Hereditary neuropathy or pain disorder

Gene: CHRNA3

Green List (high evidence)

Comment on list classification: There are more than 3 individuals reported in literature with an autonomic nervous system disorder and biallelic CHRNA3 variants. Individuals presented with severe orthostatic hypotension, nonreactive pupils, constipation, and bladder dysfunction. Hence, CHRNA3 should be promoted to Green at the next update.

Created: 10 Mar 2026, 4:03 p.m. | Last Modified: 10 Mar 2026, 4:03 p.m.

Panel Version: 7.39

PMID: 38192228 Anand et al., 2024
14yo female with CAKUT, ocular autonomic dysfunction, and severe episodes of constipation. Compound het for CHRNA3 c.769_797del, p.Phe257Leufs*5 & c.539G>A, p.Trp180*.

PMID: 37161764 Heusser et al., 2023
18 yo woman with severe orthostatic hypotension, miotic rigid pupils, impaired bladder emptying, and gastrointestinal hypomotility. Compound het for paternally inherited CHRNA3 c.907_908delCT, p.Leu303Aspfs*115 & maternal deletion of CHRNA3 exons 5 and 6.

PMID: 33947782 Shibao et al., 2021
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. Sibs in family I were compound het for CHRNA3 c.907_908delCT, (p.L303Dfs*115) / c.688 G>A (p.D230N), while proband from family II was homozygous for CHRNA3 c.907_908delCT, (p.L303Dfs*115).

PMID: 31708116 Mann et al., 2019
Report of 5 affected individuals from three unrelated families with functional lower urinary tract obstruction and secondary CAKUT. Four individuals from two families have additional dysautonomic features, including impaired pupillary light reflexes and orthostatic hypotension.
CHRNA3 variants: B1402 Macedonian patient homozygous for c.267+2T>G (essential splice), Arabic sibs in family B1717 homozygous for c.1010_1011delCA (p.Thr337Asnfs∗81), Pakistani sibs homozygous for c.1019C>G (p.Ser340*).

CHRNA3 is linked to AR Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, OMIM:191800 in OMIM (accessed 10th Mar 2026).

Created: 10 Mar 2026, 3:58 p.m. | Last Modified: 10 Mar 2026, 3:58 p.m.

Panel Version: 7.36

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, OMIM:191800

Publications

• 38192228
• 37161764
• 33947782
• 31708116

Green List (high evidence)

4 cases from 3 families are reported with biallelic LoF variants in the CHRNA3 causing familial dysautonomia:
PMID: 33947782;37161764
Sources: Literature

Created: 27 Feb 2026, 4:21 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Familial Autonomic Ganglionopathy

Publications

• PMID: 33947782
• 37161764