Whole Exome Sequencing for Patients with Intellectual Disability/Mental Retardation or ASD

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; ALCARAZ, A.; GLUJOVSKY, D.; LOPEZ, A.; REY-ARES, L.; BARDACH, A.; CIAPPONI, A; SOTO, N

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Intellectual Disability or Developmental Delay (ID/DD), and Autism Spectrum Disorders (ASD) are neurodevelopmental disorders defined by the presence of alterations in the brain function affecting a child´s behavior, memory or learning capacity.ID is characterized by the presence of intellectual and adaptative performance deficits. Its prevalence is estimated in 10/1,000 subjects.ASDs are characterized by socialization, communication and behavior disorders. Its prevalence is estimated in 60?70/10,000 subjects.ID/DD and ASD etiopathogenesis is multifactorial; therefore, their diagnosis is clinical and makes use of structured interviews or specific tests.Genetic testing for reproductive counseling and to identify specific treatments and genetic anomalies with medical vulnerabilities is indicated. It is generally carried out by g-banding kariotyping and it shows a diagnostic performance near 3%. Sometimes, fluorescent in situ hybridization (FISH) with subtelomeric probes is added, thus increasing performance by an additional 3 %. In the last past years, chromosomal microarray analysis has been increasingly used, achieving an etiological identification of up to 27% of the cases in some groups of patients.The use of Whole Exome Sequencing using new generation techniques is proposed for etiologic identification in patients with ID/DD or ASD where the results of the mentioned tests and others indicated had been negative.TechnologyWhole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) belong to the Next Generation Sequencing (NGS) or Massively Parallel Sequencing (MPS) techniques which allow rapid sequencing of a great number of DNA segments.WGS implies determining the sequence of great part of the DNA content which forms the whole genome of an individual.WES is a less expensive alternative. The exome comprises approximately 1% of the genome and it is the component encoding protein production. So far, it is the component most likely to include interpretable mutations resulting in clinical phenotypes.It has its limitations. It does not detect variants in non-coding regulatory regions or certain types of mutations. In addition, the exome capturing methods (for later sequencing) may not capture all the exones in one gene and an insufficient depth of coverage may mask pathogenic variants. The depth of coverage is the number of ?readings? or sequences generated from a DNA fragment produced at a nucleotide base level. A greater depth of coverage allows reducing the extent of the sequencing error.Result interpretation is complex and cannot always be solved. Additionally, there is a potential of secondary or incidental findings, not related with the test indication, but of value for the patient. Its reporting and documenting in databases is a strong ethical and clinical dilemma.PurposeTo assess the available evidence on the efficacy, safety and issues related with coverage policies on the use of Whole Exome Sequencing in patients with Intellectual Disability/Mental Retardation or Autism Spectrum Disorders with negative result in genetic evaluations using other tests.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsOne case series, one coverage policy, one clinical practice guideline and one policy statement were identified. No RCTs or SRs were identified.In one case series of 100 patients with an IQ below 50, published in 2012, WES was performed to the patients and parents (trios). The patients had already undergone diagnoses which included genomic profile using SNP Microarrays, tests targeted to specific genes and other indicated tests; all of them had a negative result. Diagnostic performance was 13% (ID/DD-related gene mutations were found in 13 patients).An American College of Medical Genetics and Genomics clinical genetic evaluation guideline for patients with ASD, reviewed in 2013, just states that new generation sequencing techniques will increase etiology diagnostic performance in the next few years.An US health sponsor considers this technology is experimental for all indications.ConclusionsAt present, there is scarce evidence supporting the use of WES for etiologic diagnosis in patients with ID/DD or ASD. Furthermore, the use of this technology in daily clinical practice presents negative potentially unknown effects to date as well as ethical dilemmas related to incidental findings in the analysis of genetic material in these patients.