Genetic Evaluation of Prelingual Hearing Impairment: Recommendations of an European Network for Genetic Hearing Impairment.

The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...].

MMP-9 plasma level as biomarker of cochlear implantation outcome in cohort study of deaf children.

PURPOSE: If before cochlear implantation it was possible to assay biomarkers of neuroplasticity, we might be able to identify those children with congenital deafness who, later on, were at risk of poor speech and language rehabilitation outcomes. METHODS: A group of 40 children aged up to 2 years with DFNB1-related congenital deafness was observed in this prospective cohort study over three follow-up intervals (0, 8, and 18 months) after cochlear implant (CI) activation. Children were assessed for auditory development using the LittlEARS Questionnaire (LEAQ) score, and at the same time, measurements were made of matrix metalloproteinase-9 (MMP-9) plasma levels. RESULTS: There were significant negative correlations between plasma levels of MMP-9 at 8-month follow-up and LEAQ score at cochlear implantation (p = 0.04) and LEAQ score at 18-month follow-up (p = 0.02) and between MMP-9 plasma levels at 18-month follow-up and LEAQ score at cochlear implantation (p = 0.04). As already reported, we confirmed a significant negative correlation between MMP-9 plasma level at cochlear implantation and LEAQ score at 18-month follow-up (p = 0.005). Based on this latter correlation, two clusters of good and poor CI performers could be isolated. CONCLUSIONS: The study shows that children born deaf who have an MMP-9 plasma level of less than 150 ng/ml at cochlear implantation have a good chance of attaining a high LEAQ score after 18 months of speech and language rehabilitation. This indicates that MMP-9 plasma level at cochlear implantation is a good prognostic marker for CI outcome.

Monogenic Causes of Low-Frequency Non-Syndromic Hearing Loss.

BACKGROUND: Low-frequency non-syndromic hearing loss (LFNSHL) is a rare form of hearing loss (HL). It is defined as HL at low frequencies (≤2,000 Hz) resulting in a characteristic ascending audiogram. LFNSHL is usually diagnosed postlingually and is progressive, leading to HL affecting other frequencies as well. Sometimes it occurs with tinnitus. Around half of the diagnosed prelingual HL cases have a genetic cause and it is usually inherited in an autosomal recessive mode. Postlingual HL caused by genetic changes generally has an autosomal dominant pattern of inheritance and its incidence remains unknown. SUMMARY: To date, only a handful of genes have been found as causing LFNSHL: well-established WFS1 and, reported in some cases, DIAPH1, MYO7A, TNC, and CCDC50 (respectively, responsible for DFNA6/14/38, DFNA1, DFNA11, DFNA56, and DFNA44). In this review, we set out audiological phenotypes, causative genetic changes, and molecular mechanisms leading to the development of LFNSHL. KEY MESSAGES: LFNSHL is most commonly caused by pathogenic variants in the WFS1 gene, but it is also important to consider changes in other HL genes, which may result in similar audiological phenotype.

The Genetic Background of Hearing Loss in Patients with EVA and Cochlear Malformation.

The most frequently observed congenital inner ear malformation is enlarged vestibular aqueduct (EVA). It is often accompanied with incomplete partition type 2 (IP2) of the cochlea and a dilated vestibule, which together constitute Mondini malformation. Pathogenic SLC26A4 variants are considered the major cause of inner ear malformation but the genetics still needs clarification. The aim of this study was to identify the cause of EVA in patients with hearing loss (HL). Genomic DNA was isolated from HL patients with radiologically confirmed bilateral EVA (n = 23) and analyzed by next generation sequencing using a custom HL gene panel encompassing 237 HL-related genes or a clinical exome. The presence and segregation of selected variants and the CEVA haplotype (in the 5' region of SLC26A4) was verified by Sanger sequencing. Minigene assay was used to evaluate the impact of novel synonymous variant on splicing. Genetic testing identified the cause of EVA in 17/23 individuals (74%). Two pathogenic variants in the SLC26A4 gene were identified as the cause of EVA in 8 of them (35%), and a CEVA haplotype was regarded as the cause of EVA in 6 of 7 patients (86%) who carried only one SLC26A4 genetic variant. In two individuals with a phenotype matching branchio-oto-renal (BOR) spectrum disorder, cochlear hypoplasia resulted from EYA1 pathogenic variants. In one patient, a novel variant in CHD7 was detected. Our study shows that SLC26A4, together with the CEVA haplotype, accounts for more than half of EVA cases. Syndromic forms of HL should also be considered in patients with EVA. We conclude that to better understand inner ear development and the pathogenesis of its malformations, there is a need to look for pathogenic variants in noncoding regions of known HL genes or to link them with novel candidate HL genes.

Longitudinal Changes in BDNF and MMP-9 Protein Plasma Levels in Children after Cochlear Implantation.

Congenitally deaf children who undergo cochlear implantation before 1 year of age develop their auditory skills faster than children who are implanted later. In this longitudinal study, a cohort of 59 implanted children were divided into two subgroups according to their ages at implantation-below or above 1 year old-and the plasma levels of matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and pro-BDNF were measured at 0, 8, and 18 months after cochlear implant activation, while auditory development was simultaneously evaluated using the LittlEARs Questionnaire (LEAQ). A control group consisted of 49 age-matched healthy children. We identified statistically higher BDNF levels at 0 months and at the 18-month follow-ups in the younger subgroup compared to the older one and lower LEAQ scores at 0 months in the younger subgroup. Between the subgroups, there were significant differences in the changes in BDNF levels from 0 to 8 months and in LEAQ scores from 0 to 18 months. The MMP-9 levels significantly decreased from 0 to 18 months and from 0 to 8 months in both subgroups and from 8 to 18 months only in the older one. For all measured protein concentrations, significant differences were identified between the older study subgroup and the age-matched control group.

Searching for the Molecular Basis of Partial Deafness.

Hearing is an important human sense for communicating and connecting with others. Partial deafness (PD) is a common hearing problem, in which there is a down-sloping audiogram. In this study, we apply a practical system for classifying PD patients, used for treatment purposes, to distinguish two groups of patients: one with almost normal hearing thresholds at low frequencies (PDT-EC, n = 20), and a second group with poorer thresholds at those same low frequencies (PDT-EAS, n = 20). After performing comprehensive genetic testing with a panel of 237 genes, we found that genetic factors can explain a significant proportion of both PDT-EC and PDT-EAS hearing losses, accounting, respectively, for approx. one-fifth and one-half of all the cases in our cohort. Most of the causative variants were located in dominant and recessive genes previously linked to PD, but more than half of the variants were novel. Among the contributors to PDT-EC we identified OSBPL2 and SYNE4, two relatively new hereditary hearing loss genes with a low publication profile. Our study revealed that, for all PD patients, a postlingual hearing loss more severe in the low-frequency range is associated with a higher detection rate of causative variants. Isolating a genetic cause of PD is important in terms of prognosis, therapeutic effectiveness, and risk of recurrence.

Hearing Loss as the Main Clinical Presentation in NLRP3-Associated Autoinflammatory Disease.

The NLRP3 gene mutations are the cause of autosomal dominant autoinflammatory disorders (NLRP3-AID). Recently, hearing loss (HL) has been found to be the sole or major manifestation of NLRP3-AID. Here, we tested 110 autosomal dominant HL families with a custom panel of 237 HL genes and found one family carrying the NLRP3 c.1872C>G, p.Ser624Arg mutation. Functional studies revealed that this novel variant is a gain of function mutation, leading to increased activity of caspase-1 and subsequent oversecretion of proinflammatory interleukin-1ß. Clinical reanalysis of the affected individuals, together with serological evidence of inflammation and pathological cochlear enhancement on FLAIR-MRI images, guided our diagnosis to atypical NLRP3-AID. The study highlights the role of genetic analysis in patients with progressive postlingual HL. This can help to identify individuals with hereditary HL as a consequence of NLRP3-AID and allow timely and effective treatment with interleukin-1-receptor antagonist.

Update on CD164 and LMX1A genes to strengthen their causative role in autosomal dominant hearing loss.

Novel hearing loss (HL) genes are constantly being discovered, and evidence from independent studies is essential to strengthen their position as causes of hereditary HL. To address this issue, we searched our genetic data of families with autosomal dominant HL (ADHL) who had been tested with high-throughput DNA sequencing methods. For CD164, only one pathogenic variant in one family has so far been reported. For LMX1A, just two previous studies have revealed its involvement in ADHL. In this study we found two families with the same pathogenic variant in CD164 and one family with a novel variant in LMX1A (c.686C>A; p.(Ala229Asp)) that impairs its transcriptional activity. Our data show recurrence of the same CD164 variant in two HL families of different geographic origin, which strongly suggests it is a mutational hotspot. We also provide further evidence for haploinsufficiency as the pathogenic mechanism underlying LMX1A-related ADHL.

Prospective cohort study reveals MMP-9, a neuroplasticity regulator, as a prediction marker of cochlear implantation outcome in prelingual deafness treatment.

Because of vast variability of cochlear implantation outcomes in prelingual deafness treatment, identification of good and poor performers remains a challenging task. To address this issue, we investigated genetic variants of matrix metalloproteinase 9 (MMP9) and brain-derived neurotrophic factor (BDNF) and plasma levels of MMP-9, BDNF, and pro-BDNF that have all been implicated in neuroplasticity after sensory deprivation in the auditory pathway. We recruited a cohort of prelingually deaf children, all implanted before the age of 2, and carried out a prospective observation (N = 61). Next, we analyzed the association between (i) functional MMP9 (rs20544, rs3918242, rs2234681) and BDNF (rs6265) gene variants (and their respective protein levels) and (ii) the child's auditory development as measured with the LittlEARS Questionnaire (LEAQ) before cochlear implant (CI) activation and at 8 and 18 months post-CI activation. Statistical analyses revealed that the plasma level of MMP-9 measured at implantation in prelingually deaf children was significantly correlated with the LEAQ score 18 months after CI activation. In the subgroup of DFNB1-related deafness (N = 40), rs3918242 of MMP9 was significantly associated with LEAQ score at 18 months after CI activation; also, according to a multiple regression model, the ratio of plasma levels of pro-BDNF/BDNF measured at implantation was a significant predictor of overall LEAQ score at follow-up. In the subgroup with DFNB1-related deafness, who had CI activation after 1 year old (N = 22), a multiple regression model showed that rs3918242 of MMP9 was a significant predictor of overall LEAQ score at follow-up.

Molecular Inversion Probe-Based Sequencing of USH2A Exons and Splice Sites as a Cost-Effective Screening Tool in USH2 and arRP Cases.

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.

TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss.

Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (ADHL). To determine the role of TBC1D24 in the development of ADHL and to characterize the TBC1D24-related ADHL, clinical exome sequencing or targeted multigene (n = 237) panel were performed for probands (n = 102) from multigenerational ADHL families. In four families, TBC1D24-related HL was found based on the identification of three novel, likely pathogenic (c.553G>A, p.Asp185Asn; c.1460A>T, p. His487Leu or c.1461C>G, p.His487Gln) and one known (c.533C>T, p.Ser178Leu) TBC1D24 variant. Functional consequences of these variants were characterized by analyzing the proposed homology models of the human TBC1D24 protein. Variants not only in the TBC (p.Ser178Leu, p.Asp185Asn) but also in the TLDc domain (p.His487Gln, p.His487Leu) are involved in ADHL development, the latter two mutations probably affecting interactions between the domains. Clinically, progressive HL involving mainly mid and high frequencies was observed in the patients (n = 29). The progression of HL was calculated by constructing age-related typical audiograms. TBC1D24-related ADHL originates from the cochlear component of the auditory system, becomes apparent usually in the second decade of life and accounts for approximately 4% of ADHL cases. Given the high genetic heterogeneity of ADHL, TBC1D24 emerges as an important contributor to this type of HL.

Functional Polymorphism of MMP9 and BDNF as Potential Biomarker of Auditory Neuroplasticity in Prelingual Deafness Treatment With Cochlear Implantation-A Retrospective Cohort Analysis.

Genetic biomarkers of neuroplasticity in deaf children treated with cochlear implantation (CI) might facilitate their clinical management, especially giving them better chances of developing proficient spoken language. We investigated whether carrying certain variants of the genes encoding matrix metalloproteinase MMP9 and neurotrophin brain-derived neurotrophic factor (BDNF), involved in synaptic plasticity, can be taken as prognostic markers of how well auditory skills might be acquired. Association analysis of functional MMP9 rs3918242 and BDNF rs6265 variants and the child's auditory development measured at CI activation and 1, 5, 9, 14, and 24 months post CI activation with LittlEARS Questionnaire (LEAQ) was conducted in a group of 100 children diagnosed with DFNB1-related deafness, unilaterally implanted before the age of 2 years. Statistical analysis in the subgroup implanted after 1 year of life (n = 53) showed significant association between MMP9 rs3918242 and LEAQ scores at 1 month (p = .01), at 5 months (p = .01), at 9 months (p = .01), and at 24 months (p = .01) after CI activation. No significant associations in the subgroup implanted before 1 year of life were observed. No significant associations between the BDNF rs6265 and LEAQ score were found. Multiple regression analysis (R2 = .73) in the subgroup implanted after 1 year of life revealed that MMP9 rs3918242 was a significant predictor of treatment outcome. In conclusion, C/C rs3918242 MMP9 predisposes their deaf carriers to better CI outcomes, especially when implanted after the first birthday, than carriers of C/T rs3918242MMP9.

Complex Phenotypic Presentation of Syndromic Hearing Loss Deciphered as Three Separate Clinical Entities: How Genetic Testing Guides Final Diagnosis.

BACKGROUND: Genetically determined prelingual hearing loss (HL) may occur in an isolated or syndromic form. OBJECTIVE: The aim of the study was to unravel the genetic cause of medical problems in a 21-year-old woman, whose phenotypic presentation extended beyond Stickler syndrome and included enlarged vestibular aqueduct (EVA) and persistent microhematuria. METHODS AND RESULTS: After sequencing of clinical exome, a known de novo COL2A1 pathogenic variant (c.1833+1G>A, p.?) causative for Stickler syndrome and one paternally inherited pathogenic change in COL4A5 (c.1871G>A, p.Gly624Asp) causative for X-linked Alport syndrome were found. No pathogenic variants, including those within the SLC26A4 5' region (Caucasian EVA haplotype), explaining the development of EVA, were identified. CONCLUSIONS: The study reveals a multilocus genomic variation in one individual and provides a molecular diagnosis of two HL syndromes that co-occur in the proband independent of each other. For the third entity, EVA, no etiological factor was identified. Our data emphasize the relevance of detailed clinical phenotyping for accurate genotype interpretation. Focus on broadening the phenotypic spectrum of known genetic syndromes may actually obscure patients with multiple molecular diagnoses.

High expression of Matrix Gla Protein in Schnyder corneal dystrophy patients points to an active role of vitamin K in corneal health.

PURPOSE: Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disorder characterized by corneal lipid accumulation and caused by UBIAD1 pathogenic variants. UBIAD1 encodes a vitamin K (VK) biosynthetic enzyme. To assess the corneal and vascular VK status in SCD patients, we focused on matrix Gla protein (MGP), a VK-dependent protein. METHODS: Conformation-specific immunostainings of different MGP maturation forms were performed on corneal sections and primary keratocytes from corneal buttons of two SCD patients with UBIAD1 p.Asp112Asn and p.Asn102Ser pathogenic variants and unrelated donors. Native or UBIAD1-transfected keratocytes were used for gene expression analysis. Plasma samples from SCD patients (n = 12) and control individuals (n = 117) were subjected for inactive desphospho-uncarboxylated MGP level measurements with an ELISA assay. RESULTS: Substantial amounts of MGP were identified in human cornea and most of it in its fully matured and active form. The level of mature MGP did not differ between SCD and control corneas. In primary keratocytes from SCD patients, a highly increased MGP expression and presence of immature MGP forms were detected. Significantly elevated plasma concentration of inactive MGP was found in SCD patients. CONCLUSION: High amount of MGP and the predominance of mature MGP forms in human cornea indicate that VK metabolism is active in the visual system. Availability of MGP seems of vital importance for a healthy cornea and may be related to protection against corneal calcification. Systemic MGP findings reveal a poor vascular VK status in SCD patients and indicate that SCD may lead to cardiovascular consequences.

Effect of donor non-muscle myosin heavy chain (MYH9) gene polymorphisms on clinically relevant kidney allograft dysfunction.

BACKGROUND: Despite its established association with chronic kidney disease (CKD) the role of myosin-9 (MYH9) gene variation on transplanted kidney function remains unknown. This study aimed at evaluating the effect of donor MYH9 nephrogenic variants on renal allograft function within the first post transplantation year. METHODS: In the longitudinal kidney transplant study 207 deceased donors were genotyped for previously known risk MYH9 single nucleotide polymorphisms (SNPs). The predictor was MYH9 high-risk variants status. The primary outcome was mean eGFR found in low vs. high risk MYH9 genotypes between third and twelfth post-transplant month, the secondary outcome was the risk of proteinuria. RESULTS: Distribution of genotypes remained in Hardy-Weinberg equilibrium. The T allele of rs3752462 (dominant model, TT or TC vs. CC) was associated with higher filtration rate (P = 0.05) in a multivariate analysis after adjusting for delayed graft function and donor sex. Two G alleles of rs136211 (recessive model, GG vs. GA or AA) resulted in doubling the risk of proteinuria (OR = 2.22; 95% CI = 1.18-4.37, P = 0.017) after adjusting for donor and recipient sex. CONCLUSION: Deceased donor kidneys of European descent harboring MYH9 SNPs rs3752462 T allele show significantly superior estimated filtration rate while those of rs136211 GG genotype excessive risk of proteinuria. These findings, if replicated, may further inform and improve individualization of allocation and treatment policies.

Two Novel Pathogenic Variants Confirm RMND1 Causative Role in Perrault Syndrome with Renal Involvement.

RMND1 (required for meiotic nuclear division 1 homolog) pathogenic variants are known to cause combined oxidative phosphorylation deficiency (COXPD11), a severe multisystem disorder. In one patient, a homozygous RMND1 pathogenic variant, with an established role in COXPD11, was associated with a Perrault-like syndrome. We performed a thorough clinical investigation and applied a targeted multigene hearing loss panel to reveal the cause of hearing loss, ovarian dysfunction (two cardinal features of Perrault syndrome) and chronic kidney disease in two adult female siblings. Two compound heterozygous missense variants, c.583G>A (p.Gly195Arg) and c.818A>C (p.Tyr273Ser), not previously associated with disease, were identified in RMND1 in both patients, and their segregation with disease was confirmed in family members. The patients have no neurological or intellectual impairment, and nephrological evaluation predicts a benign course of kidney disease. Our study presents the mildest, so far reported, RMND1-related phenotype and delivers the first independent confirmation that RMND1 is causally involved in the development of Perrault syndrome with renal involvement. This highlights the importance of including RMND1 to the list of Perrault syndrome causative factors and provides new insight into the clinical manifestation of RMND1 deficiency.

Cochlear Implantation Outcome in Children with DFNB1 locus Pathogenic Variants.

Almost 60% of children with profound prelingual hearing loss (HL) have a genetic determinant of deafness, most frequently two DFNB1 locus (GJB2/GJB6 genes) recessive pathogenic variants. Only few studies combine HL etiology with cochlear implantation (CI) outcome. Patients with profound prelingual HL who received a cochlear implant before 24 months of age and had completed DFNB1 genetic testing were enrolled in the study (n = 196). LittlEARS questionnaire scores were used to assess auditory development. Our data show that children with DFNB1-related HL (n = 149) had good outcome from the CI (6.85, 22.24, and 28 scores at 0, 5, and 9 months post-CI, respectively). A better auditory development was achieved in patients who receive cochlear implants before 12 months of age. Children without residual hearing presented a higher rate of auditory development than children with responses in hearing aids over a wide frequency range prior to CI, but both groups reached a similar level of auditory development after 9 months post-CI. Our data shed light upon the benefits of CI in the homogenous group of patients with HL due to DFNB1 locus pathogenic variants and clearly demonstrate that very early CI is the most effective treatment method in this group of patients.

First confirmatory study on PTPRQ as an autosomal dominant non-syndromic hearing loss gene.

BACKGROUND: Biallelic PTPRQ pathogenic variants have been previously reported as causative for autosomal recessive non-syndromic hearing loss. In 2018 the first heterozygous PTPRQ variant has been implicated in the development of autosomal dominant non-syndromic hearing loss (ADNSHL) in a German family. The study presented the only, so far known, PTPRQ pathogenic variant (c.6881G>A) in ADNSHL. It is located in the last PTPRQ coding exon and introduces a premature stop codon (p.Trp2294*). METHODS: A five-generation Polish family with ADNSHL was recruited for the study (n = 14). Thorough audiological, neurotological and imaging studies were carried out to precisely define the phenotype. Genomic DNA was isolated from peripheral blood samples or buccal swabs of available family members. Clinical exome sequencing was conducted for the proband. Family segregation analysis of the identified variants was performed using Sanger sequencing. Single nucleotide polymorphism array on DNA samples from the Polish and the original German family was used for genome-wide linkage analysis. RESULTS: Combining clinical exome sequencing and family segregation analysis, we have identified the same (NM_001145026.2:c.6881G>A, NP_001138498.1:p.Trp2294*) PTPRQ alteration in the Polish ADNSHL family. Using genome-wide linkage analysis, we found that the studied family and the original German family derive from a common ancestor. Deep phenotyping of the affected individuals showed that in contrast to the recessive form, the PTPRQ-related ADNSHL is not associated with vestibular dysfunction. In both families ADNSHL was progressive, affected mainly high frequencies and had a variable age of onset. CONCLUSION: Our data provide the first confirmation of PTPRQ involvement in ADNSHL. The finding strongly reinforces the inclusion of PTPRQ to the small set of genes leading to both autosomal recessive and dominant hearing loss.

Overinterpretation of high throughput sequencing data in medical genetics: first evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss.

BACKGROUND: Hearing loss (HL) is the most common disability of human senses characterized by a great allelic heterogeneity. GJB2 and TMPRSS3 are two well-known HL genes typically underlying its monogenic form. Recently, TMPRSS3/GJB2 digenic inheritance has been proposed. As results of genetic testing can be easily overinterpreted, we aimed to verify the hypothesis. METHODS: From genetic database of HL patients with at least one TMPRSS3 pathogenic variants we have selected individuals with additional GJB2 pathogenic variants. All of the available family members were recruited for the study. Segregation analysis of the respective TMPRSS3 and GJB2 pathogenic variants was performed within the families. RESULTS: The strategy has allowed to identify four individuals who were double heterozygous for known pathogenic TMPRSS3 and GJB2 variants. Two individuals from different families had GJB2 c.35delG and TMPRSS3 c.208delC and in two other individuals from one family GJB2 c.35delG together with TMPRSS3 c.1343T>C variants were found. None of these subjects has ever reported hearing problems and their hearing status was normal. CONCLUSIONS: Our data provide evidence against TMPRSS3/GJB2 digenic inheritance of HL. As high throughput sequencing is increasingly used for genetic testing, particular caution should be taken to provide the patients with accurate genetic counseling.

Clinical diversity in patients with Schnyder corneal dystrophy-a novel and known UBIAD1 pathogenic variants.

PURPOSE: Schnyder corneal dystrophy (SCD) is a rare inherited disease that leads to gradual vision loss by the deposition of lipids in the corneal stroma. The aim of this study is to report a novel pathogenic variant in the UBIAD1 gene and present clinical and molecular findings in Polish patients with SCD. METHODS: Individuals (n = 37) originating from four Polish SCD families were subjected for a complete ophthalmological check-up and genetic testing. Corneal changes were visualized by slit-lamp examination, anterior segment optical coherent tomography (AS-OCT), and in vivo confocal microscopy (IVCM). RESULTS: In a proband with primarily mild SCD that progressed rapidly at the end of the fifth decade of life, a novel missense pathogenic variant in UBIAD1 (p.Thr120Arg) was identified. The other studied SCD family represents the second family reported worldwide with the UBIAD1 p.Asp112Asn variant. SCD in the remaining two families resulted from a frequently identified p.Asn102Ser pathogenic variant. All affected subjects presented a crystalline form of SCD. The severity of corneal changes was age-dependent, and their morphology and localization are described in detail. CONCLUSION: The novel p.Thr120Arg is the fourth SCD-causing variant lying within the FARM motif of the UBIAD1 protein, which underlines a high importance of this motif for SCD pathogenesis. The current study provides independent evidence for the pathogenic potential of UBIAD1 p.Asp112Asn and new information useful for clinicians.