TYPE Case Report PUBLISHED 18 October 2022 DOI 10.3389/fgene.2022.998898 Case report: De novo pathogenic OPEN ACCESS variant in WFS1 causes EDITED BY Katarina Trebušak Podkrajšek, University of Ljubljana, Slovenia Wolfram-like syndrome debuting REVIEWED BY Lisa Schimmenti, with congenital bilateral Mayo Clinic, United States Pranav Mathur, Otonomy Inc., United States deafness *CORRESPONDENCE Laura Alías, Laura Alías 1,2*, Miguel López de Heredia 3, Sabina Luna 4, lalias@santpau.cat Núria Clivillé 1, Lídia González-Quereda 1,2, Pía Gallano 1,2, SPECIALTY SECTION This article was submitted to Genetics of Júlia de Juan 5, Albert Pujol 5, Santiago Diez 6, Susana Boronat 7, Common and Rare Diseases, César Orús 5, Adriana Lasa 1,2 and María del Prado Venegas 5 a section of the journal 1 Frontiers in Genetics Genetics Department, IIB Sant Pau, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain, 2 U705—Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud RECEIVED 20 July 2022 Carlos III, Madrid, Spain, 3Centre for Biomedical Network Research on Rare Diseases (CIBERER), ACCEPTED 29 September 2022 Instituto de Salud Carlos III, Madrid, Spain, 4Ophthalmology Department, Hospital de la Santa Creu I PUBLISHED 18 October 2022 Sant Pau, Barcelona, Spain, 5Otorhinolaringologyst Department, Hospital de la Santa Creu I Sant Pau, CITATION Barcelona, Spain, 6Otorhinolaringology Department, Hospital Esperit Sant, Santa Coloma de Alías L, López de Heredia M, Luna S, Gramenet, Spain, 7Child Neurology Unit, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain Clivillé N, González-Quereda L, Gallano P, de Juan J, Pujol A, Diez S, Boronat S, Orús C, Lasa A and Venegas MP (2022), Background: Congenital deafness could be the first manifestation of a Case report: De novo pathogenic variant in WFS1 causes Wolfram-like syndrome such as in Usher, Pendred, and Wolfram syndromes. Therefore, a syndrome debuting with congenital genetic study is crucial in this deficiency to significantly improve its diagnostic bilateral deafness. efficiency, to predict the prognosis, to select the most adequate treatment Front. Genet. 13:998898. doi: 10.3389/fgene.2022.998898 required, and to anticipate the development of other associated clinical COPYRIGHT manifestations. © 2022 Alías, López de Heredia, Luna, Clivillé, González-Quereda, Gallano, de Case presentation: We describe a young girl with bilateral congenital profound Juan, Pujol, Diez, Boronat, Orús, Lasa deafness, who initially received a single cochlear implant. The genetic study of and Venegas. This is an open-access her DNA using a custom-designed next-generation sequencing (NGS) panel article distributed under the terms of the Creative Commons Attribution License detected a de novo pathogenic heterozygous variant in the WFS1 gene related (CC BY). The use, distribution or to Wolfram-like syndrome, which is characterized by the presence of other reproduction in other forums is permitted, provided the original symptoms such as optic atrophy. Due to this diagnosis, a second implant was author(s) and the copyright owner(s) are placed after the optic atrophy onset. The speech audiometric results obtained credited and that the original with both implants indicate that this work successfully allows the patient to publication in this journal is cited, in accordance with accepted academic develop normal speech. Deterioration of the auditory nerves has not been practice. No use, distribution or observed. reproduction is permitted which does not comply with these terms. 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. Frontiers in Genetics 01 frontiersin.org Alías et al. 10.3389/fgene.2022.998898 KEYWORDS WFS1 gene, congenital hearing loss, NGS, Wolfram-like syndrome, optic atrophy Introduction for an endoglycosidase H-sensitive protein called wolframin (Inoue et al., 1998) localized to the endoplasmic reticulum Congenital deafness may be caused by genetic etiology in (ER) membrane and secretory granules. Wolframin plays a more than 60% of cases in developed countries. These genetic role in Ca2+ homeostasis regulation at the cellular and ER cases could either be syndromic (SHL, 30%), in which the hearing levels, which contributes to the quality control systems for loss is accompanied by other associated clinical manifestations, protein folding and regulation of the ER stress response. or non-syndromic (NSHL, 70%), in which the hearing loss Wolframin is highly expressed in the heart, lungs, specific remains as the only symptom in the patient. regions of the brain, pancreas, liver, kidney, skeletal muscle, More than 400 syndromes manifest SHL, and among them, optical nerve, and the auditory pathway. There are more than Usher, Pendred, and Wolfram syndromes have been described. 100 reported pathogenic genetic variants that cause WS due to Identifying patients who may develop SHL when the only the abnormal wolframin activity or protein levels (Heredia et al., manifestation presented by the patient is hearing loss might 2013); however, genotype–phenotype correlations have not been be highly valuable for proper patient management. described. Wolfram syndrome (WS; OMIM #222300; previously known Bi-allelic loss of function variants in wolframin trigger a as DIDMOAD) is a rare (1 in 500,000–1,000,000) (Blanco- cascade of ER and mitochondrial dysfunction that ultimately Aguirre et al., 2015) autosomal recessive disease, initially leads to apoptosis and cellular death (Takei et al., 2006; Bonnet described as a combination of early-onset diabetes mellitus, Wersinger et al., 2014), especially of pancreatic beta-cells and progressive optic nerve atrophy, diabetes insipidus, and neurons. This effect on neurons leads to neurodegeneration due sensorineural hearing loss associated with other variable to an evident cellular degradation of myelin (Lugar et al., 2016). clinical manifestations (Barrett et al., 1995). Molecular genetic studies have shown that wolframin There are two types of WS with many overlapping features, deficiency may impair early neuronal survival and delay type I and type II, differentiated by their genetic cause due to neuronal development (Cagalinec et al., 2016). Furthermore, pathogenic variants in the wolframin ER transmembrane postmortem histopathological studies specify that the most glycoprotein (WFS1), most frequently, and CISD2 genes, affected brain regions in WS are the sensory pathways, respectively. WFS1 pathogenic variants have been linked to brainstem, cerebellum, and hypothalamus. In the visual Wolfram and Wolfram-like syndromes, which include cases system, the optic nerves appear grossly atrophic, and with just one pathogenic variant in heterozygosis not meeting microscopic examination reveals the loss of retinal ganglion the WS diagnostic criteria (Barrett et al., 1995; Inoue et al., 1998; neurons and myelinated axons throughout the visual Takei et al., 2006; Heredia et al., 2013; Blanco-Aguirre et al., pathways with relative preservation of the visual cortex. 2015). Wolfram syndrome is an autosomal recessive disorder Within the auditory pathway, studies have found loss of the caused by bi-allelic variants in WFS1, whereas Wolfram-like organ of Corti (the functional unit of the inner ear) in the basal syndrome is a dominant condition caused by a single turns of the cochlea, fibers in the cochlear nerve, and neurons in heterozygous pathogenic variant in WFS1. This gene encodes the cochlear nuclei and inferior colliculus (Shannon et al., 1999). FIGURE 1 Timeline with relevant episodes in the case report presented. Frontiers in Genetics 02 frontiersin.org Alías et al. 10.3389/fgene.2022.998898 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. In addition, altered wolframin disturbs the balance of calcium means of otoacoustic emissions, brainstem-evoked potentials, ions in the inner ear, which interferes with the hearing process and audiometry. Otoacoustic emissions showed no response in (Takeda et al., 2001). both ears, and no V-wave at 90 dB nHL was found when In this work, we describe a girl, who is clinically diagnosed performing brainstem-evoked potentials (Figure 2A), and also, with congenital deafness, in which NGS results determined the no response was obtained in pure-tone audiometry when presence of a heterozygous de novo missense variant in WFS1 and stimulated at high intensity at all frequencies studied was predicted to be pathogenic by different in silico prediction (Figure 2C). Since a hearing response was not obtained with algorithms. the most powerful hearing aids on the market, a cochlear implant We describe the genotype–phenotype relationship in this was chosen. patient and the early treatment performed, emphasizing the The radiological study performed to evaluate cochlear importance of the exhaustive and personalized follow-up that implant placement with cranial computed tomography (CT) allowed us to anticipate the onset of other clinical symptoms and magnetic resonance imaging (MRI) showed neither related to WS, thus improving patient’s quality of life through an disease-related changes in the central nervous system nor early management. cochlear, nerve, or auditory pathway malformations. A cochlear implant (CI 513, cochlear) was placed in the right ear when the patient was 3 years old. Case presentation In order to see if there is a genetic cause for patient’s deafness, an NGS genetic study was performed when the patient was The patient, a 13-year-old female (Figure 1), without 7.2 years old, using an in-house TruSeq Custom Amplicon previous familial history of hearing loss, at an age of 1.6 years panel (TSCA) from Illumina (Supplementary Table S1). was diagnosed with profound bilateral deafness in both ears by Amplicons were then paired-end sequenced using a MiSeq Frontiers in Genetics 03 frontiersin.org Frontiers in Genetics Alías et al. TABLE 1 Genetic variants detected in the affected patient after the NGS analysis. Six of them were identified as synonymous variants or classified as benign/likely benign by in silico software. The variants in bold were selected because its genetic consequence according to the ACMG guidelines (Richards et al., 2015) and being predicted as pathogenic by several in silico software applications (ClinVar, PolyPhen, and SIFT). GRCh37 (hg 19) was considered as the reference. The RNA splicing effect in missense and synonymous variants was discarded by Alamut software. Gene Chr Coordinate Freq Read Depth HGVSc HGVSp Consequence ClinVar PolyPhen SIFT dbSNP ACMG Classification depth variant ID criteria ADGRV1 5 89,990,447 48,2 110 53 NM_032119.3: p.Arg2625His Missense Likely Benign rs201214794 BA1, BS1, Class 1—benign c.7874G>A benign (0.018) and BS2 ADGRV1 5 90,020,923 46,3 164 76 NM_032119.3: p.Pro3309Pro Synonymous rs16869042 BA1 and Class 1—benign c.9927T>G BS2 CDH23 10 73,569,731 31 84 26 NM_022124.5: p.Ile2959Ile Synonymous rs373709237 PM2, BP7, Class 2—likely c.8877C>T and BP6 benign 04 GJA1 6 121,768,897 30,9 139 43 NM_000165.3: p.Asn302Asp Missense Benign Tolerated rs775532447 PM2 and Class 3—VUS c.904A>G (0.012) (0.16) PP2 GJA1 6 121,768,924 30,9 139 43 NM_000165.3: p.Ala311ValfsTer37 Frameshift rs778110855 PVS1 Class 4—likely c.932delC pathogenic GJA1 6 121,769,050 30,5 141 43 NM_000165.3: p.Leu353Leu Synonymous PM2, BP4, Class 2—likely c.1057T>C and BP7 benign MY O 7A 11 76,883,797 25 12 3 NM_000260.3: p.Ala601Thr Missense Benign Tolerated rs782481491 PM2 Class 3—VUS c.1801G>A (0.245) (0.34) WFS1 4 6,303,573 49,1 322 158 NM_006005.3: p.Ala684Val Missense Pathogenic Probably Deleterious rs387906930 PM2, Class c.2051C>T damaging (0) PM5, 5—pathogenic (0.992) PM1, PP3, and PP5 Chr and Coordinate, are the chromosome and coordinates where the gene is located. Freq indicates the variant frequency detected in sequencing. HGVSc and HGVSp shows the naming at DNA and protein levels according to HGVS convenctions. 10.3389/fgene.2022.998898 frontiersin.org Alías et al. 10.3389/fgene.2022.998898 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. sequencer (Illumina), with a read length of 150 base pairs. Given the result of the genetic study and to anticipate the Different variants were detected (Table 1 and Supplementary possible appearance of other associated symptoms, the patient Figure S1) by VariantStudio and DNAnexus software was referred to an endocrinologist, who has, so far, ruled out the applications, and only one of them was in silico predicted as presence of diabetes mellitus or insipidus, an ophthalmologist, pathogenic. A c.2051C>T nucleotide change was observed in the and also a neuropediatrician. g.6303573 position of chromosome 4 (GRCh37), causing an The patient’s initial eye examination performed at the age of alanine exchange for valine (p.Ala684Val) in WFS1 gene 8.2 years included visual acuity (VA), color vision test, (NM_006005.3). Sanger sequencing confirmed the presence of biomicroscopy, funduscopy, visual field, optical coherence a heterozygous c.2051C>T variant in the patient’s WFS1 gene but tomography (OCT), and visual-evoked potentials (Figure 3). The not in either of her parents (Supplementary Figure S1). ophthalmologic manifestation in the patient included reducing Therefore, the pathogenic variant in our patient was acuity, dyschromatopsia, and visual field deficit. Despite showing categorized as de novo. correct VA at log MAR 0.0 in each eye and no alterations in the color Additionally, NGS analysis showed a heterozygous deletion test, fundoscopy and retinography showed bilateral papillary pallor c.932delC in the g.121768924 position of chromosome 6 (GRCh37), and marked thinning of the peripapillary RNFL retinal nerve fiber resulting in p.Ala311Valfs37* in the GJA1 gene (NM_00165.3). After layer on OCT. No signs of vascular narrowing and/or diabetic Sanger sequencing validation, an exhaustive analysis with BLAST ® retinopathy were detected, all suggestive of optic atrophy. In (NCBI) showed that the sequence corresponded instead to the FER successive ophthalmologic controls, these findings have remained tyrosine kinase (FER) pseudogene in chromosome 5 (NG_011445.2) stable without progression. This pathology is not subject to optical (Supplementary Figure S1), which presents more than 90% homology correction. with the GJA1’s sequence. In the context of the Spanish public health system, when this We ruled out the presence of the p.Arg445His missense patient was diagnosed with deafness, only one cochlear implant was pathogenic variant in the OPA1 gene in all family members by approved by the authorities. However, because the patient had both Sanger sequencing as OPA1 pathogenic variants are the most optic atrophy and profound bilateral deafness, a second cochlear frequent genetic cause behind optic atrophy associated with implant was allowed to be placed in the left ear at the age of 10.3 years. deafness (Amati-Bonneau et al., 2003). After 9 years with the cochlear implant in the right ear and then Frontiers in Genetics 05 frontiersin.org Alías et al. 10.3389/fgene.2022.998898 3 years in the left ear, we studied the evolution of the speech The clinical manifestations of the patient described in this recognition tests and the post-implant neural response. Auditory work are related to sensory neurodevelopmental disorders perception and speech tests improved significantly after the placement (congenital bilateral deafness and progressive optic atrophy), of both cochlear implants (Figure 2D). The hearing threshold in pure- suggesting that the neurons of the sensory organs (retinal tone audiometry with both cochlear implants at conversational ganglion cells, hair cells, and auditory nerves) would be more frequencies was 20 dB. Speech audiometry results varied in both susceptible to the wolframin insufficiency caused by the WFS1 ears due to the time of hearing deprivation and years of follow-up after genetic variant present in this patient. It was believed that the placement of both implants. After 9 years of follow-up since the first neurological manifestations appeared in the late stages of the cochlear implant, the results in the right ear showed 70% speech disease, but recent evidences gathered from WS patients indicate recognition at a sound loudness level (SPL) of 70 dB, while the left ear that some of these neurological abnormalities are present even at results showed 65% speech recognition at the same intensity. V-wave an early age, as seen in the present case (Hershey et al., 2012). curves were recorded at electrodes 6, 11, 16, and 22 at a level between Some neuropathological studies have been performed based 140 and 167 CL, showing good morphology and replicability, which on cranial MRI and postmortem brain histopathological studies suggests good neural conduction from the auditory nerve to the of patients affected by WS. Through these studies, it has been anatomical generator (the inferior colliculus) of the brainstem possible to identify the brain regions and structures involved and (Figure 2B). affected by WS. Interestingly, the most affected brain regions are the sensory pathways, brainstem, cerebellum, and hypothalamus (Shannon et al., 1999). Discussion In the visual system of WS patients, the optic nerves appear grossly atrophic, and microscopic examination reveals loss of We describe a patient diagnosed with congenital deafness, retinal ganglion neurons and myelinated axons in all visual who presents a heterozygous de novo missense pathogenic pathways, with relative preservation of the visual cortex variant (p.Ala684Val) in the WFS1 gene. The p.Ala684Val (Lugar et al., 2016). Grenier et al. (2016) described a variant 1) is not observed in the gnomAD v2.1.1 dataset, 2) progressive decrease in visual acuity (VA) and significantly has been previously reported on 16 independent occasions as decreased retinal nerve fiber layer (RNFL) thickness in a pathogenic/likely pathogenic with strong evidence (ClinVar ID: group of patients affected by WS compared to a group of VCV000030556), and 3) exhibited a different missense change at patients with Wolfram-like syndrome. We observed a decrease the same codon (p.Ala684Thr) which has been reported to be to 53 µm of the RNFL in the right eye and 52 µm in the left eye, associated with WS in compound heterozygosis (Waschbisch respectively, during the 3-year follow-up of our patient’s optic et al., 2011). Therefore, this variant could be classified as atrophy. This result is similar to those described by Grenier. pathogenic, according to the recommendation of ACMG/AMP However, VA and visual fields were not affected. This could be guidelines (Richards et al., 2015). This genetic variant was explained by the young age of the patient and the short follow- previously reported in compound heterozygosity in a patient up time. with full WS (Tessa et al., 2001) and in six families in Within the auditory pathway, published studies have found heterozygosis linked to autosomal-dominant WS-like that pathogenic variants in the WFS1 gene affect the entire syndrome (Rendtorff et al., 2011), showing a wide spectrum auditory pathway, from the organ of Corti to the nuclei of the of the severity and type of clinical manifestations. Different pons (Genís et al., 1997). Likewise, molecular genetic studies have pathogenic variants in WFS1 may give rise to different disease shown that wolframin deficiency can impair early neuronal phenotypes, but genotype–phenotype correlations for either WS survival and delay neuronal development (Cagalinec et al., or Wolfram-like syndrome have been elusive, especially due to 2016). WFS1 is expressed during brain development, and the low number of described patients and the large number of molecular pathways affected by wolframin deficiency also play reported variants (Heredia et al., 2013). crucial roles in early brain development, for example, As the patient has not developed diabetes mellitus and only neurogenesis, neuronal migration, or myelination. Recent one mutated allele was found in WFS1, the patient was diagnosed neuroimaging studies suggest that abnormal myelin with Wolfram-like syndrome, according to the available development is a primary neuropathologic feature of WS that guidelines (Tranebjærg et al., 2020). is observed from an early age (Lugar et al., 2019). One possible Expression of the p.Ala684Val pathogenic variant in HEK explanation is that wolframin deficiency impairs the function of cells showed a significantly decreased protein expression myelinating oligodendrocytes and interferes with myelin compared to wild-type wolframin (Rendtorff et al., 2011). As development. Another explanation could be that ER stress the variant has been shown in heterozygosis, we could deduce triggers oligodendrocyte death and facilitates myelin from these data that the patient might have reduced wolframin degeneration. However, functional studies of the WFS1 gene in levels. oligodendrocytes and glial cells are limited (Samara et al., 2019). Frontiers in Genetics 06 frontiersin.org Alías et al. 10.3389/fgene.2022.998898 The damage caused by the WFS1 genetic variant described in the Conclusion studied patient at the level of the auditory pathway and the brain has not been related. The correlation of specific variants with the age at NGS’s usefulness allowed us to detect the presence of which the different symptoms in WS or Wolfram-like syndromes pathogenic variants in genes related to WS in a patient with debut or progress has not been related either. It is believed that based congenital deafness without a family history. We would like to on the few patients with the p.Ala684Val variant described, including highlight the importance of including the study of the genes the patient described here it could first affect the auditory and optical responsible for hereditary syndromic hearing loss in patients, pathways and that the variability in onset ages might be due to the who are only affected by this disease without a family history, activity of undescribed modulating genes. Interestingly, another especially when these patients are very young. pathogenic variant affecting the same amino acid (p.Ala 684Thr) An early detection of the pathogenic variant in the WFS1 has been described in WS patients (Waschbisch et al., 2011). The gene has been essential to anticipate the natural evolution of the patient showed the full characteristic spectrum of WS symptoms, clinical manifestations and to successfully treat the patient probably because two compound heterozygotic pathogenic variants described in this work. As a result of early intervention with were found in WFS1. Current data available suggest that the cochlear implants, the functionality of the auditory pathway spectrum of symptoms shown by WS and Wolfram-like patients might be maintained, which was critical for the patient’s might be due to wolframin levels in the pancreatic beta-cells and quality of life after the onset of optic atrophy. visual and auditory pathways, but still, the difference in wolframin Currently, the patient is under the care of an levels does not explain the variability in the onset and order of otorhinolaryngologist, endocrinologist, ophthalmologist, and appearance of the symptoms. audiologist, as well as a psychologist, because mood disorders There is currently no effective, scientifically proven treatment to have been related to WFS1-associated diseases. intervene or remediate damage to the visual or auditory pathways in A complete genomic analysis, such as exome or whole- WS or Wolfram-like syndrome. However, there is a technological genome sequencing, should be considered in the near future management that helps restore deafness. The cochlear implant in cases of patients presenting with congenital deafness, replaces the function of the cochlea and would explain the good especially when hearing loss gene panel studies are results obtained in the patient if wolframin was located only at the inconclusive, in order to be able to identify genetic variants level of the cochlea. However, as previously mentioned, the presence not described in the literature, particularly in those cases of SHL of wolframin is distributed along the auditory pathway, which raises where the appearance of other clinical manifestations can be the question if the auditory nerve atrophy shown in WS patients anticipated. might be due to the partial or complete depletion of wolframin or by the lack of stimuli. The evidence from this patient is that the auditory nerve atrophy is secondary, so an early intervention might conserve Data availability statement its functionality. There is no evidence in the literature on how auditory nerve stimulation through the cochlear implant would The datasets for this article are not publicly available due to act favoring the transmission of sound, connecting the patient to concerns regarding participant/patient anonymity. Request to the “sound world” and allowing the comprehension of words. We access the datasets should be directed to the corresponding hypothesize that the cochlear implant stimulates the auditory nerve, author. resynchronizing the ascending auditory pathway, presumably delaying the process of axonal demyelination and allowing the patient to perceive and understand sounds. All this would be Author contributions supported by the fact that we have observed the good results obtained from the auditory point of view in the patient with the This work has been conceived by MV and LA. The placement of both cochlear implants at an early age, before experiments were designed by MV, SL, SB, AL, and LA. Data demyelination progressed to the axonal level. These results have analysis was carried out by all authors. All authors read the been demonstrated at the audiometric and speech recognition levels manuscript, and all of them have been involved in the critical and by obtaining a correct neuronal response when stimulating the discussion of this work. Finally, MV, ML, and LA wrote the auditory nerves through a cochlear implant. manuscript. Although deep phenotypic descriptions of patients with WS and Wolfram-like syndrome are still needed to deepen our knowledge on the evolution of the syndromes, patients with Acknowledgments deleterious pathogenic variants in WFS1 would significantly benefit from early cochlear implantation to preserve a fully The authors thank the family for their participation in the functional auditory pathway, thus improving their quality of life. study. Frontiers in Genetics 07 frontiersin.org Alías et al. 10.3389/fgene.2022.998898 Conflict of interest organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or The authors declare that the research was conducted in the claim that may be made by its manufacturer, is not guaranteed or absence of any commercial or financial relationships that could endorsed by the publisher. be construed as a potential conflict of interest. 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Evidence for altered neurodevelopment and neurodegeneration in 1016/j.jns.2010.08.044 Frontiers in Genetics 08 frontiersin.org