{"id":2810,"date":"2022-10-01T21:23:37","date_gmt":"2022-10-01T21:23:37","guid":{"rendered":"https:\/\/neuropediatoolbox.org\/?p=2810"},"modified":"2026-06-22T16:50:37","modified_gmt":"2026-06-22T16:50:37","slug":"estirando-de-la-cuerda-cuando-el-diagnostico-no-llega-a-la-primera","status":"publish","type":"post","link":"https:\/\/neuropediatoolkit.org\/en\/estirando-de-la-cuerda-cuando-el-diagnostico-no-llega-a-la-primera\/","title":{"rendered":"Pulling the rope. What to do when a diagnosis is not reached."},"content":{"rendered":"

We are evaluating a child with a neurodevelopmental disorder, in whom we suspect a genetic cause because they present suggestive findings (such as associated multiple congenital malformations). We have performed an aCGH<\/a> which turned out to be normal. We have also performed a clinical exome (mendeliome)<\/a> which has not provided us with conclusive information. Where do we go from here?<\/p>\n\n\n\n

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Re-evaluate variants of uncertain significance.<\/div><\/summary>
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There may be a possibility of reclassifying them; review the guideline on this.<\/a><\/p>\n<\/div><\/details>\n\n\n\n

Review the appendices of the genetic report for relevant information.<\/div><\/summary>
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The geneticist may have identified a pathogenic variant in a recessive gene<\/strong>, that is compatible with your clinical suspicion, but not finding a second pathogenic variant, they did not report it in the main body text. If the phenotype is consistent with the clinical suspicion, you may need to continue investigating: <\/p>\n\n\n\n

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Make sure there is no variant of uncertain significance on the other allele.<\/div><\/summary>
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To confirm this, it is necessary to perform a parental segregation study; if both variants are found in trans, your suspected diagnosis will be strengthened. <\/p>\n<\/div><\/details>\n\n\n\n

Check for the existence of biomarkers.<\/div><\/summary>
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If the autosomal recessive gene has biomarkers<\/a> that allow its study, it can be an efficient strategy to perform a targeted study (enzymatic, biochemical) and, if abnormalities are detected, perform more sophisticated diagnostic tests (RNA sequencing) looking for deep intronic mutations. <\/p>\n<\/div><\/details>\n\n\n\n

Consider the possibility of performing an MLPA of the affected gene.<\/div><\/summary>
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Several mutational mechanisms may combine (compound heterozygosity<\/a>), bear in mind that small deletions<\/a> may have gone undetected in both tests (exome and aCGH). <\/p>\n\n\n\n

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https:\/\/bmcmedgenomics.biomedcentral.com\/articles\/10.1186\/s12920-021-01053-3<\/figcaption><\/figure>\n\n\n\n

https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3759716\/<\/a><\/p>\n<\/div><\/details>\n<\/div>\n<\/div><\/details>\n\n\n\n

Review the possibility that it is a disease not diagnosable by sequencing.<\/div><\/summary>
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There are some genetic diseases not diagnosable by exome sequencing<\/a> with currently available technology. If the phenotype is compatible with any of them, it may be necessary to request specific diagnostic tests. <\/p>\n<\/div><\/details>\n\n\n\n

Re-evaluate the phenotype periodically in search of new orienting symptoms.<\/div><\/summary>
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You can try to refine your phenotypic description<\/a> using the HPO codes. This will make it easier for the geneticist to apply computer filters for data re-analysis.<\/p>\n\n\n\n

With the phenotypic description using HPO codes, you can use computerized differential diagnosis tools, such as phenomyzer<\/a>.<\/p>\n<\/div><\/details>\n\n\n\n

Ask your geneticist to re-analyze the raw sequencing data after 2-5 years if they have not done so automatically. <\/div><\/summary>
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There are multiple scientific publications showing an increase of between 10-15% in diagnostic yield through the re-analysis of sequencing data 12-24 months after it was performed. This is a consequence of the rapid accumulation of scientific knowledge that is taking place: <\/p>\n\n\n\n