Case report: De novo pathogenic variant in WFS1 causes Wolfram-like syndrome debuting with congenital bilateral deafness

Abstract

Background: Congenital deafness could be the first manifestation of a syndrome such as in Usher, Pendred, and Wolfram syndromes. Therefore, a genetic study is crucial in this deficiency to significantly improve its diagnostic efficiency, to predict the prognosis, to select the most adequate treatment required, and to anticipate the development of other associated clinical manifestations. Case presentation: We describe a young girl with bilateral congenital profound deafness, who initially received a single cochlear implant. The genetic study of her DNA using a custom-designed next-generation sequencing (NGS) panel detected a de novo pathogenic heterozygous variant in the WFS1 gene related to Wolfram-like syndrome, which is characterized by the presence of other symptoms such as optic atrophy. Due to this diagnosis, a second implant was placed after the optic atrophy onset. The speech audiometric results obtained with both implants indicate that this work successfully allows the patient to develop normal speech. Deterioration of the auditory nerves has not been observed. Conclusion: The next-generation sequencing technique allows a precise molecular diagnosis of diseases with high genetic heterogeneity, such as hereditary deafness, while this was the only symptom presented by the patient at the time of analysis. The NGS panel, in which genes responsible for both syndromic and non-syndromic hereditary deafness were included, was essential to reach the diagnosis in such a young patient. Early detection of the pathogenic variant in the WFS1 gene allowed us to anticipate the natural evolution of the disease and offer the most appropriate management to the patient.

Keywords: NGS; WFS1 gene; Wolfram-like syndrome; congenital hearing loss; optic atrophy.

FIGURE 1

Timeline with relevant episodes in the case report presented.

FIGURE 2

(A) Auditory brainstem potential performed at an age of 1 year, showing the potentials performed in both the right (R) and left (L) ears at different dB HL (90, 85, and 80) levels. (B) Auditory brainstem potential performed at an age of 13 years using the implanted electrode in the right ear. The V-wave curve (v) recorded from the electrodes 1, 2, 4, and 6 of the cochlear implant in the right ear (R). (C). Pre- and post-implant audiometries showing the age when performed. Orange = right ear and sky blue = left ear. (D). Evolution of the auditory and speech perception tests over patient age. The panel shows the percentage of word discrimination at 60 dB (bluish green-dashed line and dots), the percentage of consonant identification (the orange solid line and dots), and the percentage of vowel identification at 60 dB (the sky blue dotted line and dots) at tested ages.

FIGURE 3

(A) Fundoscopy showing optic nerve pallor and bilateral atrophy. (B) Retinal nerve fiber layer (RNFL) analysis by time-domain optical coherence tomography of both eyes at 12.3 years of age using Cirrus HD-OCT and SW Ver 11.5.254532 (Carl Zeiss Meditec), showing from the top to bottom the RNFL thickness maps and the nasal (N) to temporal (T) quadrants’ extracted tomographs. Graphical representation of the RNFL thickness from all quadrants is also shown at the right of the images. (C) RNFL thickness (in micrometers) in function of the patient’s age showing linear regression (black solid line), 95% confidence interval (gray area), and prediction outside measured ages (blue dotted line). The Pearson correlation coefficient and p-value are shown in each panel. RE = right eye; LE = left eye; µm = micrometers.