LHFPL5 splice site variant in a cat with deafness and vestibular dysfunction

Should children with an enlarged vestibular aqueduct be restricted from playing contact sports?

The audiological features of hearing loss (HL) in patients with autosomal recessive deafness type 1A (DFNB1A) caused by splice site variants of the GJB2 gene are less studied than those of patients with other variants of this gene. In this study, we present the audiological features of DFNB1A in a large cohort of 134 patients with the homozygous splice site variant c.-23+1G>A and 34 patients with other biallelic GJB2 genotypes (n = 168 patients with DFNB1A). We found that the preservation of hearing thresholds in the speech frequency range (PTA0.5,1.0,2.0,4.0 kHz) in patients with the c.[-23+1G>A];[-23+1G>A] genotype is significantly better than in patients with the "severe" c.[35delG];[35delG] genotype (p = 0.005) and significantly worse than in patients with the "mild" c.[109G>A];[109G>A] genotype (p = 0.041). This finding indicates a "medium" pathological effect of this splice site variant on hearing function. A detailed clinical and audiological analysis showed that in patients with the c.[-23+1G>A];[-23+1G>A] genotype, HL is characterized as congenital or early onset (57.5% onset before 12 months), sensorineural (97.8%), bilateral, symmetrical (82.8%), variable in severity (from mild to profound HL, median hearing threshold in PTA0.5,1.0,2.0,4.0 kHz is 86.73±21.98 dB), with an extremely "flat" audioprofile, and with a tendency toward slow progression (a positive correlation of hearing thresholds with age, r = 0.144, p = 0.041). In addition, we found that the hearing thresholds in PTA0.5,1.0,2.0,4.0 kHz were significantly better preserved in females (82.34 dB) than in males (90.62 dB) (p = 0.001). We can conclude that in patients with DFNB1A caused by the c.-23+1G>A variant, male sex is associated with deteriorating auditory function; in contrast, female sex is a protective factor.

The Finnish distribution of clinical Usher syndrome (USH) types is 40% USH3, 34% USH1 and 12% USH2. All patients with USH3 carry the founder mutation in clarin 1 (CLRN1), whereas we recently reported three novel myosin VIIA (MYO7A) mutations in two unrelated patients with USH1. This study was carried out to further investigate the USH mutation spectrum in Finnish patients. We analysed samples from nine unrelated USH patients/families without known mutations and two USH3 families with atypically severe phenotype. The Asper Ophthalmics USH mutation chip was used to screen for known mutations and to evaluate the chip in molecular diagnostics of Finnish patients. The chip revealed a heterozygous usherin (USH2A) mutation, p.N346H, in one patient. Sequencing of MYO7A and/or USH2A in three index patients revealed two novel heterozygous mutations, p.R873W in MYO7A and c.14343+2T>C in USH2A. We did not identify definite pathogenic second mutations in the patients, but identified several probably nonpathogenic variations that may modify the disease phenotype. Possible digenism could not be excluded in two families segregating genomic variations in both MYO7A and USH2A, and two families with CLRN1 and USH2A. We conclude that there is considerable genetic heterogeneity of USH1 and USH2 in Finland, making molecular diagnostics and genetic counselling of patients and families challenging.

Red ginseng delays age-related hearing and vestibular dysfunction in C57BL/6 mice

Usher syndrome (USH) is an autosomal recessive disorder characterized by congenital sensorineural hearing impairment and retinitis pigmentosa. Classification distinguishes three clinical types of which type I (USH1) is the most severe, with vestibular dysfunction as an added feature. To date, 15 genes and 3 loci have been identified with the USH1G gene being an uncommon cause of USH. We describe an atypical USH1G-related phenotype caused by a novel homozygous missense variation in a patient with profound hearing impairment and relatively mild retinitis pigmentosa, but no vestibular dysfunction. A 26-year-old female patient with profound congenital sensorineural hearing loss, nyctalopia and retinitis pigmentosa was studied. Audiometric, vestibular and ophthalmologic examination was performed. A panel of 13 genes was tested by next-generation sequencing (NGS). While the hearing loss was confirmed to be profound, the vestibular function resulted normal. Although typical retinitis pigmentosa was present, the age at onset was unusually late for USH1 syndrome. A novel homozygous missense variation (c.1187T>A, p.Leu396Gln) in the USH1G gene has been identified as causing the disease in our patient. Genetic and phenotypic heterogeneity are very common in both isolated and syndromic retinal dystrophies and sensorineural hearing loss. Our findings widen the spectrum of USH allelic disorders and strength the concept that variants in genes that are classically known as underlying one specific clinical USH subtype might result in unexpected phenotypes.

Vestibular Dysfunction in Patients with Enlarged Vestibular Aqueduct.

Here we describe the second case of primary microcephaly caused by a novel homozygous splice-site variant at the NCAPD2 gene. The proband was born with microcephaly, and developed intellectual disability. Whole exome sequencing identified a canonical splice-site variant, c.3477+2T>C, at the NCAPD2 gene. Sanger sequencing showed that the proband and her sibling, a symptomatic fetus, carried a homozygous c.3477+2T>C variant, while the unaffected parents were heterozygous and her younger brother had wild-type alleles. To date, only one case of primary microcephaly with a homozygous splice-site pathogenic variant at the NCAPD2 gene has been reported. Our study of two siblings provides additional evidence that NCAPD2 is a causative gene of primary microcephaly. This finding adds new knowledge in the etiology of microcephaly and contributes to more accurate counseling of affected families.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, poor social skills, and difficulties with communication. Beyond these core signs and symptoms, the majority of subjects with ASD have some degree of auditory and vestibular dysfunction. Dysfunction in these sensory modalities is significant as normal cognitive development depends on an accurate representation of our environment. The hearing difficulties in ASD range from deafness to hypersensitivity and subjects with ASD have abnormal sound-evoked brainstem reflexes and brainstem auditory evoked potentials. Vestibular dysfunction in ASD includes postural instability, gait dysfunction, and impaired gaze. Untreated vestibular dysfunction in children can lead to delayed milestones such as sitting and walking and poor motor coordination later in life. Histopathological studies have revealed that subjects with ASD have significantly fewer neurons in the auditory hindbrain and surviving neurons are smaller and dysmorphic. These findings are consistent with auditory dysfunction. Further, the cerebellum was one of the first brain structures implicated in ASD and studies have revealed loss of Purkinje cells and the presence of ectopic neurons. Together, these studies suggest that normal auditory and vestibular function play major roles in the development of language and social abilities, and dysfunction in these systems may contribute to the core symptoms of ASD. Further, auditory and vestibular dysfunction in children may be overlooked or attributed to other neurodevelopmental disorders. Herein we review the literature on auditory and vestibular dysfunction in ASD. Based on these results we developed a brainstem model of central auditory and vestibular dysfunction in ASD and propose that simple, non-invasive but quantitative testing of hearing and vestibular function be added to newborn screening protocols.

Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids.

BackgroundPyruvate carboxylase deficiency (PCD; MIM#266150) is a rare autosomal recessive disorder characterized by a wide range of clinical features, including delayed neurodevelopment, elevated pyruvate levels, lactic acidosis, elevated ketone levels, and hyperammonemia. The pyruvate carboxylase (PC) gene was identified to be the disease-causing gene for PCD. A novel homozygous splice variant in the PC gene was identified in a Chinese boy, but the pathogenicity is still unclear. The objective of the present study was to determine the effect of this splice-site variant by reverse transcription analysis.MethodsWe reported the clinical course of a 20-month-old Chinese pediatric patient who was diagnosed with PCD using whole-exome sequencing (WES). The effects of the variant on mRNA splicing were analyzed through the transcript analysis in vivo.ResultsThe results of metabolic blood and urine screening suggested PCD by employing tandem mass spectrometry. WES revealed a novel homozygous splice-site variant (c.1825+5G>A) in the PC gene. in vivo transcript analysis indicated that the splice-site variant caused the retention of 192 bp of the intron.ConclusionThus, c.1825+5G>A was established as a pathogenic variant, thereby enriching the mutational spectrum of the PC gene and providing a basis for the genetic diagnosis of PCD.

Brittle cornea syndrome (BCS) is a rare autosomal recessive connective tissue disease characterized by variable combinations of corneal thinning and fragility, corneal ruptures either spontaneously or after minor trauma, blue sclerae, keratoconus, keratoglobus, and high myopia. So far, mutations in 2 genes, PRDM5 and ZNF469, have been associated with BCS. The purpose of this study is to describe novel mutations in the PRDM5 gene in patients with BCS. Using homozygosity mapping with single-nucleotide polymorphism markers followed by whole-exome sequencing, we identified a novel homozygous splice site variant (c.93+5G>A) in the PRDM5 gene in a consanguineous Pakistani family with 4 affected individuals. Reverse transcription-polymerase chain reaction analysis from lymphocyte-derived RNA failed to reveal any exon skipping because of this splice site variant. A homozygous variant (c.11T>G; p.Gln4Pro) in SEC24D also segregated with the disease in this particular family. One previously known mutation (c.974del; p.Cys325LeufsX2) was identified in a sporadic patient with BCS from Serbia. The current study revealed a novel mutation in the PRDM5 gene in a BCS family and recurrent mutation in a sporadic BCS patient. A variant in the SEC24D gene also segregated in the BCS family, although its role in the disease remains unclear.

Cystic Fibrosis (CF) patients frequently use aminoglycosides (AGS) to treat CF exacerbation due to colonization with Pseudomonas aeruginosa. Although AGS can cause vestibular and auditory sensory losses that can negatively impact quality of life, little is known about the prevalence of vestibular loss in this population. The aim of this study was to determine the prevalence of hearing loss and/or vestibular dysfunction in CF patients treated with AGS. The relationship between hearing status and vestibular status was also investigated. Hearing was determined to be normal or abnormal based on pure tone air and bone conduction thresholds. Vestibular outcome was divided into four categories; normal, non-lateralized vestibular dysfunction, unilateral loss, and bilateral loss based on results of post head shaking testing, positional and positioning testing, bithermal calorics, sinusoidal, and rotational step testing. Of our cohort of 71 patients, 56 (79%) patients have vestibular system dysfunction while only 15 (21%) have normal vestibular system function. Overall, 16 patients (23%) have hearing loss. In considering the relationship between auditory and vestibular function, 12 (17%) demonstrated both normal hearing and normal vestibular function and 13 (18%) have both hearing loss and abnormal vestibular function. Of the 55 (78%) patients with normal hearing, 43 (61%) have vestibular dysfunction, while 3 (4%) of patients with normal vestibular function have hearing loss. These results suggest that monitoring hearing alone is insufficient to detect ototoxicity in CF patients being treated with systemic AGS.

To describe the prevalence of auditory and vestibular dysfunction in individuals with systemic sclerosis (SS) and the hypotheses to explain these changes. We performed a systematic review without meta-analysis from PubMed, LILACS, Web of Science, SciELO and SCOPUS databases, using a combination of keywords "systemic sclerosis AND balance OR vestibular" and "systemic sclerosis AND hearing OR auditory." We included articles published in Portuguese, Spanish, or English until December 2011 and reviews, letters, and editorials were excluded. We found 254 articles, out of which 10 were selected. The study design was described, and the characteristics and frequency of the auditory and vestibular dysfunctions in these individuals were listed. Afterwards, we investigated the hypothesis built by the authors to explain the auditory and vestibular dysfunctions in SS. Hearing loss was the most common finding, with prevalence ranging from 20 to 77%, being bilateral sensorineural the most frequent type. It is hypothesized that the hearing impairment in SS is due to vascular changes in the cochlea. The prevalence of vestibular disorders ranged from 11 to 63%, and the most frequent findings were changes in caloric testing, positional nystagmus, impaired oculocephalic response, changes in clinical tests of sensory interaction, and benign paroxysmal positional vertigo. High prevalence of auditory and vestibular dysfunctions in patients with SS was observed. Conducting further research can assist in early identification of these abnormalities, provide resources for professionals who work with these patients, and contribute to improving the quality of life of these individuals.

Attention-deficit/hyperactivity disorder (ADHD) and anxiety-related disorders occur at rates 2–3 times higher in deaf compared with hearing children. Potential explanations for these elevated rates and the heterogeneity of behavioral disorders...

Attention-deficit/hyperactivity disorder (ADHD) and anxiety-related disorders occur at rates 2-3 times higher in deaf compared with hearing children. Potential explanations for these elevated rates and the heterogeneity of behavioral disorders associated with deafness have usually focused on socio-environmental rather than biological effects. Children with the 22q11.2 deletion or duplication syndromes often display hearing loss and behavioral disorders, including ADHD and anxiety-related disorders. Here, we show that mouse mutants with either a gain or loss of function of the T-Box transcription factor gene, Tbx1, which lies within the 22q11.2 region and is responsible for most of the syndromic defects, exhibit inner ear defects and hyperactivity. Furthermore, we show that (1) inner ear dysfunction due to the tissue-specific loss of Tbx1 or Slc12a2, which encodes a sodium-potassium-chloride cotransporter and is also necessary for inner ear function, causes hyperactivity; (2) vestibular rather than auditory failure causes hyperactivity; and (3) the severity rather than the age of onset of vestibular dysfunction differentiates whether hyperactivity or anxiety co-occurs with inner ear dysfunction. Together, these findings highlight a biological link between inner ear dysfunction and behavioral disorders and how sensory abnormalities can contribute to the etiology of disorders traditionally considered of cerebral origin.SIGNIFICANCE STATEMENT This study examines the biological rather than socio-environmental reasons why hyperactivity and anxiety disorders occur at higher rates in deaf individuals. Using conditional genetic approaches in mice, the authors show that (1) inner ear dysfunction due to either Tbx1 or Slc12a2 mutations cause hyperactivity; (2) it is vestibular dysfunction, which frequently co-occurs with deafness but often remains undiagnosed, rather than auditory dysfunction that causes hyperactivity and anxiety-related symptoms; and (3) the severity of vestibular dysfunction can predict whether hyperactivity or anxiety coexist with inner ear dysfunction. These findings suggest a need to evaluate vestibular function in hearing impaired individuals, especially those who exhibit hyperactive and anxiety-related symptoms.