Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants.

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, I-5) and another subject from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small non-reactive pupils, and constipation. All three affected members had low norepinephrine levels and diffuse panautonomic failure. Results: Whole exome sequencing of DNAs from subjects (I-4, I-5) showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115) /c.688G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, alpha 3 subunit (CHRNA3) gene. The II-3 from the second family was homozygous for the same frameshift(fs) variant (p.L303Dfs*115// p.L303Dfs*115). The CHRNA3 encodes a critical subunit of the 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 three individuals from two unrelated families who presented with severe nOH, miosis, and constipation. These subjects had rare pathologic variants in the CHRNA3 gene that co-segregate with and are predicted to be the likely cause of their diffuse panautonomic failure.