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 eight unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/8) or EIF2AK2 (7/8). Features seen in these eight individuals include white matter alterations (8/8), developmental delay (8/8), impaired language (8/8), cognitive impairment (7/8), ataxia (6/8), dysarthria in probands with verbal ability (6/6), hypotonia (6/8), hypertonia (5/8), and involuntary movements (3/8). Individuals with EIF2AK2variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and patient-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 EIF2a), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter disease (CACH/VWM), a leukoencephalopathy 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.
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.
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