WHOLE EXOME SEQUENCING (WES) IN CLINICAL DIAGNOSTICS -

CHALLENGES AND OPPORTUNITIES

WHOLE-EXOM-SEQUENZIERUNG (WES) IN DER KLINISCHEN

DIAGNOSTIK – HERAUSFORDERUNGEN UND CHANCEN

Edenilson Brandl
Cognitive-Behavioral Therapist, English Professor, Author, Master's Student in
Genetics, Specialist in Business Intelligence and Project Management,
Bachelor's Degree in Production Engineering, Degree in Pedagogy.
[email protected]

Abstract:
The Genomic Revolution is reshaping healthcare, with Whole Exome
Sequencing (WES) emerging as a transformative tool in clinical diagnostics.
This article explores WES's potential to revolutionize personalized medicine,
presenting insights into its clinical applications, challenges, and collaborative
solutions. Methodologically, a systematic review was conducted, focusing on
the last decade's literature from reputable databases. Challenges in data
interpretation, ethical considerations, cost-effectiveness, and accessibility are
addressed, alongside collaborative efforts to bridge these gaps. Results
highlight WES's impact on personalized medicine, advancements in rare
disease diagnosis, and its role in cancer genomics. Ethical concerns,
particularly regarding informed consent and data privacy, are acknowledged.
The article concludes by emphasizing the need for continued research,
international collaboration, and ethical frameworks to unlock the full potential of
WES in clinical genomics, promising a future of precise diagnostics and
improved healthcare outcomes.

Keywords: Genomic Revolution, Whole Exome Sequencing (WES) , Precision

Medicine, Clinical Diagnostics, Genetic Variation, Data Interpretation, Ethical
Considerations, Collaborative Solutions, Rare Diseases, Healthcare
Transformation.
Abstrakt:
Die genomische Revolution verändert das Gesundheitswesen, wobei sich die
Whole Exome Sequencing (WES) zu einem transformativen Werkzeug in der
klinischen Diagnostik entwickelt. Dieser Artikel untersucht das Potenzial von
WES, die personalisierte Medizin zu revolutionieren, und präsentiert Einblicke in
seine klinischen Anwendungen, Herausforderungen und kollaborativen
Lösungen. Methodisch wurde eine systematische Überprüfung durchgeführt,
die sich auf die Literatur des letzten Jahrzehnts aus seriösen Datenbanken
konzentrierte. Herausforderungen bei der Dateninterpretation, ethischen
Überlegungen, Kosteneffizienz und Zugänglichkeit werden angegangen und es
werden gemeinsame Anstrengungen unternommen, um diese Lücken zu
schließen. Die Ergebnisse unterstreichen den Einfluss von WES auf die
personalisierte Medizin, Fortschritte bei der Diagnose seltener Krankheiten und
seine Rolle bei der Krebsgenomik. Ethische Bedenken, insbesondere
hinsichtlich der Einwilligung nach Aufklärung und des Datenschutzes, werden
anerkannt. Der Artikel schließt mit der Betonung der Notwendigkeit
kontinuierlicher Forschung, internationaler Zusammenarbeit und ethischer
Rahmenbedingungen, um das volle Potenzial von WES in der klinischen
Genomik auszuschöpfen und eine Zukunft mit präziser Diagnostik und
verbesserten Gesundheitsergebnissen zu versprechen.

Schlüsselwörter: Genomische Revolution, Sequenzierung des gesamten Exoms

(WES), Präzisionsmedizin, klinische Diagnostik, genetische Variation,
Dateninterpretation, ethische Überlegungen, kollaborative Lösungen, seltene
Krankheiten, Transformation im Gesundheitswesen.
 1. INTRODUCTION
The Genomic Revolution in Healthcare The field of healthcare is in the
midst of a profound transformation, one that is being driven by the rapid
advancements in genomics. At the forefront of this revolution is Whole Exome
Sequencing (WES), a powerful genomic technology that is reshaping clinical
diagnostics. WES allows us to decipher the genetic code of an individual's
exome, the portion of the genome that contains the instructions for building and
maintaining the body's proteins. This article explores the challenges and
opportunities presented by WES in the realm of clinical diagnostics, shedding
light on its potential to revolutionize personalized medicine.
Unlocking Genetic Insights WES offers an unprecedented opportunity
to unlock the intricate secrets of our genetic makeup. By examining the exome,
which comprises approximately 1-2% of our entire genome but harbors many
disease-causing mutations, WES enables clinicians and researchers to identify
genetic variations associated with a wide array of medical conditions. From rare
genetic disorders to cancer predisposition and pharmacogenomics, WES
provides a comprehensive view of an individual's genetic profile. This wealth of
genetic information opens doors to precise diagnoses, personalized treatment
strategies, and the potential to improve patient outcomes.
Navigating Challenges and Hurdles However, with great promise come
significant challenges. WES introduces complexities in data analysis,
interpretation, and ethical considerations. The volume of genetic data generated
is vast, requiring advanced bioinformatics tools and expertise. Ensuring data
security and privacy is paramount, especially in the context of sensitive medical
information. Moreover, the cost-effectiveness and accessibility of WES in
clinical settings are important considerations to address. This article will delve
into these challenges and explore the strategies and solutions being developed
to harness the full potential of WES in clinical diagnostics.
The Path Forward As we stand at the intersection of genomics and
clinical medicine, the opportunities afforded by WES are nothing short of
transformative. The path forward involves collaborative efforts among clinicians,
geneticists, researchers, and policymakers to harness the potential of WES in
clinical diagnostics responsibly and effectively. In the sections that follow, we will
delve deeper into the challenges and opportunities, providing insights into the
evolving landscape of WES in healthcare and its pivotal role in shaping the
future of personalized medicine.
Pioneering Precision Medicine The introduction of Whole Exome
Sequencing (WES) into the realm of clinical diagnostics marks a pivotal moment
in the journey towards precision medicine. The human exome, encompassing
the coding regions of genes, contains a wealth of genetic information that plays
a central role in health and disease. WES, with its capability to sequence these
regions comprehensively, has emerged as a transformative tool for healthcare
professionals. It holds the promise of uncovering the genetic underpinnings of
complex diseases, enabling tailored treatments, and offering invaluable insights
into an individual's unique genetic makeup.
Challenges on the Diagnostic Horizon While WES offers a path to
unparalleled medical insights, it does not come without its set of challenges and
complexities. This article will delve into the hurdles faced in integrating WES
into clinical practice, including data interpretation, ethical considerations, and
cost-effectiveness. The analysis of vast genomic data generated by WES
demands sophisticated bioinformatics and data management solutions.
Safeguarding patient privacy and ensuring ethical use of genetic information are
of paramount concern. Additionally, questions related to the accessibility and
affordability of WES in diverse healthcare settings are pressing issues that
require careful navigation.
Bridging the Gap: Collaborative Solutions In response to these
challenges, researchers, clinicians, and policymakers are actively collaborating
to bridge the gap between the potential of WES and its practical application.
Initiatives to standardize data interpretation and clinical reporting are underway.
Efforts to streamline the cost and accessibility of WES for patients and
healthcare systems are being explored. Furthermore, discussions around the
ethical use of genetic information are shaping responsible guidelines. This
article will explore these collaborative solutions in-depth, shedding light on the
ongoing efforts to maximize the benefits of WES in clinical diagnostics.
Embarking on a Journey of Exploration As we embark on a journey of
exploration into the world of WES in clinical diagnostics, it is clear that the
challenges are matched by the immense opportunities. WES has the potential
to revolutionize how we diagnose and treat diseases, offering hope to
individuals facing rare genetic disorders and complex medical conditions. In the
upcoming sections, we will delve deeper into these challenges and
opportunities, offering a comprehensive understanding of the evolving
landscape of WES in clinical diagnostics and its transformative role in the
pursuit of precision medicine.
2. METHODOLOGY AND DEVELOPMENT
Literature Selection and Search Criteria The methodology for this
systematic review involved a comprehensive search of relevant scientific
literature from reputable databases such as PubMed, Web of Science, and
Google Scholar. A combination of keywords including "Whole Exome
Sequencing," "WES," "clinical diagnostics," and "precision medicine" was used
to identify scholarly articles, research papers, and reviews. We focused on
publications from the last decade to ensure relevance and up-to-date
information. To maintain the quality and reliability of sources, peer-reviewed
journals and articles were prioritized in the selection process.
Data Extraction and Synthesis Upon identifying relevant literature, a
systematic approach was applied to extract pertinent information. Key data
points included the clinical applications of WES, challenges encountered in its
implementation, emerging solutions, and ethical considerations. Each article
was scrutinized to extract insights related to the challenges and opportunities
associated with WES in clinical diagnostics. Data synthesis involved
categorizing findings into thematic areas, such as data interpretation, ethical
guidelines, cost-effectiveness, and collaborative efforts. This structured
approach allowed for a comprehensive analysis of the state-of-the-art in WES
for clinical use.
Quality Assessment and Bias Mitigation To maintain the quality and
rigor of this systematic review, a critical quality assessment was conducted on
the selected literature. Articles were evaluated based on the credibility of the
sources, research methodologies employed, and the relevance of the findings
to the topic of WES in clinical diagnostics. Additionally, efforts were made to
mitigate potential biases by considering diverse perspectives and including
studies that presented both challenges and opportunities. This approach
ensured a balanced and evidence-based review of the subject matter.
 Thematic Framework and Content Organization The findings from the
systematic review were organized into a thematic framework to provide a
coherent structure for the article. This framework guided the organization of the
subsequent sections, enabling a clear presentation of the challenges and
opportunities associated with WES in clinical diagnostics. By structuring the
content around these themes, the article aims to offer readers a comprehensive
understanding of the complexities and potential of WES as a transformative tool
in the field of healthcare.
Clinical Applications and Precision Medicine A prominent theme that
emerged from our systematic review is the diverse range of clinical applications
for Whole Exome Sequencing (WES). WES has proven instrumental in
diagnosing rare genetic disorders with elusive genetic origins, providing
answers to patients and their families who have long sought an accurate
diagnosis. Beyond rare diseases, WES is increasingly utilized in oncology,
allowing for the identification of somatic mutations in cancer genomes. This
information aids in tailoring treatments and predicting disease progression,
showcasing the pivotal role of WES in advancing precision medicine.
Data Interpretation and Bioinformatics Challenges While the clinical
applications of WES are promising, our review also highlighted the significant
challenge of data interpretation. The vast amount of genomic data generated by
WES necessitates sophisticated bioinformatics tools and expertise for accurate
and meaningful interpretation. This challenge extends to distinguishing
pathogenic variants from benign ones and understanding the clinical relevance
of genetic variations. Researchers and clinicians are actively working on
improving data analysis pipelines and developing standardized protocols to
enhance the accuracy and efficiency of data interpretation, thus addressing this
critical challenge.
Ethical Considerations and Informed Consent Ethical considerations
surrounding WES featured prominently in our review. The potential for the
inadvertent discovery of secondary findings, such as genetic predispositions to
other diseases, raises complex ethical dilemmas. Ensuring informed consent
and facilitating genetic counseling for patients undergoing WES are essential
steps in addressing these ethical concerns. Striking a balance between
providing patients with valuable health information and respecting their
autonomy and privacy is an ongoing challenge that healthcare providers and
policymakers must navigate carefully.
Collaborative Efforts and Future Directions Collaboration emerged as
a recurring theme throughout our systematic review. The challenges posed by
WES in clinical diagnostics are being met through concerted efforts among
clinicians, geneticists, bioinformaticians, and policymakers. Multidisciplinary
teams are working to establish best practices, develop ethical guidelines, and
optimize data-sharing mechanisms. Additionally, the integration of WES into
large-scale research initiatives, such as the Precision Medicine Initiative,
reflects the commitment to harnessing WES's full potential in clinical
diagnostics. As we move forward, fostering collaboration and addressing the
challenges outlined in this review will be pivotal in unlocking the vast
opportunities that WES offers in advancing precision medicine and improving
patient outcomes.
Cost-Effectiveness and Accessibility Our systematic review also
highlighted the critical issue of cost-effectiveness and accessibility associated
with WES. The high cost of sequencing and data analysis can pose barriers to
widespread adoption in clinical practice, limiting its accessibility to a broader
population. However, efforts are underway to reduce costs, including
advancements in sequencing technology and streamlined data analysis
processes. Policymakers and healthcare stakeholders are actively exploring
reimbursement models and insurance coverage to make WES more affordable
and accessible to patients, ensuring that the benefits of this technology are not
limited to a select few.
Continuous Advancements and Technological Innovation The rapidly
evolving nature of genomic technologies, including WES, was a recurring theme
in our review. Researchers and industry leaders continue to make significant
advancements, driving the field forward. These innovations encompass
improvements in sequencing accuracy, data processing speed, and the
development of more comprehensive exome capture kits. Additionally, the
integration of artificial intelligence and machine learning into bioinformatics tools
holds promise for enhancing data interpretation. As technology continues to
evolve, it is likely to address some of the challenges currently associated with
WES, opening new avenues for clinical diagnostics.
 Genetic Diversity and Representation Another notable aspect of our
review is the importance of genetic diversity and representation in genomic
research and clinical diagnostics. Many studies and databases predominantly
include populations of European ancestry, leading to disparities in genetic
knowledge and diagnostic accuracy for individuals from diverse backgrounds.
Addressing this bias is crucial to ensure equitable access to the benefits of
WES. Efforts are underway to include more diverse populations in genomic
research, with a focus on improving the representation of underrepresented
communities, thus promoting fairness and accuracy in clinical diagnostics.
Conclusion and Future Prospects In conclusion, our systematic review
underscores the transformative potential of Whole Exome Sequencing (WES) in
clinical diagnostics. While challenges persist, ranging from data interpretation to
ethical considerations and accessibility, collaborative efforts among
stakeholders offer promising solutions. The continuous advancements in
technology and the commitment to improving genetic diversity in research bode
well for the future of WES. As we move forward, it is imperative that we address
these challenges systematically to harness the full potential of WES in
personalized medicine, offering patients accurate diagnoses, tailored
treatments, and improved healthcare outcomes.
3. RESULTS
Personalized Medicine and Targeted Therapies One of the most
striking findings in our systematic review is the transformative impact of Whole
Exome Sequencing (WES) on personalized medicine and targeted therapies.
WES provides a comprehensive view of an individual's genetic makeup,
enabling clinicians to tailor treatments based on genetic variants. This approach
has been particularly promising in oncology, where targeted therapies can be
matched to specific genetic mutations, leading to improved treatment outcomes
and fewer side effects. The ability to identify rare and novel genetic variants
through WES has opened new avenues for precision medicine, fundamentally
reshaping the way we approach clinical diagnostics and treatment strategies.
Data Integration and Multi-Omics Approaches Our review also
highlighted the growing emphasis on data integration and multi-omics
approaches in conjunction with WES. Genomic information is just one piece of
the puzzle. Integrating WES data with other 'omics' data, such as
transcriptomics, proteomics, and metabolomics, provides a more holistic
understanding of disease mechanisms. This holistic approach has the potential
to uncover complex interactions, biomarkers, and therapeutic targets that might
be missed when focusing solely on genomic data. Collaborative initiatives and
bioinformatics tools are evolving to facilitate the integration of multi-omics data,
underscoring the importance of a comprehensive approach in clinical
diagnostics.
Ethical Challenges and Informed Consent Ethical considerations
continue to be a central concern in the context of WES. Our review revealed
ongoing debates and discussions regarding the handling of incidental findings,
informed consent, and data privacy. Balancing the benefits of WES with ethical
principles is a complex task. Ensuring that patients fully understand the
implications of genetic testing and incidental findings is crucial. Ethical
guidelines are being developed to provide clear frameworks for both clinicians
and researchers, emphasizing the importance of respecting patients' autonomy
and privacy while maximizing the potential benefits of WES.
Real-World Implementation and Health Economics Finally, the real-
world implementation of WES in clinical practice and the associated health
economics were recurring themes in our systematic review. While the clinical
benefits of WES are evident, challenges related to reimbursement, resource
allocation, and cost-effectiveness must be addressed. Policymakers and
healthcare providers are grappling with the integration of WES into healthcare
systems, considering the economic impact and long-term sustainability. Striking
a balance between clinical utility and cost-effectiveness is an ongoing challenge
that requires careful consideration as WES becomes more integral to routine
clinical diagnostics.
Whole Exome Sequencing (WES) has emerged as a powerful tool for
diagnosing rare and undiagnosed genetic disorders, demonstrating a
remarkable diagnostic yield across numerous studies (Retterer et al., 2016).
WES has the advantage of identifying more than one genetic condition, even
when the clinical presentation does not make it obvious that there is more than
one diagnosis (Retterer et al., 2016). It has facilitated targeted therapies and
personalized treatment plans, significantly improving the quality of care for
individuals with rare diseases (Retterer et al., 2016). The diagnostic yield of
WES has been estimated to be >50% if implemented currently as a first-line test
for developmental disorders (Wright et al., 2018). Clinical implementation of
WES has revolutionized genetic diagnostics of individuals suspected of having
a Mendelian disorder by improving diagnostic yield and accelerating the
discovery of novel disease genes (Yépez et al., 2022). Furthermore, WES has
been shown to increase the diagnostic yield for genetically heterogeneous
(monogenic) disorders to up to 58%, depending on the clinical preselection of
the cohort and subset(s) of genes analyzed (Deden et al., 2020).
The diagnostic yield of WES has been steadily improving, and it has
been critical and effective in diagnosing patients with neurodevelopmental
disorders (Trinh et al., 2019). Additionally, WES has been shown to be highly
relevant in prenatal diagnostics, with the ability to detect single gene causes of
nonimmune hydrops fetalis and fetal structural anomalies (Gabriel et al., 2021).
Moreover, WES has been used successfully for diagnostics of genetic diseases
in critically ill neonates and infants, with a significant diagnostic yield for
monogenic disorders (Scholz et al., 2021). The mean molecular diagnostic yield
of WES in neurodevelopmental disorders has been reported to be 35% for
intellectual disability or neurodevelopmental delay, 45% for epilepsy, and 15%
for autism spectrum disorder, all of which are known cerebral palsy
comorbidities (Moreno-De-Luca et al., 2021).
Advancements in Cancer Genomics and Treatment Our review
underscored the significant advancements in cancer genomics and treatment
enabled by WES. The systematic analysis of tumor genomes using WES has
enabled the identification of driver mutations and the development of targeted
therapies. These therapies, tailored to the genetic profile of the tumor, have
shown promise in improving patient outcomes and minimizing adverse effects.
Furthermore, WES has played a crucial role in unraveling the complexity of
cancer genomes, shedding light on the intricate interplay of genetic alterations.
As a result, it has become a cornerstone in advancing precision oncology and
has the potential to revolutionize cancer diagnostics and treatment strategies.
Challenges in Data Interpretation and Bioinformatics While the
benefits of WES are evident, the review highlighted persistent challenges in
data interpretation and bioinformatics. The sheer volume of data generated by
WES necessitates sophisticated algorithms and computational tools for
accurate variant calling and clinical interpretation. Researchers and clinicians
continue to grapple with distinguishing pathogenic variants from benign ones,
particularly in the context of rare genetic disorders. Standardized pipelines and
rigorous quality control measures are essential to ensure the reliability and
reproducibility of WES results. Addressing these bioinformatics challenges
remains crucial to maximizing the clinical utility of WES.
Ethical and Social Implications Ethical considerations emerged as a
significant theme in the systematic review. The potential for the incidental
discovery of secondary findings, including genetic predispositions to other
diseases, poses ethical dilemmas. Ensuring informed consent, offering genetic
counseling, and defining the boundaries of what findings should be reported are
topics of ongoing debate. Additionally, issues related to data privacy and
protection were underscored, emphasizing the importance of robust ethical
frameworks in the use of WES. Navigating these ethical and social implications
is essential as WES becomes more integrated into clinical practice.
4. FINAL CONSIDERATIONS
Advancements in Rare Disease Research The systematic review
further highlighted the significant advancements in rare disease research
facilitated by Whole Exome Sequencing (WES). Researchers have leveraged
WES to not only diagnose rare genetic disorders but also to expand our
understanding of the genetic underpinnings of these conditions. The compilation
of extensive genomic data has enabled the discovery of novel disease-causing
genes, providing critical insights into disease mechanisms. Moreover,
collaborative efforts in data sharing and international consortia have accelerated
the pace of rare disease gene discovery. These findings hold the promise of
developing targeted therapies for conditions that were previously considered
untreatable, underscoring the transformative potential of WES in the field of rare
diseases.
Integration of Genomic Data into Clinical Practice Our review revealed
a growing trend in the integration of genomic data into routine clinical practice.
Healthcare institutions and genetic clinics are increasingly adopting WES as
part of their diagnostic toolkit. This integration has been particularly pronounced
in pediatric and neonatal care, where timely diagnosis can be a matter of life
and death. Clinicians are leveraging WES to offer precise diagnoses, inform
treatment decisions, and provide families with valuable prognostic information.
The rise of multidisciplinary teams, consisting of geneticists, clinicians, and
bioinformaticians, has been pivotal in translating genomic data into actionable
clinical insights.
Challenges in Genetic Counseling and Informed Decision-Making
While the clinical utility of WES is evident, the review also highlighted
challenges in the realm of genetic counseling and informed decision-making.
Patients and their families often grapple with complex genetic information,
making informed choices about potential treatments and reproductive decisions
more intricate. Genetic counseling services are essential in helping individuals
comprehend the implications of WES results. Moreover, ensuring that
individuals have access to these services and receive culturally sensitive
support is an ongoing challenge. Addressing these issues is crucial for ethical
and responsible implementation of WES in clinical diagnostics.
The Future of Clinical Genomics In conclusion, the systematic review
underscores the pivotal role of Whole Exome Sequencing (WES) in advancing
clinical genomics. The technology's ability to diagnose rare diseases, inform
cancer treatment decisions, and expand our genetic knowledge is
transformative. However, it is not without its challenges, from data interpretation
to ethical considerations. As we look to the future, continued research,
international collaboration, and ethical frameworks will be essential in
harnessing the full potential of WES. The integration of genomics into clinical
practice is likely to become increasingly common, offering patients more precise
diagnoses, personalized treatment options, and the hope for improved
healthcare outcomes.
Personalized Medicine and Beyond As the systematic review
culminates, it becomes evident that Whole Exome Sequencing (WES) has
ushered in an era of personalized medicine with unprecedented potential. The
ability to decipher an individual's exome – the functional portion of their genome
– enables healthcare providers to tailor treatments with pinpoint accuracy. By
identifying genetic mutations and variants, clinicians can match therapies to the
unique genetic makeup of patients, increasing treatment efficacy and
minimizing side effects. This marks a significant leap forward in the evolution of
healthcare, aligning with the broader trend of precision medicine.
 Collaborative Research and Data Sharing Throughout the review, the
importance of collaborative research and data sharing in the realm of WES is
underscored. Genomic data is most valuable when it is part of a large, diverse
dataset. Collaborative initiatives, such as international consortia and data-
sharing platforms, play a pivotal role in advancing our understanding of
genomics and rare diseases. The cooperative spirit of the scientific community
in sharing data and insights not only accelerates research but also enhances
the chances of identifying new disease-causing genes and potential therapeutic
targets.
Ethical Considerations and Informed Consent The ethical
considerations surrounding WES cannot be overstated. The review has shed
light on the complex issues related to informed consent, incidental findings, and
data privacy. Ensuring that patients fully understand the implications of WES
and providing them with the option to consent to various levels of genetic
information disclosure is an ongoing challenge. Balancing the pursuit of medical
knowledge with the protection of individuals' genetic privacy requires
comprehensive ethical frameworks. The healthcare community must continue to
address these concerns to ensure responsible and patient-centered
implementation of WES.
A Path Forward in Clinical Genomics In conclusion, the systematic
review presents a compelling case for the transformative role of Whole Exome
Sequencing (WES) in clinical diagnostics. Its ability to diagnose rare diseases,
guide cancer treatment decisions, and revolutionize personalized medicine is
evident. However, the journey ahead involves not only technical advancements
but also a commitment to ethical and responsible practices. The path forward in
clinical genomics lies in fostering collaboration, sharing data, upholding ethical
standards, and ensuring equitable access to the benefits of WES. As WES
continues to evolve, it holds the promise of improving the lives of countless
individuals, making healthcare more precise, and unlocking the mysteries of the
human genome.
 REFERENCES
Deden, C., Neveling, K., Zafeiropopoulou, D., Gilissen, C., Pfundt, R., Rinne, T.,
… & Zelst-Stams, W. (2020). Rapid whole exome sequencing in pregnancies to
identify the underlying genetic cause in fetuses with congenital anomalies
detected by ultrasound imaging. Prenatal Diagnosis, 40(8), 972-983.
https://doi.org/10.1002/pd.5717
Gabriel, H., Korinth, D., Ritthaler, M., Schulte, B., Battke, F., Kaisenberg, C., …
& Biskup, S. (2021). Trio exome sequencing is highly relevant in prenatal
diagnostics. Prenatal Diagnosis, 42(7), 845-851.
https://doi.org/10.1002/pd.6081
Moreno-De-Luca, A., Millan, F., Pesacreta, D., Elloumi, H., Oetjens, M., Teigen,
C., … & Martin, C. (2021). Molecular diagnostic yield of exome sequencing in
patients with cerebral palsy. Jama, 325(5), 467.
https://doi.org/10.1001/jama.2020.26148
Retterer, K., Juusola, J., Cho, M., Vitazka, P., Millan, F., Gibellini, F., … & Bale,
S. (2016). Clinical application of whole-exome sequencing across clinical
indications. Genetics in Medicine, 18(7), 696-704.
https://doi.org/10.1038/gim.2015.148
Scholz, T., Blohm, M., Kortüm, F., Bierhals, T., Lessel, D., Ven, A., … & Hempel,
M. (2021). Whole-exome sequencing in critically ill neonates and infants:
diagnostic yield and predictability of monogenic diagnosis. Neonatology, 118(4),
454-461. https://doi.org/10.1159/000516890
Trinh, J., Kandaswamy, K., Werber, M., Weiss, M., Oprea, G., Kishore, S., … &
Rolfs, A. (2019). Novel pathogenic variants and multiple molecular diagnoses in
neurodevelopmental disorders. Journal of Neurodevelopmental Disorders,
11(1). https://doi.org/10.1186/s11689-019-9270-4
Wright, C., McRae, J., Clayton, S., Gallone, G., Aitken, S., Fitzgerald, T., … &
Firth, H. (2018). Making new genetic diagnoses with old data: iterative
reanalysis and reporting from genome-wide data in 1,133 families with
developmental disorders. Genetics in Medicine, 20(10), 1216-1223.
https://doi.org/10.1038/gim.2017.246
Yépez, V., Gusic, M., Kopajtich, R., Mertes, C., Smith, N., Alston, C., … &
Prokisch, H. (2022). Clinical implementation of rna sequencing for mendelian
disease diagnostics. Genome Medicine, 14(1). https://doi.org/10.1186/s13073-
022-01019-9