Alterations in respiratory epithelial gene SPDEF segregate with severe disease in a family with variable response to COVID19 infection

ABSTRACT

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 infectionthree 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