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

Multiple congenital anomalies and developmental delay in a boy associated with a de novo 16p13.3 deletion

We describe a patient with multiple congenital anomalies including tracheobronchomalacia, CT-proven metopic craniosynostosis, glandular hypospadias and severe ventral chordee, torticollis, esotropia, strabismus, fifth finger clinodactyly, hallux valgus, and global developmental delay. Using high resolution chromosomal microarray analysis, we identified a de novo deletion of 555 kb on chromosome 16p13.3, 444 kb telomeric to the CREBBP gene and 623 kb centromeric of PKD1. Review of the literature revealed numerous reports of individuals with deletions involving adjacent regions including CREBBP, but only one overlapping with this isolated region of 16p13.3. Haploinsufficiency for one or more of the 25 candidate genes in the deleted genomic region may be responsible for these clinical features. No copy number variants (CNVs) span the entire region, but several small CNVs within the 555 kb genomic region reduce the likelihood for effects due to haploinsufficiency to 18 genes. © 2011 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83208/1/33808_ftp.pd

Chromosomal Imbalances in Patients with Congenital Cardiac Defects: A Meta‐analysis Reveals Novel Potential Critical Regions Involved in Heart Development

ObjectiveCongenital cardiac defects represent the most common group of birth defects, affecting an estimated six per 1000 births. Genetic characterization of patients and families with cardiac defects has identified a number of genes required for heart development. Yet, despite the rapid pace of these advances, mutations affecting known genes still account for only a small fraction of congenital heart defects suggesting that many more genes and developmental mechanisms remain to be identified.DesignIn this study, we reviewed 1694 described cases of patients with cardiac defects who were determined to have a significant chromosomal imbalance (a deletion or duplication). The cases were collected from publicly available databases (DECIPHER, ISCA, and CHDWiki) and from recent publications. An additional 68 nonredundant cases were included from the University of Michigan. Cases with multiple chromosomal or whole chromosome defects (trisomy 13, 18, 21) were excluded, and cases with overlapping deletions and/or insertions were grouped to identify regions potentially involved in heart development.ResultsSeventy‐nine chromosomal regions were identified in which 5 or more patients had overlapping imbalances. Regions of overlap were used to determine minimal critical domains most likely to contain genes or regulatory elements involved in heart development. This approach was used to refine the critical regions responsible for cardiac defects associated with chromosomal imbalances involving 1q24.2, 2q31.1, 15q26.3, and 22q11.2.ConclusionsThe pattern of chromosomal imbalances in patients with congenital cardiac defects suggests that many loci may be involved in normal heart development, some with very strong and direct effects and others with less direct effects. Chromosomal duplication/deletion mapping will provide an important roadmap for genome‐wide sequencing and genetic mapping strategies to identify novel genes critical for heart development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111936/1/chd12179.pd