All currently available stocks of MDA-MB-435 cells are derived from the M14 melanoma cell line and can no longer be considered a model of breast cancer. These cells are still a valuable system for the study of cancer metastasis and the extensive literature using these cells since 1982 represent a valuable new resource for the melanoma research community.

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In 1996, a practice guideline on genetic counseling for advanced paternal age was published. The current document updates the state of knowledge of advanced paternal age effects on single gene mutations, chromosome anomalies, and complex traits.

Original research article INTRODUCTIONSignificant advances in copy-number detection have broadened the mutation spectrum for many clinical genetic disorders. 1,2 Intragenic deletion mutations are of considerable frequency in many disease genes, such as PAX6, CDKL5, and STXPB1. Recurrent rearrangements between segmentally duplicated sequences are also associated with a number of syndromic disorders. 3 For these known disorders, targeted gene testing by multiplex ligation-dependent amplification or exon-focused arrays has been useful. With the increasing uptake of exome sequencing into the clinical diagnostic approach, the need for testing previously uncharacterized genes for pathogenic copynumber variation (CNV) is a significant consideration, not only to detect aberrations in genes that may cause disease when haplo-insufficient but also in genes associated with recessive disorders for which the mutation has been identified in only one of the alleles by exome sequencing. 4 Whereas exome sequencing is still gaining popularity as a powerful clinical tool, whole-genome chromosomal microarray analysis (CMA) has become an indispensable screening method that is now routinely used as a first-tier test for children with intellectual disability, developmental delay, or congenital anomalies. 5 In less than 10 years, the CMA designs have evolved from low-resolution arrays containing large bacterial artificial chromosome clones or <100,000 oligonucleotide probes to high-resolution versions with more than 1 million probes. 6 As a result, several groups have identified single-gene pathogenic aberrations that boost the analytical sensitivity of CMA. 7 However, although some of these more recent arrays have higher density at disease genes, they do not all cover every exon in those genes and are therefore not capable of detecting some pathogenic intragenic mutations. Separately, data from exon-focused arrays have shown that up to 40% of intragenic mutations can involve just one or two exons within a gene, and therefore it is essential to cover all exons within targeted genes. 1 Copy-number detection in clinical genetic testing eventually will occur entirely through examination of next-generation data, whereas array comparative genomic hybridization (aCGH) and other assays will serve as complementary and confirmatory methods. 8 To complement whole-exome sequencing (WES) or whole-genome sequencing data in a meaningful way, an array with coverage of virtually all exons is essential. Until the time that WES/whole-genome sequencing can be used routinely and reliably for copy-number detection, a whole-exome array can be used as the ultimate whole-genome CMA platform. Purpose: Detection of copy-number variation (CNV) is important for investigating many genetic disorders. Testing a large clinical cohort by array comparative genomic hybridization provides a deep perspective on the spectrum of pathogenic CNV. In this context, we describe a bioinformatics approach to extract CNV information from whole-exome sequencing and demonstrate its ut...

The ability of a single technology, next-generation sequencing, to provide both sequence and copy number variant (CNV) results has driven the merger of clinical cytogenetics and molecular genetics. Consequently, the distinction between the definition of a sequence variant and a CNV is blurry. As the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines for interpretation of sequence variants address CNV classification only sparingly, this study focused on adapting ACMG/AMP criteria for single-gene CNV interpretation.Methods: CNV-specific modifications of the 2015 ACMG/AMP criteria were developed and their utility was independently tested by three diagnostic laboratories. Each laboratory team interpreted the same 12 single-gene CNVs using three systems: (1) without ACMG/AMP guidance, (2) with ACMG/AMP criteria, and (3) with new modifications. A replication study of 12 different CNVs validated the modified criteria.Results: The adapted criteria system presented here showed improved concordance and usability for single-gene CNVs compared with using the ACMG/AMP interpretation guidelines focused on sequence variants. Conclusion:These single-gene CNV criteria modifications could be used as a supplement to the ACMG/AMP guidelines for sequence variants, allowing for a streamlined workflow and a step toward a uniform classification system for both sequence and copy number alterations.