Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar

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 â likely pathogenicâ (LP) or â pathogenicâ (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 reâ evaluation. Of 246 CNVs reâ 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.The ClinGen Dosage Sensitivity (DS) Map provides evidenceâ based assessments of the haploinsufficiency and triplosensitivity of genes/genomic regions. We identified 251 clinical copy number variants (CNVs) in ClinVar that overlapped known DS genes/regions but were not interpreted as â likely pathogenicâ or â pathogenic;â these were sent back to their original laboratories for reâ evaluation. Of the 246 that were reâ evaluated, 63.0% resulted in updated classifications, showing that the ClinGen DS Map can be an effective initial step in CNV classification discrepancy resolution.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146425/1/humu23610_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146425/2/humu23610.pd

Partial Deletion of ANKRD11 Results in the KBG Phenotype Distinct from the 16q24.3 Microdeletion Syndrome

KBG syndrome (OMIM 148050) is a very rare genetic disorder characterized by macrodontia, distinctive craniofacial abnormalities, short stature, intellectual disability, skeletal, and neurologic involvement. Approximately 60 patients have been reported since it was first described in 1975. Recently mutations in ANKRD11 have been documented in patients with KBG syndrome, and it has been proposed that haploinsufficiency of ANKRD11 is the cause of this syndrome. In addition, copy number variation in the 16q24.3 region that includes ANKRD11 results in a variable phenotype that overlaps with KBG syndrome and also includes autism spectrum disorders and other dysmorphic facial features. In this report we present a 2½-year-old African American male with features highly suggestive of KBG syndrome. Genomic microarray identified an intragenic 154 kb deletion at 16q24.3 within ANKRD11. This child\u27s mother was mosaic for the same deletion (present in approximately 38% of cells) and exhibited a milder phenotype including macrodontia, short stature and brachydactyly. This family provides additional evidence that ANKRD11 causes KBG syndrome, and the mild phenotype in the mosaic form suggests that KBG phenotypes might be dose dependent, differentiating it from the more variable 16q24.3 microdeletion syndrome. This family has additional features that might expand the phenotype of KBG syndrome

Detection of Chromosomal Aberrations by a Whole-Genome Microsatellite Screen

Chromosomal aberrations are a common cause of multiple anomaly syndromes that include developmental and growth retardation. Current microscopic techniques are useful for the detection of such aberrations but have a limit of resolution that is above the threshold for phenotypic effect. We hypothesized that a genomewide microsatellite screen could detect chromosomal aberrations that were not detected by standard cytogenetic techniques in a portion of these individuals. To test this hypothesis, we performed a genomewide microsatellite screen of patients, by use of a currently available genetic-marker panel that was originally designed for meiotic mapping of Mendelian traits. We genotyped ∼400 markers on 17 pairs of parents and their children who had normal karyotypes. By using this approach, we detected and confirmed two cases of segmental aneusomy among 11 children with multiple congenital anomalies. These data demonstrate that a genomewide microsatellite scan can be used to detect chromosomal aberrations that are not detected by microscopic techniques