Disclaimer: This technical standard is designed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to this standard is voluntary and does not necessarily assure a successful medical outcome. This standard should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with this standard. They also are advised to take notice of the date any particular standard was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Purpose: Copy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing-based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health. Methods: To assist clinical laboratories in the classification and reporting of CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics has developed the following professional standards in collaboration with the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen) project. Results: This update introduces a quantitative, evidence-based scoring framework; encourages the implementation of the fivetier classification system widely used in sequence variant classification; and recommends "uncoupling" the evidencebased classification of a variant from its potential implications for a particular individual. Conclusion: These professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories.

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole genome and exome sequencing of 40 cases, identified two subtypes that differ in severity of aneuploidy, transcriptional profile and submicroscopic genetic alterations. Near haploid cases with 24–31 chromosomes harbor alterations targeting receptor tyrosine kinase- and Ras signaling (71%) and the lymphoid transcription factor IKZF3 (AIOLOS; 13%). In contrast, low hypodiploid ALL with 32–39 chromosomes are characterized by TP53 alterations (91.2%) which are commonly present in non-tumor cells, and alterations of IKZF2 (HELIOS; 53%) and RB1 (41%). Both near haploid and low hypodiploid tumors exhibit activation of Ras- and PI3K signaling pathways, and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

(CGG)n.(CCG)n and (CTG)n.(CAG)n repeats of varying length were cloned into a bacterial plasmid, and the progression of the replication fork through these repeats was followed using electrophoretic analysis of replication intermediates. We observed stalling of the replication fork within repeated DNAs and found that this effect depends on repeat length, repeat orientation relative to the replication origin and the status of protein synthesis in a cell. Interruptions within repeated DNAs, similar to those observed in human genes, abolished the replication blockage. Our results suggest that the formation of unusual DNA structures by trinucleotide repeats in the lagging-strand template may account for the observed replication blockage and have relevance to repeat expansion in humans.

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases.

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Purpose: Deletions of distal 9p are associated with trigonocephaly, mental retardation, dysmorphic facial features, cardiac anomalies, and abnormal genitalia. Previous studies identified a proposed critical region for the consensus phenotype in band 9p23, between 11.8 Mb and 16 Mb from the 9p telomere. Here we report 10 new patients with 9p deletions; 9 patients have clinical features consistent with 9pϪ syndrome, but possess terminal deletions smaller than most reported cases, whereas one individual lacks the 9pϪ phenotype and shows a 140-kb interstitial telomeric deletion inherited from his mother. Methods: We combined fluorescence in situ hybridization and microarray analyses to delineate the size of each deletion. Results: The deletion sizes vary from 800 kb to 12.4 Mb in our patients with clinically relevant phenotypes. Clinical evaluation and comparison showed little difference in physical features with regard to the deletion sizes. Severe speech and language impairment were observed in all patients with clinically relevant phenotypes. Conclusion: The smallest deleted region common to our patients who demonstrate a phenotype consistent with 9pϪ is Ͻ2 Mb of 9pter, which contains six known genes.These genes may contribute to some of the cardinal features of 9p deletion syndrome. Genet Med 2008:10 (8): 599 -611. Key Words: 9p deletion, FISH, genotype-phenotype correlation, aCGHThe 9p deletion syndrome is characterized by trigonocephaly, moderate to severe mental retardation, low-set, malformed ears, and dysmorphic facial features, such as up-slanting palpebral fissures and a long philtrum. 1,2 Furthermore, abnormal genitalia are found in some 9pϪ patients who have a chromosomal complement of 46, XY, 3 and hypopigmentation has also been described in two independent studies. 4,5 Since the original report of the syndrome in 1973, 6 over 140 cases of 9p deletion have been documented. The breakpoints occur in bands from 9p22 to 9p24, and the large majority of patients have either terminal deletions or translocations involving another chromosome.Previous studies have delineated the size of 9p deletions in an attempt to develop genotype-phenotype correlations. In one large study, Christ et al., 2 characterized the deletion breakpoints in 24 patients with visible 9p deletions and breakpoints at 9p22 or 9p23. Markers D9S274 (14.2 Mb from the telomere) and D9S286 (8 Mb) were absent in all 24 patients with 9pϪ, whereas D9S285 (16 Mb) was present in a subset of these patients. Thus, the minimal deleted segment in this group of patients included 16 Mb of the 9p terminus. Wagstaff and Hemann 4 described a patient with typical features of 9pϪsyndrome and an interstitial deletion between 8 Mb and 19 Mb of 9p. Based on the data of Wagstaff and Hemann, 4 and from their own data, Christ et al., 2 modified their critical region, i.e., the distal 16 Mb of 9p, and concluded that the critical region for the 9pϪsyndrome lies in an ϳ8-Mb region between D9S285 and D9S286, encompassing bands 9p22-9p23.Among a number of recent publicati...

Key Points NGS-based prognostic panels may identify individuals at risk for HHMs despite not being designed for this purpose. Variant allele frequency >0.4 and gene of interest may be predictive of germ line origin.

A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype; furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias. Lineage switch following CAR-T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.