, no formal population-level cost-effectiveness or cost-utility analyses have evaluated newborn screening for PWS in Australia or comparable countries. Existing evidence provides estimates for costs-per-screen, cost-per-positive diagnosis or annual healthcare costs per patient, driven by obesity-related morbidity, respiratory issues, hospitalisation and long-term care (Refs Reference Godler, Ling, Gamage, Baker, Bui, Field, Rogers, Butler, Murgia, Leonardi, Polli, Schwartz, Skinner, Alliende, Santa Maria, Pitt, Greaves, Francis, Oertel, Wang, Simons and Amor26, Reference Baker, Arora, Amor, Date, Cross, O’Brien, Simons, Rogers, Goodall, Slee, Cahir and Godler33, Reference Butler, Manzardo, Strong, Li, Yin, Meng, Silber, Francis, Hadker, Czado, Yeh and Miller34, Reference López-Bastida, Linertová, Oliva-Moreno, Posada-de-la-Paz, Serrano-Aguilar, Kanavos, Taruscio, Schieppati, Iskrov, Baji and Delgado123, Reference Dempsey, Hall, Lanning, Barron-Millar, Huang, Cowen, Nagao, Gandhi and Bhatnagar124). However, none provide incremental cost-effectiveness ratio (ICER) or cost per quality-adjusted life year (QALY) gained estimates relating to newborn screening. As with other rare disorders, low incidence makes economic modelling sensitive to assumptions, and the absence of a clearly defined presymptomatic window complicates efforts to estimate benefits attributable solely to earlier detection. Conducting cost-effectiveness analysis of newborn screening is limited by the lack of long-term data relating to costs and health outcomes, including QALYs. Moreover, indirect societal costs, such as caregiving burden, lost productivity and long-term disability support, are substantial but difficult to measure and quantify. Without these data, the net economic impact of adding PWS remains uncertain. In summary, the lack of robust population-level cost-effectiveness evidence in Australia represents the main barrier to fulfilling this criterion.

Australian cost-of-illness evidence highlights the substantial financial burden associated with PWS. Neonatal care contributes significantly to cost burden, as most infants with PWS require special care nursery or NICU admission for hypotonia, feeding difficulties and nasogastric support. However, no Australian study has quantified condition-specific length of stay (LOS) or assessed whether earlier diagnosis shortens hospitalisation. One study estimated the mean annual cost of raising a child with PWS at AU$57,576 (95% CI: $37,030–$78,123), primarily driven by medical services, medication costs, parental income loss and care needs, with lower costs observed in individuals with higher intellectual function (Ref. Reference Baker, Arora, Amor, Date, Cross, O’Brien, Simons, Rogers, Goodall, Slee, Cahir and Godler33). Early detection may help reduce healthcare costs by enabling earlier nutritional, endocrine, developmental and behavioural interventions that help mitigate severe obesity, behavioural problems, diabetes and respiratory complications (Ref. Reference Kimonis, Tamura, Gold, Patel, Surampalli, Manazir, Miller, Roof, Dykens, Butler and Driscoll9). It may also facilitate early identification and management of respiratory complications, including hypoxia related to impaired central respiratory control, through appropriate monitoring and supportive measures such as low-flow supplemental oxygen when clinically indicated.

International data provide valuable context. A multinational study underway in the UK, Germany, France, Italy and the USA aims to quantify the economic and caregiving burden of PWS to inform future economic modelling (Ref. Reference Gevers, Obrynba, Dempsey, Yen, Hall, Lodge, Shaw, Ramage, Strong, Ward, Munetsi and Blenkiron125). In the US, healthcare costs for children with PWS are substantially higher than for unaffected peers, with total annual costs 4.9 times higher, medical costs 4.4 times higher and pharmacy costs 12.5 times higher, with the greatest expenditures observed in children under 2 years (Ref. Reference Kreher, Hoffman, Tuzil and Prawitz126). Another longitudinal retrospective case-matched control study in the US reported that children with PWS incur higher medical costs than matched controls, with commercially insured patients having 8.8 times greater total annual medical costs ($28,712 vs $3,246), primarily driven by outpatient, inpatient and medication expenses (Ref. Reference Shoffstall, Gaebler, Kreher, Niecko, Douglas, Strong, Miller, Stafford and Butler127). Although drawn from an international setting, these data are relevant to Australia given similarities in healthcare systems and diagnostic approaches.

Criterion 9: Other relevant considerations

Some additional factors warrant consideration in evaluating the inclusion of PWS in the Australian NBS program, beyond those captured by the preceding criteria. For research and translational readiness, Australia is currently at the forefront of translational genomic screening research and incorporating PWS would align with national genomics policy priorities, including the Australian Genomics Health Futures Mission (GHFM) and Genomics Health Alliance (AGHA), which advocate for responsible expansion of genomic medicine in population screening (Refs Reference Belcher, Mangelsdorf, McDonald, Curtis, Waddell and Hussey128, Reference McGaughran129). Program implementation would require clear governance frameworks for data storage, privacy, secondary findings and equitable access, particularly given the long-term retention and possible secondary use of dried bloodspots. These data reporting and storage requirements would follow the same standards already established for conditions such as SMA and SCID. These considerations are also addressed within broader ethical and regulatory reforms under the National Genomics Policy Review.

Integrating PWS into national screening programs would require robust, systematic monitoring and evaluation frameworks, with current evidence suggesting feasibility but highlighting significant policy development needs (Ref. Reference Metternick-Jones, Lister, Dawkins, White and Weeramanthri130). In Australia, the MSAC provides assessment frameworks to guide implementation (Ref. Reference O’Leary and Maxwell35). Overall, adding PWS to NBS panels is ethically justified and logistically feasible with existing technologies like MS-QMA, but will require coordination among policymakers, healthcare providers and advocacy groups to ensure successful implementation and sustained care for affected individuals.