Chromosomal Microarrays for the Etiologic Diagnosis in Patients with Intellectual Disability, Developmental Delay or Autism Spectrum

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.ASD is characterized by socialization, communication and behavior disorders. Its prevalence is estimated in 60?70/10,000 subjects.ID/DR and ASD etiopathogenesis is multifactorial, therefore, their diagnosis is clinical and make use of structured interviews or specific tests.The purpose of genetic testing is reproductive counseling and the identification of specific treatments and genetic anomalies with medical vulnerabilities. It is generally carried out by g-banding karyotyping and it shows a diagnostic yield near 3%. Sometimes, subtelomeric fluorescent in situ hybridization is added, thus increasing performance by an additional 3 %. The use of chromosomal microarrays is proposed to increase the etiologic diagnostic yield in patients with ID/DD or AST replacing or supplementing the above mentioned techniques.TechnologyChromosomal Microarrays (CMA) are panels with DNA probes to which the patient´s DNA is exposed. There are those based on array comparative genomic hybridization (aHGC) and single-nucleotide polymorphism (SNP). CMAs may be specific or targeted when including known clinically relevant genomic areas or whole genome when they have probes for the entire genome. Their resolution and specificity depend on the number of probes and the distance between the represented sequences in the genome.PurposeTo assess the evidence available on the diagnostic usefulness, safety and coverage policy related aspects on the use of chromosomal microarrays in the etiologic diagnosis of ID/DD or AST patients.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 (GPCs) and coverage policies of other health systems.ResultsOne systematic review (SR), 1 Expert Consensus, 5 GPCs, 20 case series and 8 coverage policies were identified.Diagnostic Performance and Operating Characteristics:In a SR published in 2009 including 19 studies (13,925 patients with ID/DD plus congenital anomalies), 10% of the patients were found genetic anomalies considered pathological (95%CI, 8%?12%) of different types among the studies analyzed. The number needed to test (NNT) in order to identify a causal variant was 10 and the range of false positive findings was 1% to 67%.Eighteen case series reported diagnostic yield in patients with ASD ranging from 4% in non-syndromic ASD to 27% in syndromic cases. A series published in 2010 stands out; it describes that CMA was carried out in 848 ASD patients showing a diagnostic yield of 7% (95%CI 5.5%-8.5%) and 11% of false positive results.The Impact of CMA on Clinical ManagementIn a case series published in 2012 including 46,298 patients, in 5.4% genetic disorders requiring a specific clinical approach were detected.In 2011, in a series of 1,792 cases, 54% out of 7.3% of the patients who presented pathological mutations, received a specific clinical recommendation.Two American Association of Pediatrics´ guidelines consider the technology as experimental. The American Academy of Child and Adolescent Psychiatry considers it is a possible alternative in ASD. On the other hand, the American College of Medical Genetics recommends it as first line in ASD, keeping the conventional karyotype for cases where aneuploidy is strongly suspected and the International Standard for Cytogenomic Arrays Consortium considers it is first line both in ASD and in ID/DD or congenital anomalies. Finally the English National Institute for Health and Care Excellence considers that, in ASD, it has a higher diagnostic performance than standard practices if there are dysmorphias and/or comorbid ID, but that its diagnostic performance should be better understood and the potential negative consequences of its use should be identified prior to using it in a wider population.The eight coverage policies identified, all of them from the United States, showed variability. Four health sponsors agree that the technology is experimental for this indication. Two of them require the presence of malformations and potential impact of the result on the patient´s clinical management to grant its coverage. Two health sponsors consider it is medically necessary.ConclusionsThe quality of evidence to consider that CMA have a higher diagnostic performance than conventional genetic tests. The evidence related to the impact of its results on clinical management and patient evolution is low quality. The potential impact of false positive results is unknown. Therefore, there is much controversy on its use in patients without dysmorphias or with highly suspected genetic etiology.