Neurodevelopmental disorders (NDDs) or developmental disabilities are a spectrum of conditions characterized by delay, deviance, and/or dissociation across domains of childhood development (such as motor, problem solving, social-communication, and adaptive skills) ¹. NDDs are heterogeneous in clinical presentation, resulting in variable definitions. ^2,3. For the purposes of this manuscript, the term NDD will encompass global developmental delay (GDD), intellectual disability (ID), autism spectrum disorder (ASD), and cerebral palsy. We made this designation, because for each of these conditions, there are meta-analyses supporting the diagnostic utility of genetic testing among patients without a clearly identifiable acquired etiology ^4–8. Specifically, among individuals with GDD/ID and/or ASD, the prevalence of pathogenic chromosomal copy number variants (CNVs) and single nucleotide variants (SNVs)/small indels is approximately 10–15% and 30–40%, respectively ^4,9. For CP, the prevalence of pathogenic CNVs and SNV/small indels is approximately 5% and 20–30%, respectively ^5,10.

With the expanding knowledge of genetic causes of NDDs and the rise of next-generation sequencing (NGS)¹¹, professional society guidelines pertaining to genetic testing are increasingly important in clinical care. These guidelines, or “practice parameters”, are based on comprehensive evidence reviews to inform best practices with respect to diagnosis, management, and treatment ¹². Since the early 2000s, multiple guidelines for genetic testing for NDDs have been published by a variety of specialty organizations across neurology, pediatrics, genetics, and psychiatry. These guidelines have important clinical implications, as they are frequently referenced by clinicians when determining genetic testing utility/plans. Furthermore, payers use society guidelines when writing medical policies to determine insurance coverage for genetic testing for NDDs ^13,14. The quality, consistency, and accessibility of these guidelines thus has great influence on care outcomes for children with NDDs.

Despite the key role that society guidelines play in access to genetic testing for NDDs, a summary of recommendations across professional societies does not yet exist. Consistency between guidelines is important for several reasons. If there are differing recommendations for genetic testing for NDDs, insurance companies can deny coverage for one type of test over another, citing a specific guideline which supports their position. For example, in their policy dated January 1, 2024, United Health Care has stated it will approve GS/deem it medically necessary if “neither chromosome microarray analysis (CMA) nor WES have been performed” (https://www.uhcprovider.com/content/dam/provider/docs/public/policies/medicaid-comm-plan/whole-exome-whole-genome-sequencing-cs.pdf). Second, there can be confusion among patients if providers from one medical specialty suggest one type of etiological evaluation that differs from that of another medical specialty, which can perpetuate healthcare disparities. Third, there may suboptimal utilization of healthcare costs and resources (genetic counseling visits, physician visits), as well as undue patient burden (time, expense), if individuals undergo a set of genetic tests based on one guideline that has lower diagnostic yield and lower cost-effectiveness compared to another guideline. Therefore, we aimed to fill this gap by conducting a scoping review of the literature on available U.S.-based professional society practice guidelines that contain recommendations for genetic testing of unexplained NDDs. We describe the current practice guideline landscape, highlight challenges, and provide recommendations to improve the efficiency, contemporaneity, cohesiveness, and impact of societal guidelines for genetic testing for NDDs.

The target audience for this review are clinicians, policy makers, and medical societies across multiple medical disciplines, including pediatrics, developmental-behavioral pediatrics, psychiatry, genetics, and neurology. The ultimate goal is to spearhead the creation of unified, frequently updated, and easily accessible cross-specialty society guidelines.

We conducted a scoping review including a primary search strategy and manual article selection to identify practice guidelines. In the primary search strategy, we searched articles indexed by PubMed (title, abstract, and keyword search via https://pubmed.ncbi.nlm.nih.gov/) with the following query:

Notably, we did not include the term “genetic(s)” in the search query, as society guidelines focusing on multiple aspects of care related to a specific NDD may not include this term(s) in the abstract or as part of MeSH keywords identified by the PubMed search.

We applied inclusion/exclusion criteria to the resulting articles. Inclusion criteria were: statement by a U.S. medical organization/society, focus on an NDD (specifically GDD/ID, ASD, and/or CP), and inclusion of clinical recommendations pertaining to genetic testing. Exclusion criteria were: non-English article; erratum to another article; commentary article; animal, in vitro/in vivo, biomarker, or other biological study; case report/case series; primary research article; review article or guidelines related to a specific genetic disorder; focus on a study population not of interest; focus on outcomes, management, or diagnostic practices not of interest; lack of clinical recommendations; involvement by an organization outside of the U.S.; retired guideline (if there is explicit mention of it being retired in the full PDF text of the article or the source website of the article); guideline replaced by a more contemporary version from the same medical society focusing on the same target population; and guideline/review of guidelines without involvement of a professional organization. The manual article selection phase involved a direct query of all authors to identify any additional articles meeting inclusion/exclusion criteria.

For each article included in the review, we extracted the following data:

The first author SS manually completed the article search. Both first authors completed the record screening, eligibility review, and data collection. There were no missing data. This study did not require a registered research protocol or statement of approval by an ethical standards committee.

From the primary search strategy, the PubMed query resulted in 531 articles (date of query 2023-08-16). The manual selection process yielded one additional article (American Academy of Pediatrics [AAP] 2020 practice parameter on DD ¹⁵). Of the 532 total articles, nine met inclusion criteria and 523 were excluded. The PRISMA 2020 Flow Diagram is shown in Figure 1. Characteristics of the nine included articles are shown in Table 1 and details of the genetic testing recommendations within each article are outlined in Table 2.

There are certain guidelines we included and excluded that warrant comment. We did include the American Academy of Child and Adolescence Psychiatry (AACAP) 2014 guidelines focused on ASD ¹⁶ among these nine articles. According to the AACAP, “by standard convention, Practice Parameters become outdated after five years” (https://www.aacap.org/AACAP/Resources_for_Primary_Care/Practice_Parameters_and_Resource_Centers/Practice_Parameters.aspx). However, we decided to keep this article as one of the included studies, given that (1) there was not explicit mention of this parameter being retired either in the full text of the article or in its enclosing website (https://www.jaacap.org/article/S0890-8567(13)00819-8/fulltext) (2) practitioners may not be aware of this AACAP-specific policy of retired guidelines after five years and thus may still access the full text/PDF of the guideline for application in clinical practice. We decided to include both the 2014 AAP guideline on GDD/ID ¹⁷ and the 2020 AAP guideline on DD ¹⁸, as the latter is a more general statement of developmental disorders and covers diagnosis, management as well as etiological evaluation, whereas the former is specifically focused on GDD/ID and etiological evaluation. We did not include a 2010 statement on etiological evaluation for DD/ID, ASD, and multiple congenital anomalies ⁹, as this statement was by an international organization (International Standard Cytogenomic Array Consortium), and we included only U.S. statements.

The publication years ranged from 2000 to 2022, and only five guidelines were published within the last five years (2018 and onward) ^15,19–21. The nine guidelines were from five medical societies representing four specialties (pediatrics, neurology, medical genetics, and psychiatry): American Academy of Child and Adolescence Psychiatry (AACAP), American Academy of Neurology (AAN), American Academy of Pediatrics (AAP), American College of Medical Genetics and Genomics (ACMG), and Child Neurology Society (CNS). Three guidelines focused exclusively on genetic/etiological evaluation ^17,19,22, while the remaining focused on diagnosis, management, and etiological evaluation. There were four society guidelines relevant to individuals with GDD/ID, published between 2014 to 2021 ^15,17,19,23. Four society guidelines focused exclusively on ASD ^16,21,22,24, and one guideline focused on ASD in addition to GDD/ID ¹⁵. With respect to CP, there was one contemporary society guideline, from the American Academy of Pediatrics (AAP) in 2022 ²⁰. Out of these nine guidelines, only the ACMG guidelines, published in 2021, firmly recommended WGS or ES as a first-tier test for unexplained NDDs ¹⁹. We inferred several themes from these guidelines discussed below.

Many society-based practice guidelines discussing genetic testing for NDDs (specifically GDD/ID, ASD, and CP) are more than five years old. One of the four society guidelines pertaining to individuals with GDD/ID, the AAP 2014 guidelines on GDD/ID ¹⁷, is from 10 years ago. A 2003 guideline on GDD from the AAN and CNS ²⁵ was retired and thus excluded from our scoping review; no updated guideline on GDD from these societies was identified. Among the five guidelines including ASD, only two were from the past five years: the AAP 2020 guidelines on DD ¹⁵ and the AAP 2020 guidelines on ASD ²¹. For CP, there was one recent society guideline, from the AAP in 2022 ²⁰. A 2004 guideline on CP from the AAN ²⁶ was retired and thus excluded from our scoping review; no updated guideline on CP from the AAN was identified. In summary, out of a total of nine practice guidelines published between 2000 and 2022, only 5/9 (55%) were from the past five years.

The most recently published guidelines for an NDD often do not reflect contemporary knowledge and/or availability of modern genetic testing options. For example, ES became available as a clinical test in 2011, and in 2013, the first clinical WGS became available in the U.S. (Figure 2). More recently, converging data from different disorders (NDDs or otherwise) supports first-line broad testing with ES or WGS especially to aid in narrowing a differential diagnosis or making a molecular diagnosis (the exception is that if there is a specific genetic condition like Down syndrome under consideration based on the phenotype, then targeted testing for that condition should occur first). However, numerous guidelines still do not reflect this paradigm shift in genomic evaluation.

With one exception, the most recent society guidelines pertaining to GDD/ID have recommended non-NGS technologies as first-tier genetic tests, including the following:

The one exception is the ACMG 2021 guidelines, recommending ES/WGS as a first- or second-tier test for patients with DD, ID, or congenital anomalies ¹⁹. The AAP 2020 guidelines focused on DD (including GDD and ASD) ¹⁵ do indicate that, for GDD/ID, “further testing [after CMA and Fragile X] may include ES and gene panels” without making a definitive recommendation.

The most recent society guidelines pertaining to ASD have also recommended non-NGS technologies as first-tier genetic tests, including:

Recent guidelines on CP from the AAP 2022 ²⁰ referenced genetic testing for a subset of patients (“diagnostic evaluation may include advanced genetic techniques, such as chromosomal microarray and genomic sequencing”) but did not provide detailed guidance for when this is indicated or the specific type of genetic testing that should be pursued.

It is notable that for a given NDD, there are differing recommendations for genetic testing depending on which society created them. These variations may arise as a result of the familiarity of providers in that specialty with new testing methodologies, consideration of the severity of the patients typically seen by that specialty, and differences in the year of publication as noted above. For example, a neurologist evaluating a patient with ASD may reference the most recent guidelines by the society pertinent to their specialty (i.e., CNS or AAN) ²⁴, which would suggest karyotype and Fragile X testing as first line testing. A pediatrician seeing the same patient may reference the 2020 AAP guideline on ASD ²¹ and consider sending CMA and Fragile X testing. If the patient has co-occurring ID (a common scenario given that 30–70% of children with ASD have ID ²⁷), a geneticist may adhere to the ACMG 2021 guidelines ¹⁹ and consider sending ES or WGS. As a result of these divergent recommendations, the same patient may undergo different sets of genetic testing depending on the referring clinicians who may be following practice guidelines most closely associated with their specialty.

The lack of contemporary, consistent, unified guidelines from medical societies on genetic testing for NDDs may have detrimental impacts on patients due to missed or delayed diagnosis of genetic conditions. There is high likelihood that this impact is inequitable on the basis of social determinants of health, including insurance coverage, race/ethnicity, rurality, economic and employment status, and educational background. Here, we will discuss the implications of missing and/or delaying a genetic diagnosis; outline ways in which the lack of contemporary, consistent guidelines could contribute to missed/delayed genetic diagnoses; and discuss how these effects could be felt inequitably among various demographic groups, leading to disparities in care.

Based on the above results, examples from adjacent clinical fields, and the authors’ collective expertise in the care of children with NDDs, we have created a series of recommendations for medical societies engaged in the development or updating of genetic testing practice guidelines.

Our work has a few notable limitations. First, we focused exclusively on U.S.-based genetic testing guidelines due to the differences between healthcare systems and payment structures in other countries. Nonetheless, the principles outlined in this review, including the need for modernized guidelines across specialties for different NDDs, may still be relevant to healthcare systems in different countries. Second, we limited our scoping review to include only GDD/ID, ASD, and CP, three major NDDs for which there is scientific evidence regarding the utility of genetic testing. Over time, our scientific knowledge may expand to include an understanding of the yield of genetic testing for other NDDs, such as ADHD⁷⁹, reiterating the need to continually update and revise society guidelines. We did not evaluate primary data used to develop these guidelines. Third, we acknowledge that improvements in professional society guidelines for genetic testing for NDDs must be accompanied by provider education and advocacy among policymakers in order to have optimal impact on clinical care. Providers often cite lack of genetic knowledge/confidence as a reason for lack of testing or referring for genetic testing ^63,64,80. For non-geneticists, education efforts should include both “standard” and intensive training options, depending on providers’ intentions to order/interpret/disclose testing on their own or alongside a genetic counselor, or refer to genetic counseling for testing only. For non-geneticists, guidelines for the interpretation and communication of genetic testing results should be established and included in provider education programs. Beyond educational deficiencies, providers also cite insurance barriers as a major reason for lack of genetic testing usage ^41,43,80. Engagement with payer administrators to highlight evidence of cost effectiveness ⁸¹ alongside diagnostic and management benefits may be helpful ⁸². Within oncology genetic testing and payer coverage, there has been a call for incorporating regularly-updated society guidelines in the health technology assessment process used in coverage decision-making ⁸³. A similar approach should be considered for NDDs. Fourth, we acknowledge that the spectrum and diagnostic yield of genetic testing for other NDDs, such as attention deficit hyperactivity disorder (ADHD) and specific learning disabilities, are not addressed in this scoping review but should be added in the future as additional literature regarding these disorders is published. Fifth, we acknowledge that societal guideline updates may be in progress that are not reflected in this article. For example, the American Academy of Neurology and Child Neurology Society are working on updated quality measures for genetic testing for GDD/ID, epilepsy, and CP.

Genetic testing remains a rapidly evolving field with falling costs and improved diagnostic yields. Like other clinical guidelines, an appropriate balance must be struck between the current evidence base and flexibility to remain relevant over time. As the applications of genetic testing have greater impact on early diagnosis and intervention, there must be a greater involvement of all stakeholders, including payers, policymakers, and family advocacy groups.