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 "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation.

Behavioral characterization of a white-throated sparrow homozygous for the ZAL2(m) chromosomal rearrangement.

The white-throated sparrow is rapidly becoming an important model in the genetics of social behavior because of a chromosomal rearrangement that segregates with a behavioral phenotype. Within a population, 50 % of individuals are heterozygous for a rearranged chromosome 2 (ZAL2(m)). These birds sing more and are more aggressive than the other 50 %, who lack the rearrangement.

Chromosomal microarray versus karyotyping for prenatal diagnosis.

Background: Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis.

Methods: Samples from women undergoing prenatal diagnosis at 29 centers were sent to a central karyotyping laboratory.

Cleft palate in a multigenerational family with a microdeletion of 20p12.3 involving BMP2.

Cleft palate (CP) is a frequent and recognizable birth defect attributed to a variety of etiologies including genetic abnormalities and environmental exposures. Bone morphogenetic proteins (BMPs) are involved in embryonic signaling important for a number of developmental processes including bone formation and palate morphogenesis. Recently, haploinsufficiency of BMP2 was associated with syndromic forms of CP.

An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.

Purpose: Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care.

Segmental duplications mediate novel, clinically relevant chromosome rearrangements.

Copy number studies have led to an explosion in the discovery of new segmental duplication-mediated deletions and duplications. We have analyzed copy number changes in 2419 patients referred for clinical array comparative genomic hybridization studies. Twenty-three percent of the abnormal copy number changes we found are immediately flanked by segmental duplications > or =10 kb in size and > or =95% identical in direct orientation, consistent with deletions and duplications generated by non-allelic homologous recombination.

Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray.

Purpose: Array comparative genomic hybridization is rapidly becoming an integral part of cytogenetic diagnostics. We report the design, validation, and clinical utility of an oligonucleotide array which combines genome-wide coverage with targeted enhancement at known clinically relevant regions.

Methods: Probes were placed every 75 kb across the entire euchromatic genome to establish a chromosomal "backbone" with a resolution of approximately 500 kb, which is increased to approximately 50 kb in targeted regions.