Exome first approach to reduce diagnostic costs and time – retrospective analysis of 111 individuals with rare neurodevelopmental disorders

Klau, Julia; Jamra, Rami Abou; Radtke, Maximilian; Oppermann, Henry; Lemke, Johannes R.; Beblo, Skadi; Popp, Bernt

doi:10.1038/s41431-021-00981-z

Cited by 28 publications

(21 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Through the bibliometric study carried out in this review, and the subsequent manual analyses, we found that exome sequencing was the most prevalent sequencing approach in the field, and that rare neoplastic diseases were the most prevalent clinical scenario. Exome sequencing continues to be a good starting point for the genetic diagnosis of RDs, as it provides a cost-effective and efficient way to identify disease-causing variants 20 . However, depending on the specific rare disease context, genome sequencing may be necessary to provide a complete diagnosis, including the analysis of non-coding variations, CNVs, or chromosomal rearrangements 21,22 .…”

Section: Discussionmentioning

confidence: 99%

A systematic review on machine learning approaches in the diagnosis of rare genetic diseases

Roman‐Naranjo

Parra-Perez

López-Escámez

2023

Preprint

View full text Add to dashboard Cite

Background: The diagnosis of rare genetic diseases is often challenging due to the complexity of the genetic underpinnings of these conditions and the limited availability of diagnostic tools. Machine learning (ML) algorithms have the potential to improve the accuracy and speed of diagnosis by analyzing large amounts of genomic data and identifying complex multiallelic patterns that may be associated with specific diseases. In this systematic review, we aimed to identify the methodological trends and the ML application areas in rare genetic diseases. Methods: We performed a systematic review of the literature following the PRISMA guidelines to search studies that used ML approaches to enhance the diagnosis of rare genetic diseases. Studies that used DNA-based sequencing data and a variety of ML algorithms were included, summarized, and analyzed using bibliometric methods, visualization tools, and a feature co-occurrence analysis. Findings: Our search identified 22 studies that met the inclusion criteria. We found that exome sequencing was the most frequently used sequencing technology (59%), and rare neoplastic diseases were the most prevalent disease scenario (59%). In rare neoplasms, the most frequent applications of ML models were the differential diagnosis or stratification of patients (38.5%) and the identification of somatic mutations (30.8%). In other rare diseases, the most frequent goals were the prioritization of rare variants or genes (55.5%) and the identification of biallelic or digenic inheritance (33.3%). The most employed method was the random forest algorithm (54.5%). In addition, the features of the datasets needed for training these algorithms were distinctive depending on the goal pursued, including the mutational load in each gene for the differential diagnosis of patients, or the combination of genotype features and sequence-derived features (such as GC-content) for the identification of somatic mutations. Conclusions: ML algorithms based on sequencing data are mainly used for the diagnosis of rare neoplastic diseases, with random forest being the most common approach. We identified key features in the datasets used for training these ML models according to the objective pursued. These features can support the development of future ML models in the diagnosis of rare genetic diseases. Keywords: artificial intelligence, rare diseases, precision medicine, rare variants, DNA-sequencing, genomics

show abstract

Section: Discussionmentioning

confidence: 99%

A systematic review on machine learning approaches in the diagnosis of rare genetic diseases

Roman‐Naranjo

Parra-Perez

López-Escámez

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The occurrence of NCDs with a high incidence rate among a population affects both public health and the healthcare system by affecting individuals’ productivity and increasing their absenteeism due to the disease itself and/or its consequences, such as emotional wellbeing or increasing the caregiver burden. Studies indicate that more than one-third of the healthcare system’s resources is spent on patients with genetic, chromosomal, or congenital disorders [ 13 , 14 , 15 , 16 , 17 ]. Consequences resulting from the increase in the number of individuals with lifetime health issues contradict the public health recommendation (No.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Consanguineous Marriage among Saudi Citizens of Albaha, a Cross-Sectional Study

Albanghali

2023

IJERPH

View full text Add to dashboard Cite

Consanguineous marriage (CM) is a prevalent kind of relationship in Muslim and Arab countries, and this type of relationship is linked to several health risks. This study was conducted to determine the prevalence of (CM), its associated hereditary diseases, and health-related issues among Saudi citizens in Albaha. This cross-sectional study was conducted between March 2021 to April 2021. Saudi citizens in Albaha who were aged ≥ 18 years and willing to participate were eligible for the study. A total of 1010 participants were included in this study. In total, 757 participants were married, widowed, or divorced. CM partnerships comprised 40% (N = 302) of the marriages among participants, of which first- and second-cousin marriages comprised 72% and 28%, respectively. The prevalence of CM among the participants’ parents was lower than that among the participants (31% versus 40%, respectively). Children of participants in a CM were more likely to have cardiovascular diseases (p < 0.001), blood diseases (anaemia, thalassemia) (p < 0.001), cancer (p = 0.046), hearing loss and speech disorder (p = 0.003), and ophthalmic diseases (p = 0.037). Albaha showed a high percentage of consanguinity. An educational program must be established to enhance the population’s knowledge of the consequences of CM. The current national premarital screening program should be extended to involve more screening tests for common hereditary diseases that result from CM.

show abstract

“…Heterogeneity, with multiple nonspecific features, suggests a genetic-first approach; therefore, whole-exome sequencing (WES), which covers the entire coding sequence, is becoming the current standard of care [ 8 , 9 , 10 , 11 ]. The literature emphasizes the “exome first” approach as the first-line test in the diagnostic pathway of individuals with NDDs and/or epilepsy and highlights the accelerating impact on diagnostic time intervals and reduced costs [ 12 , 13 ]. The currently achievable diagnostic yield of WES in DEE S is 31–53% [ 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

Musante

Costa

Zanus

et al. 2022

Genes

View full text Add to dashboard Cite

Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.

show abstract

Exome first approach to reduce diagnostic costs and time – retrospective analysis of 111 individuals with rare neurodevelopmental disorders

Cited by 28 publications

References 41 publications

A systematic review on machine learning approaches in the diagnosis of rare genetic diseases

A systematic review on machine learning approaches in the diagnosis of rare genetic diseases

Prevalence of Consanguineous Marriage among Saudi Citizens of Albaha, a Cross-Sectional Study

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

Contact Info

Product

Resources

About