key: cord-0870409-rqmktiw1
authors: Ziats, Catherine; Jones, Julie; Ziats, Mark; Friez, Michael
title: OP505 Alterations in respiratory epithelial gene SPDEF segregate with severe disease in a family with variable response to COVID19 infection
date: 2021-04-30
journal: Molecular Genetics and Metabolism
DOI: 10.1016/s1096-7192(21)00583-7
sha: ab9e14362f4f6e878d031143c5e29403862084b3
doc_id: 870409
cord_uid: rqmktiw1

Background: The clinical spectrum of coronavirus disease 2019 (COVID19) is wide. While some individuals have severe disease, themajority of individuals are either asymptomatic or have mildsymptoms with minimal hypoxia. There is emerging evidence thatrare genetic variation can contribute to risk for more severe COVID19infection. The goal of this study was to investigate if rare geneticvariation was contributing to severe disease presentation in a familywith varying clinical responses to COVID19 infection.Methods: This case series describes clinical, laboratory and radiographicfeatures in a three generation family of seven individualswithout previous known immunodeficiency that were all directlyexposed to COVID19. Four individuals developed COVID19 infection:three individuals had critical disease, and one had mild symptoms.Three exposed family members were asymptomatic and did not haveclinical evidence of COVID19 infection. All family members werepreviously healthy and did not have a history ofmajor chronic diseaseincluding respiratory disease, known immunodeficiency, or any othergenetic disorder. Exome sequencing analysis was completed toinvestigate monogenic risk factors segregating with severe diseasein this family.Results: Seven family members spanning three generations wereincluded in final analysis. Individuals with severe COVID19 diseasewere male, had a mean age of 71 years old (range 61–87), and a meanbody mass index (BMI) of 27 (range 28–32). All three severely affectedmales were intubated and died within 33 days of presentation (mean25 days, range 16–33 days). One female family member with COVID19infection and a milder clinical coursewas 68 years old on presentationand had a BMI of 34. She did not require intubation but was mildlyhypoxic on room air requiring nasal cannula for oxygenation. All fourfamily members with symptomatic COVID19 infection receivedRemdesivir antiviral therapy and systemic steroids as part of thetreatment course. Unaffected family members (n = 3) had a mean ageof 35 years old (range 30–58). All were exposed to affected familymembers and all remained clinically asymptomatic. Whole exomesequencing and segregation analysis of this family identified amissense alteration of SPDEF that segregated with family memberswith severe COVID19 infection and was not detected in the mildlyaffected and unaffected family members. SPDEF is a transcriptionfactor that is highly intolerant to loss of function (pLI 0.97). Thealteration detected in this family (c.830G>A;p.Gly277Asp) is withinthe functional DNA binding domain of the protein product, and ispredicted to be damaging by in-silico models.Conclusions: Here we report exome findings from a family withvariable clinical response to COVID19 infection and describe a raremissense alteration in SPDEF segregating with severe COVID19infection. SPDEF is essential for goblet cell differentiation andmucociliary clearance within respiratory epithelial cells and has arole in mediating innate immune response. This report demonstratesthat studying large families with variable clinical outcomes can be auseful approach for identifying rare genetic variation associated withincreased risk for severe COVID19 infection. Moreover, our findingsprovide insight into the putative link between the altered inflammatoryresponse and respiratory comprise observed in some individualswith severe COVID19 infection

Public Health -Health Services and Implementation OP505 Alterations in respiratory epithelial gene SPDEF segregate with severe disease in a family with variable response to COVID19 infection Catherine Ziats, MD 1 , Julie Jones, PhD 1 , Mark Ziats, MD, PhD 2 , Michael Friez, PhD 1 . 1 Greenwood Genetic Center; 2 Self Regional Healthcare Background: The clinical spectrum of coronavirus disease 2019 (COVID19) is wide. While some individuals have severe disease, the majority of individuals are either asymptomatic or have mild symptoms with minimal hypoxia. There is emerging evidence that rare genetic variation can contribute to risk for more severe COVID19 infection. The goal of this study was to investigate if rare genetic variation was contributing to severe disease presentation in a family with varying clinical responses to COVID19 infection. Methods: This case series describes clinical, laboratory and radiographic features in a three generation family of seven individuals without previous known immunodeficiency that were all directly exposed to COVID19. Four individuals developed COVID19 infection: three individuals had critical disease, and one had mild symptoms. Three exposed family members were asymptomatic and did not have clinical evidence of COVID19 infection. All family members were previously healthy and did not have a history of major chronic disease including respiratory disease, known immunodeficiency, or any other genetic disorder. Exome sequencing analysis was completed to investigate monogenic risk factors segregating with severe disease in this family. Results: Seven family members spanning three generations were included in final analysis. Individuals with severe COVID19 disease were male, had a mean age of 71 years old (range 61-87), and a mean body mass index (BMI) of 27 (range 28-32). All three severely affected males were intubated and died within 33 days of presentation (mean 25 days, range 16-33 days). One female family member with COVID19 infection and a milder clinical course was 68 years old on presentation and had a BMI of 34. She did not require intubation but was mildly hypoxic on room air requiring nasal cannula for oxygenation. All four family members with symptomatic COVID19 infection received Remdesivir antiviral therapy and systemic steroids as part of the treatment course. Unaffected family members (n = 3) had a mean age of 35 years old (range 30-58). All were exposed to affected family members and all remained clinically asymptomatic. Whole exome sequencing and segregation analysis of this family identified a missense alteration of SPDEF that segregated with family members with severe COVID19 infection and was not detected in the mildly affected and unaffected family members. SPDEF is a transcription factor that is highly intolerant to loss of function ( pLI 0.97). The alteration detected in this family (c.830G>A; p.Gly277Asp) is within the functional DNA binding domain of the protein product, and is predicted to be damaging by in-silico models.

Conclusions: Here we report exome findings from a family with variable clinical response to COVID19 infection and describe a rare missense alteration in SPDEF segregating with severe COVID19 infection. SPDEF is essential for goblet cell differentiation and mucociliary clearance within respiratory epithelial cells and has a role in mediating innate immune response. This report demonstrates that studying large families with variable clinical outcomes can be a useful approach for identifying rare genetic variation associated with increased risk for severe COVID19 infection. Moreover, our findings provide insight into the putative link between the altered inflammatory response and respiratory comprise observed in some individuals with severe COVID19 infection. 

Most published studies on exome/genome sequencing (ES/GS) are focused on the US and other high-income countries such as the UK. However, although interest in using ES/GS in routine clinical care has grown around the world, there have been few analyses examining where testing is available, how it is funded, and how different health systems are addressing implementation challenges. Countries have different availability of testing and approaches to payer coverage and public funding for ES/GS. This variation can lead to differences in an individual's chance of disease diagnosis and potential treatments according to which country they live in and where in that country they reside. Understanding the differences in availability and funding and the evolution of these differences may help inform future challenges and potential solutions for implementation of genomic technologies into practice. We examined the availability and funding of exome and genome sequencing for suspected genetic diseases worldwide (ES/GS). Given that there are few peer-reviewed data sources describing testing in countries other than the U.S., we compiled data from the gray literature (e.g., white papers, market analyses, industry websites) and interviews with global experts. We also used exploratory case studies across three diverse health care systems:

/national (UK)

publicly funded/provincial (Canada)

Molecular Genetics and Metabolism 132S1 (2021) S325-S364 Contents lists available at SciVerse ScienceDirect Molecular Genetics and Metabolism j ou r n al ho m ep ag e: w w w