Somatic tumor mutations in moderate risk cancer genes: Targets for germline confirmatory testing.

BACKGROUND: Recent changes in oncology practice guidelines indicate that mutations in cancer susceptibility genes identified on tumor genomic profiling (TGP) should prompt confirmatory germline testing. Our study aimed to determine the proportion of patients with TGP-identified mutations in moderate risk breast and ovarian cancer genes who previously would not have been considered for germline testing. METHODS: From January 2013 to September 2020, 7468 adult Stanford Health Care patients underwent TGP on solid tumor samples and 166 had TGP-identified mutations in moderate risk breast and ovarian cancer susceptibility genes (ATM, BRIP1, CHEK2, PALB2, RAD51C and RAD51D). Retrospective chart reviews were performed on 160 patients. Cases were analyzed to determine eligibility for germline testing using established NCCN criteria, and somatic and germline results were compared where both were available. RESULTS: Nearly half (45.3% [73/160]) of patients would not have been eligible for germline testing if not for a TGP-identified mutation in a moderate risk breast or ovarian cancer gene. Of the 64 cases that underwent germline testing, about half (51.5% [33/64]) had results that confirmed germline origin of the TGP finding. High rates of germline confirmation were found in PALB2 (100% [5/5]), ATM (40% [14/35]), CHEK2 (61.5% [8/13]), and BRIP1 (57.1% [4/7]). CONCLUSION: Our study shows that the presence of TGP-identified mutations in moderate risk breast and ovarian cancer genes increases eligibility for germline testing beyond those that would be eligible based largely on personal and family history criteria alone. Additionally, results of germline testing in these newly eligible cases supports that this expanded eligibility captures individuals with hereditary cancer syndromes that would not have otherwise been identified.

De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

Genetics and Precision Medicine: Heritable Thoracic Aortic Disease.

Heritable thoracic aortic disease (HTAD) can have life-threatening consequences if not diagnosed early. Affected individuals and at-risk family members benefit from both cardiology and genetic evaluations, including genetic testing. Important information can be obtained through family history, medical history, and genetic testing to help guide management and assess risk. A genetic diagnosis can guide cardiovascular management (type and frequency of vascular imaging, timing of surgical intervention), risk assessment for arterial aneurysm/dissection, evaluation of nonvascular features, and familial testing.

Use of genetic risks in pediatric organ transplantation listing decisions: A national survey.

There is a limited supply of organs for all those who need them for survival. Thus, careful decisions must be made about who is listed for transplant. Studies show that manifesting genetic disease can impact listing eligibility. What has not yet been studied is the impact genetic risks for future disease have on a patient's chance to be listed. Surveys were emailed to 163 pediatric liver, heart, and kidney transplant programs across the United States to elicit views and experiences of key clinicians regarding each program's use of genetic risks (ie, predispositions, positive predictive testing) in listing decisions. Response rate was 42%. Sixty-four percent of programs have required genetic testing for specific indications prior to listing decisions. Sixteen percent have required it without specific indications, suggesting that genetic testing may be used to screen candidates. Six percent have chosen not to list patients with secondary findings or family histories of genetic conditions. In hypothetical scenarios, programs consider cancer predispositions and adult-onset neurological conditions to be relative contraindications to listing (61%, 17%, and 8% depending on scenario), and some consider them absolute contraindications (5% and 3% depending on scenario). Only 3% of programs have formal policies for these scenarios, but all consult genetic specialists at least "sometimes" for results interpretation. Our study reveals that pediatric transplant programs are using future onset genetic risks in listing decisions. As genetic testing is increasingly adopted into pediatric medicine, further study is needed to prevent possible inappropriate use of genetic information from impacting listing eligibility.