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Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants
Cyndya A Shibao1, Karen Joos2, John A Phillips2
1From the Department of Medicine (C.S., J.H.N., B.B., A.D., D.R., I.B.), Department of Ophthalmology and Visual Sciences, Biomedical Engineering (K.J.), Department of Pediatrics (J.A.P., J.C., R.H.), and Department of Biochemistry (J.M., J.C.), Vanderbilt University Medical Center, Nashville, TN; Department of Internal Medicine (J.S.), Washington University in St. Louis, MO; Department of Medical and Molecular Genetics (F.V.), Indiana University School of Medicine, Indianapolis, IN; and Baylor Genetics and Baylor College of Medicine (Y.Y.), Baylor College of Medicine, Houston, TX. cyndya.shibao@vumc.org.
Objective:
To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure.
Methods:
Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure.
Results:
Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex.
Conclusions:
We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.
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