Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.
Detection of copy number variations (CNVs) is a first-tier clinical diagnostic test for children with neurodevelopmental disorders (NDD), which reveals the genetic cause of the disorder in more than 20%. These are mostly known microdeletion/microduplication syndromes, but variants of unknown clinical significance (VOUS) and ambiguous CNVs can also be detected. An example of the last two are abnormalities in the DOCK8 gene. Conflicting interpretations of CNVs affecting DOCK8 can be found in the literature. Deletions were predicted to have a impact in carriers with variable clinical manifestations, where duplications have been proposed as benign variants. In our study, CNV screening was performed in a cohort involving 439 probands with suspected NDD. We identified known microdeletion/microduplication syndromes in 19% and VOUS CNVs in 8% of patients. Among these, three patients had a CNV encompassing the DOCK8 gene. Although diverse clinical presentations are noted in our three patients, comparison of their phenotypes revealed that abnormalities in cognition and communication, aggressive behaviour and mood swings are common to all of them. Therefore, a clinical relevance, in terms of influencing the psychiatric clinical picture of patients, is proposed for the CNVs disrupting the DOCK8 gene, regardless of whether it is a deletion or duplication.
The introduction of array CGH in clinical diagnostics has led to the discovery of many new microdeletion/microduplication syndromes. Most of them are rare and often present with a variable range of clinical anomalies. In this study we report three patients with a de novo overlapping microdeletion of chromosome bands 12q15q21.1. The deletions are similar to 2.5Mb in size, with a 1.34-Mb common deleted region containing six RefSeq genes. All three patients present with learning disability or developmental delay, nasal speech and hypothyroidism. In this paper we will further elaborate on the genotype-phenotype correlation associated with this deletion and compare our patients with previously reported cases
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