Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants. Novel Genetic Cause of Neurogenic Orthostatic Hypotension

Background: To identify and determine the molecular basis of a new Mendelian cause of familial neurogenic orthostatic hypotension (nOH). Method: The proband developed disabling nOH at 39 yrs of age. He was evaluated at the Vanderbilt Autonomic Dysfunction Center and was diagnosed with severe autonomic failure and small nonreactive pupils. Plasma norepinephrine levels were abnormally low, and dopamine levels were within normal limits. Of note, his sister had onset of nOH in her late teens. Their parents, brother and the proband's three children were healthy. Findings: Patient was referred to the UDN where whole exome sequencing of DNAs from the proband and his affected sister showed that both were compound heterozygotes for c.907_908delCT (p.L303Dfs*115) /c.688G>A (p.D230N) variants in the acetylcholine receptor, neuronal nicotinic, alpha 3 subunit (CHRNA3) gene. CHRNA3 is a subunit of nicotinic acetylcholine receptors (nAChRs) that regulates blood pressure through modulation of synaptic transmission in the autonomic ganglia. The frameshift (fs) and missense CHRNA3 variants were inherited from the sibs' mother and father, respectively, and their non-affected brother was a nl/p.D230N heterozygote. The fs variant is obviously pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). Furthermore, we predict from structural modeling that the p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits and that it would destabilize the nAChR pentameric complex. Interestingly, homozygous knock-out mice without detectable CHRNA3 had autonomic failure and dilated pupils. In humans, the presence of acquired nAChR autoantibodies against the alpha 3 subunit is associated with nOH and non-reactive pupils. Interpretation: We report sibs affected with autonomic failure and miosis of unknown etiology who are compound heterozygotes for CHRNA3 variants that co segregate with and have predicted effects on nAChR structure that suggest they likely cause this family's nOH. Funding Statement: The study was supported by Vanderbilt CTSA grant 1UL1 RR000445 from NACTS/NIH and NIH/NINDS U54 30 NS065736; JAP, JDC, JHN and RH was supported in part by NIH Common Fund and NIH/NHGRI UO1HG007674. Declaration of Interests: C.A.S. has received research grant from Doris Duke Foundation. I.B. and C.A.S. received grant support from Office of Orphan Products Development. Food and Drug Administration, Grant #FD-R-04778-01-A3. C.A.S. has received speaker honorarium from Lundbeck Pharmaceuticals. I.B., and C.A.S. received consulting honoraria from Lundbeck and Theravance Biopharma. C.A.S is member of the Board for the American Autonomic Society. Ethics Approval Statement: Both affected sibs were referred to the Undiagnosed Diseases Network (UDN). They were enrolled at the Vanderbilt clinical site, and they consented to the study (IRB protocol NHGRI 15-HG0130) before any genetic studies were done.