Approximately 1 in 5 individuals diagnosed with CRC at age younger than 50 years carries a germline mutation associated with cancer; nearly half of these do not have clinical histories typically associated with the identified syndrome. Germline testing with multigene cancer panels should be considered for all young patients with CRC.

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.

Cancer genetics professionals face a new opportunity and challenge in adapting to the availability of cancer genetic testing panels, now available as a result of Next Generation Sequencing (NGS) technology. While cancer panels have been available for over a year, we believe that there is not yet enough data to create practice guidelines. Despite this, a year of experience allows us to provide our opinion on points to consider as cancer genetic counselors incorporate this testing technology into genetic counseling practice models. NGS technology offers the ability to potentially diagnose hereditary cancer syndromes more efficiently by testing many genes at once for a fraction of what it would cost to test each gene individually. However, there are limitations and additional risks to consider with these tests. Obtaining informed consent for concurrent testing of multiple genes requires that genetics professionals modify their discussions with patients regarding the potential cancer risks and the associated implications to medical management. We propose dividing the genes on each panel into categories that vary by degree of cancer risk (e.g. penetrance of the syndrome) and availability of management guidelines, with the aim to improve patient understanding of the range of information that can come from this testing. The increased risk for identifying variants of uncertain significance (VUS) when testing many genes at once must be discussed with patients. Pretest genetic counseling must also include the possibility to receive unexpected results as well as the potential to receive a result in the absence of related medical management guidelines. It is also important to consider whether a single gene test remains the best testing option for some patients. As panels expand, it is important that documentation reflects exactly which genes have been analyzed for each patient. While this technology holds the promise of more efficient diagnosis for many of our patients, it also comes with new challenges that we must recognize and address.

Purpose Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of prostate cancer. Our aim was to describe the prevalence of pathogenic germline variants in cancer predisposing genes in men with prostate cancer and at least one additional primary cancer. Patients and Methods Using a multi-gene panel, we sequenced germline DNA from 102 men with prostate cancer and at least one additional primary cancer who also met one or more of the following criteria: 1) age ≤ 55 at diagnosis of first malignancy, 2) rare tumor type or atypical presentation of a common tumor, and/or 3) three or more primary malignancies. Cancer family history and clinicopathologic data were independently reviewed by a clinical genetic counselor to determine if the patient met established criteria for testing for a hereditary cancer syndrome. Results Sequencing identified ~3500 variants. Nine protein truncating deleterious mutations were found across six genes including BRCA2, ATM, MLH1, BRIP1, PALB2, and FGFR3. Likely pathogenic missense variants were identified in CHEK2 and HOXB13. In total, 11/102 (10.8%) subjects were found to have pathogenic or likely pathogenic mutations in cancer predisposing genes. The majority of these men (64%) did not meet current clinical criteria for germline testing. Conclusion Men with prostate cancer and at least one additional primary cancer are enriched for harboring a germline deleterious mutation in a cancer predisposing gene that may impact cancer prognosis and treatment, but most do not meet current criteria for clinical genetic testing.

Congenital disorders of glycosylation (CDG) comprise a clinically and biochemically heterogeneous group of monogenetic-inherited, multisystemic diseases that affect the biosynthesis of N- and/or O-glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic-orientated GDP-mannose:Man(3-4) GlcNAc(2)-PP-dolichol alpha-1,2-mannosyltransferase (ALG11), who presented an accumulation of shortened dolichol-linked oligosaccharides leading to CDG-Ip (ALG11-CDG). Here we describe an improved metabolic labeling method that allowed the identification of three new CDG-Ip cases that were missed so far in routine diagnostics. Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life.

High tunnels are unheated structures covered with polyethylene (PE) glazing to protect high-value crops from adverse weather. The objective of this study was to raise soil temperatures to determine the efficacy of soil solarization using clear mulch on the soil surface and glazing or no glazing on a high tunnel during the hottest months of the year in the semiarid southwestern United States. Solarization trials were conducted in May and June 2013 in two high tunnels in southern Arizona. Highest soil temperatures were reached with the combination of a high tunnel covered with glazing and the soil covered with PE mulch. Average daily soil temperatures were 48 and 47 °C and average degree hours (DH) per day (base temperature 45 °C) were over 14 at soil depths of 5 and 15 cm. The average daily maximum soil temperature at 5- and 15-cm depth was 63.4 and 52 °C, respectively. The second highest soil temperatures were reached when the soil was covered with PE mulch without high tunnel glazing, which resulted per day in 5.2 DH above 45 °C at 5 cm and less than one DH at 15-cm depth. Glazing on the high tunnel without covering the soil surface raised soil temperatures only at the 5-cm depth above 45 °C, but not further down. High tunnel producers in the low desert areas in the southwestern United States can complete solarization in less than 1 week, depending on the organism to be controlled, when the soil is fallow during the summer months with glazing on the high tunnel and on the soil surface.

10596 Background: Tumor CGP may identify both somatic and GL variants, though confirmatory testing is required to verify which variants originate from the GL. Studies have shown CGP can identify patients who both do and do not meet criteria for genetic counseling (GC). Ideally, improved annotation from tumor CGP could more appropriately direct GC referrals. We explore how a computational algorithm might be used to influence GC and confirmatory GL testing for variants in inherited cancer predisposition genes. Methods: 849 patients from the Aurora Oncology Precision Medicine Program who had routine hybrid-capture based CGP by Foundation Medicine from 8/2018-8/2020 were eligible. A previously published algorithm, SGZ (Sun et al PMID 29415044) which incorporates allele frequency, aneuploidy, and admixed copy number modeling was used to predict whether each single nucleotide variant (SNV) was GL or somatic. SGZ predictions for SNVs in 24 actionable inherited cancer predisposition genes were available to Aurora for review as part of standard screening to identify appropriate GC referrals. For patients who had GL testing, variants in genes on both assays were compared. Results: 76 pathogenic (P) or likely pathogenic (LP) variants predicted to be GL by SGZ were detected in 73/849 (9%) patients: ATM (7), BAP1 (2), BRCA1 (13), BRCA2 (8), BRIP1 (1), CHEK2 (18), FH (0), FLCN (2), MLH1 (1), MSH2 (0), MSH6 (3), MUTYH (12), PALB2 (3), PMS2 (1), POLE (0), RAD51C (1), RAD51D (0), RET (1), SDHA/B/C/D (0,0,0,0), TSC2 (0), and VHL (3). 27/73 (37%) patients had GL testing. 25/26 (96%) variants were confirmed to be GL in origin and 1 additional variant was detected by CGP in a region not interrogated by the GL assay: ATM (2/2), BRCA1 (6/6), BRCA2 (2/2), BRIP1 (1/1), CHEK2 (9/9), FLCN (0*/1), MSH6 (1/1), MUTYH (2/2), PALB2 (1/1), RAD51C (1/1), and VHL (0/1). Variants were confirmed in bladder, breast, CRC, glioma, NSCLC, ovary, pancreas, prostate, sarcoma, and gastric cancer. The VHL variant was discordant in a leiomyosarcoma. Conclusions: We identified the potential real-world clinical impact of computationally screening solid tumor patients undergoing routine CGP for potential P/LP GL variants. Predicting GL results with SGZ for 24 inherited cancer predisposition genes was highly concordant with confirmatory GL testing independent of tumor type. CGP annotations can facilitate GC referral and GL testing for at-risk patients, particularly in tumor types which may not typically meet guidelines for GL testing.[Table: see text]

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