Monogenic hearing loss

Gene: CACNA1D

Green List (high evidence)

Comment on list classification: There are more than 3 unrelated families reported with biallelic CACNA1D variants and hearing loss. Heterozygous individuals in those families were asymptomatic. Hence, this gene should be promoted to Green at the next update, with MOI set to BIALLELIC, autosomal or pseudoautosomal.

Created: 17 Apr 2026, 2:29 p.m. | Last Modified: 17 Apr 2026, 2:33 p.m.

Panel Version: 5.68

PMID: 21131953 Baig et al., 2011
Report of 2 consanguineous Pakistani families with bradycardia and congenital deafness, harbouring c.1208_1209insGGG (p.Gly403_Val404insGly) variant in CACNA1D.

PMID: 30498240 Liaqat et al., 2018
5 Pakistani families with Sinoatrial node dysfunction and deafness and homozygous CACNA1D variants- 1 family with p.(A376V), and 4 pedigrees with a founder variant p.(G403_V404insG) - common distant ancestor confirmed, same as families in PMID: 21131953.

PMID: 30054272 Garza-Lopez et al., 2018
Male proband of Arabic descent with moderate hearing impairment and intellectual disability, homozygous for CACNA1D c.1701G>C, p.Gln567His variant.

PMID: 32747562 Rayyan et al., 2020
Palestinian population study of 491 families with hearing loss. In 4 families, the same homozygous CACNA1D p.(Ala376Val) founder variant was found to be responsible for moderate hearing loss associated with cardiac anomalies, including prolonged atrioventricular conduction on an electrocardiogram.

Functional evidence: PMID: 10929716 Platzer et al., 2000 - Cacna1d-deficient mice were deaf due to degeneration of outer and inner hair cells. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia).

The link between CACNA1D and autosomal recessive sinoatrial node dysfunction and deafness has been classified as Moderate in ClinGen (Hearing loss GCEP, 2024).

Created: 17 Apr 2026, 2:28 p.m. | Last Modified: 17 Apr 2026, 2:35 p.m.

Panel Version: 5.68

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Sinoatrial node dysfunction and deafness, OMIM:614896; sinoatrial node dysfunction and deafness, MONDO:0013960

Publications

• 21131953
• 30498240
• 30054272
• 32747562

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
#614896:Sinoatrial node dysfunction and deafness[Deafness, congenital sensorineural, severe to profound; Sinoatrial node dysfunctionBradycardiaSyncopal episodes; Caused by mutation in the alpha-1D subunit of the L-type voltage-dependent calcium channel gene (CACNA1D,)]; #615474:Primary aldosteronism, seizures, and neurologic abnormalities[Cortical blindness (in one patient); Left ventricular hypertrophyBiventricular hypertrophy (in one patient)Ventricular septal defect (in one patient)Patent foramen ovale (in one patient)Second-degree heart block (in one patient); Hypertension, neonatalPulmonary artery hypertension (in one patient); Renal stones (in one patient); Global developmental delaySeizures, generalized tonic-clonicSeizures, myoclonicSeizures, complex partialCerebral palsySpastic quadriplegia (in one patient)Athetosis, mild (in one patient); Movement disorder; Verbal outbursts (in one patient); Metabolic alkalosis; Elevated aldosteroneHigh aldosterone/renin ratioLow plasma renin activity; Hypokalemia]

Publications

• PMID:10611367
• 10929716
• 11441182
• 11875398
• 1309651
• 1309948
• 1324226
• 1659003
• 1664412
• 1849233
• 20139964
• 21131953
• 23913001
• 23913004