Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, ...the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL‐specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL.
The Hearing Loss Variant Curation Expert panel was created within ClinGen with the goals of standardizing variant interpretation in hearing loss, resolving existing discrepancies in submitted variant classifications in ClinVar and providing expert variant classifications for hearing loss. Here we present specifications of the ACMG/AMP variant interpretation guidelines for hearing loss and the results of a pilot project in which these specifications were applied to 51 variants in the CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA, and USH2A genes.
Renal coloboma syndrome SCHIMMENTI, Lisa A
European journal of human genetics : EJHG,
12/2011, Letnik:
19, Številka:
12
Journal Article
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Renal coloboma syndrome (RCS), also called papillorenal syndrome, is an autosomal dominant condition characterized by optic nerve dysplasia and renal hypodysplasia. The eye anomalies consist of a ...wide and sometimes excavated dysplastic optic disc with the emergence of the retinal vessels from the periphery of the disc, frequently called optic nerve coloboma or morning glory anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst and pigmentary macular dysplasia. The kidney abnormalities consist of small and abnormally formed kidneys known as renal hypodysplasia. Histologically, kidneys exhibit fewer than the normal number of glomeruli and these glomeruli are enlarged, a finding called oligomeganephronia. Consequences of the ocular malformations include decreased visual acuity and retinal detachment. Consequences of the renal hypodysplasia include hypertension, proteinuria and renal insufficiency that frequently progresses to end-stage kidney disease. High frequency hearing loss has been reported. Autosomal dominant mutations in PAX2 can be identified in nearly half of all patients with clinical findings suggestive of RCS, however, the majority of published cases have mutations in PAX2, thus biasing the known information about the phenotype.
Sensorineural hearing loss (SNHL) occurs commonly as part of mitochondriopathies and varies in severity and onset. In this study, we characterized hearing with specific consideration for hearing loss ...as a potential early indicator of mitochondrial disease (MD). We hypothesize that genetic testing at the earliest detection of SNHL may lead to an earlier MD diagnosis.
We reviewed the clinical and audiometric data of 49 patients undergoing genetic testing for MD.
One-third of individuals with molecularly confirmed MD presented with SNHL. On average, patients had hearing loss at least 10 years before genetic testing. The collective audiometric profile includes mild to moderate SNHL at lower frequencies and moderate SNHL at 2 kHz and higher frequencies.
This study suggests that screening for SNHL could be an early indicator of MD. We propose that the audiometric profile for those with a MD diagnosis may have clinical triage utility.
Transmembrane channel-like protein isoform 1 (TMC1) is a major component of the mechano-electrical transducer (MET) channel in cochlear hair cells and is subject to numerous mutations causing ...deafness. We report a new dominant human deafness mutation,
p.T422K, and have characterized the homologous mouse mutant,
p.T416K, which caused deafness and outer hair cell (OHC) loss by the fourth postnatal week. MET channels showed decreased Ca
permeability and resting open probability, but no change in single-channel conductance or expression. Three adjacent deafness mutations are
p.L416R, p.G417R, and p.M418K, the last homologous to the mouse
that exhibits similar channel effects. All substitute a positive for a neutral residue, which could produce charge screening in the channel pore or influence binding of an accessory subunit. Channel properties were compared in mice of both sexes between dominant (
p.T416K,
p.D569N) and recessive (
p.W554L,
p.D528N) mutations of residues near the putative pore of the channel.
p.W554L and p.D569N exhibit reduced maximum current with no effect on single-channel conductance, implying a smaller number of channels transported to the stereociliary tips; this may stem from impaired TMC1 binding to LHFPL5.
p.D528N, located in the pore's narrowest region, uniquely caused large reductions in MET channel conductance and block by dihydrostreptomycin (DHS). For
p.T416K and
p.D528N, transduction loss occurred between P15 and P20. We propose two mechanisms linking channel mutations and deafness: decreased Ca
permeability, common to all mutants, and decreased resting open probability in low Ca
, confined to dominant mutations.
Transmembrane channel-like protein isoform 1 (TMC1) is thought to be a major component of the mechanotransducer channel in auditory hair cells, but the protein organization and channel structure are still uncertain. We made four mouse lines harboring
point mutations that alter channel properties, causing hair cell degeneration and deafness. These include a mouse homolog of a new human deafness mutation pT416K that decreased channel Ca
permeability by introducing a positively-charged amino acid in the putative pore. All mutations are consistent with the channel structure predicted from modeling, but only one, p.D528N near the external face of the pore, substantially reduced channel conductance and Ca
permeability and virtually abolished block by dihydrostreptomycin (DHS), strongly endorsing its siting within the pore.
OBJECTIVES/GOALS: The characterization of the zebrafish as an animal model for Cockayne Syndrome may guide us towards role of Transcription-Coupled Nucleotide Excision Repair (TC-NER) defects in ...sensorineural hearing loss. METHODS/STUDY POPULATION: To examine our model, we have developed a zebrafish line with a 9+1 base-pair deletion in the ercc6 gene using TALENs. Mutation has since been confirmed by PCR and subsequent restriction digest with StuI. A series of assays evaluating hair cell morphology, structure and function, as well as ribbon synapse structure, will be used to analyze potential differences between the ercc6 mutant zebrafish line a their wild-type siblings. Additionally, electron microscopy will be used to assess differences in hair cell ultrastructure between the ercc6 mutant zebrafish line a their wild-type siblings. Finally, UVC exposure assays will be used to determine the role TC-NER plays in our novel zebrafish model, and evaluate its potential implications in sensorineural hearing loss. RESULTS/ANTICIPATED RESULTS: We anticipate that biallelic loss of function mutations in the zebrafish ercc6 gene will result in abnormalities in hair cell structure, mechanotransduction, or cell number. Additionally, we anticipate that hair cell ultrastructure and ribbon synapse structure will be impacted by loss of ercc6 expression. DISCUSSION/SIGNIFICANCE: Hearing loss mechanisms associated with defects in TC-NER are yet to be described. We believe our model will provide the tools for a faster and efficient way to carry out Cockayne Syndrome studies while laying the groundwork for the association between TC-NER and hearing loss.
Morpholino oligonucleotides are the most common anti-sense "knockdown" technique used in zebrafish (Danio rerio). This review discusses common practices for the design, preparation, and deployment of ...morpholinos in this vertebrate model system. Off-targeting effects of morpholinos are discussed as well as method to minimize this potentially confounding variable via co-injection of a tP53-targeting morpholino. Finally, new uses of morpholinos are summarized and contextualized with respect to the complementary, DNA-based knockout technologies recently developed for zebrafish.
The
(
) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in
mutants, we focused on the ribbon synapse and evaluated ultrastructure, ...number and distribution of immunolabeled ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that
zebrafish have fewer glutamatergic vesicles tethered to ribbon synapses, yet maintain a comparable ribbon area. In
hair cells, immunolocalization of Ctbp2 showed fewer ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells.
mutants have fewer postsynaptic densities - as assessed by MAGUK immunolabeling - compared to wild-type zebrafish. We quantified the circular swimming behavior of
mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in
mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of
mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the ribbon synapse - in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta - shift swimming behavior and improve acoustic startle response.
Bosma arhinia microphthalmia syndrome (Bosma syndrome)(OMIM 603457) is a congenital condition characterized by microphthalmia with coloboma, arhinia and endocrine findings in the setting of normal ...intelligence and brain structure. This condition is quite rare with fewer than 50 case reports and series. Although pathogenesis is presumed to be genetic, the cause remains unknown. We report an individual with Bosma syndrome who had bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism requiring growth hormone treatment in childhood, and normal intelligence. Clinical evaluation was significant for a geometrically abnormal aorta with effacement of the sinotubular ridge, a finding not previously reported in this condition. An MRI revealed absent olfactory bulbs. Suggested criteria for diagnosis of Bosma should include arhinia, hypoplastic maxilla, normal cognition, and hypogonadotropic hypogonadism in males.
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