A Novel X-linked Mutation of CACNA1F Gene in Two Male Siblings Presenting Nystagmus

Objectives: CACNA1F, located on Xp11.23, encodes for α1F subunit of the retinal Cav1.4, an L-type voltage gated Ca²⁺ channel, mainly expressed on the photoreceptor ribbon synapse. Mutations of this gene cause functional alterations of the channel, leading to a variety of visual impairments. We describe two male siblings with early onset nystagmus and positive family history for visual defects due to a novel mutation of CACNA1F.

Content: Methods: Both brothers experienced an uneventful pregnancy and perinatal period. Patient 1, 7 years old, and patient 2, 2 years old, were both referred to our Center at 2 months of age because of nystagmus. Both periodically underwent neurological, neurovisual, and cognitive level examinations. Brain magnetic resonance imaging (MRI), electroretinography (ERG), visual-evoked potentials (VEP), plasmatic/urinary amino-acids dosage, and whole-exome sequencing (WES) were also performed.

Results: Patient 1: the neurovisual evaluation reported head turned to the right and horizontal nystagmus which impairs fixation, smooth pursuit, and saccades and persists at follow-up. Visual acuity was always mildly impaired, while contrast sensitivity improved for low contrasts. Myopia, astigmatism, and retinal hypopigmentation were also described. An expressive language delay was detected, whereas the cognitive level was normal. Since the age of 6 years, ERG and VEP were altered. Patient 2: the neurovisual examination reported chin down head posture, with the head turned to the right and tilted on the left shoulder, associated to left gaze and horizontal nystagmus which impairs fixation, smooth pursuit, and saccades, and persistent at follow-up. Visual acuity was mildly impaired, while contrast sensitivity later appeared for medium contrast. Myopia, astigmatism, and retinal hypopigmentation were also detected. An expressive language delay was identified. ERG was normal but VEP was pathological. Brain MRI and plasmatic/urinary amino acids were normal in both cases. WES showed the same novel CACNA1F mutation (p.Arg975Gln), confirmed by Sanger's sequencing. Because of the presence of visual defects in multiple male maternal relatives, the genetic testing was extended showing the X-linked inheritance of the mutation.

Conclusion: The p.Arg975Gln mutation identified in these brothers has no reference in literature yet. The phenotype hereby described partially overlap with those of the already known disorders linked to CACNA1F mutations.

Publication History

Article published online:
16 March 2022