Non-Syndromic Hearing Loss Panel

PLUSbpg-method Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 3–4 weeks. SEQbpg-method Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 3–4 weeks. DEL/DUPbpg-method Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 3–4 weeks.

Test code: EA0201

The Blueprint Genetics Non-Syndromic Hearing Loss Panel is a 93 gene test for genetic diagnostics of patients with clinical suspicion of non-syndromic genetic deafness or sensorineural hearing loss, unilateral and bilateral.

The inheritance of most types of non-syndromic hearing loss is autosomal recessive. However, also autosomal dominant as well as X-linked forms are present. Genes and mutations causative for sensorineural non-syndromic hearing loss are often population-specific and the clinical utility of this Panel varies consequently. In addition to non-syndromic hearing loss, this Panel have differential diagnostics power to some specific syndromes with hearing loss (for example Usher syndrome, Baraitser-Winter syndrome, branchio-oto-renal (BOR) syndrome), but in general, the Syndromic Hearing Loss Panel is recommended for genetic diagnostic of patients with hearing loss interlinked with symptoms affecting other parts of the body. In addition to protein coding regions, two disease causing intronic variants of HGF gene are targeted in this Panel. This Panel is included in the Comprehensive Hearing Loss and Deafness Panel.

About Non-Syndromic Hearing Loss

Sensorineural hearing loss is a genetically very heterogenous group of phenotypes varying in severity and causes. Non-syndromic sensorineural hearing loss is a partial or total loss of hearing that occurs in isolation, without other associated medical disorders. Hearing loss can be unilateral or bilateral and it can be stable or progressive. In addition, specific types of non-syndromic hearing loss may show distinctive pattern of hearing loss for high, middle or low tones. Some 75%-to-85% of congenital hereditary hearing impairnment have non-syndromic origin and the prevalence is estimated to be 3-4:10000 neonates and increases with age. In many populations, mutations in GJB2 are the most prevalent explaining up to 50% of all non-syndromic hearing losses.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

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Genes in the Non-Syndromic Hearing Loss Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ACTG1* Deafness, Baraitser-Winter syndrome AD 17 37
ADCY1 Deafness AR 1 1
BDP1* Hearing loss AD/AR 1
BSND Sensorineural deafness with mild renal dysfunction, Bartter syndrome AR 10 21
CABP2 Deafness AR 1 6
CCDC50 Deafness AD 1 3
CDH23 Deafness, Usher syndrome AR/Digenic 48 294
CEACAM16 Deafness AD 3 3
CIB2 Deafness, Usher syndrome AR 4 15
CLDN14 Deafness AR 8 11
CLIC5 Deafness AR 1 1
COCH Deafness AD 10 27
COL4A6 Deafness, with cochlear malformation XL 12 4
COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) AD/AR 17 51
CRYM Deafness AD 2 3
DCDC2 Deafness AR 4 11
DFNA5 Deafness AD 6 8
DFNB31 Deafness, Usher syndrome AR 9 28
DFNB59 Deafness AR 7 19
DIABLO Deafness AD 1 2
DIAPH1 Deafness AD 4 12
DIAPH3 Non-syndromic sensorineural deafness AD/AR 1 6
DSPP Dentin dysplasia, Dentinogenesis imperfecta, Deafness, with dentinogenesis imperfecta AD 8 48
ELMOD3 Deafness AR 1 1
EPS8 Deafness AR 1 2
ESPN* Deafness AD/AR 7 11
ESRRB Deafness AR 8 16
EYA4 Dilated cardiomyopathy (DCM) AD 8 22
FAM65B Deafness AR 1 1
GIPC3 Deafness AR 9 17
GJB2 Deafness, Bart-Pumphrey syndrome, Keratoderma, palmoplantar, with deafness, Vohwinkel syndrome, Hystrix-like ichthyosis with deafness, Keratitis-icthyosis-deafness syndrome AD/AR/Digenic 96 385
GJB3 Deafness AD/Digenic 8 37
GJB6 Deafness AR/Digenic 8 28
GPSM2 Deafness, Chudley-McCullough syndrome AR 10 11
GRHL2 Ectodermal dysplasia/short stature syndrome AD/AR 6 6
GRXCR1 Deafness AR 4 9
GRXCR2 Deafness AR 1 1
HGF Deafness AR 4 12
HOMER2 Deafness AD 2 2
ILDR1 Deafness AR 4 22
KARS Charcot-Marie-Tooth disease AR 6 14
KCNQ4 Deafness AD 24 35
LHFPL5 Deafness AR 4 10
LOXHD1 Deafness AR 12 37
LRTOMT Deafness AR 6 16
MARVELD2 Deafness AR 6 15
MET Deafness, Renal cell carcinoma, papillary AD/AR 13 23
MIR96 Deafness AD 2 4
MSRB3 Deafness AR 4 2
MYH9 Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness AD 19 113
MYH14 Deafness, Peripheral neuropathy, myopathy, hoarseness, and hearing loss AD 6 26
MYO1A Deafness AD 1 16
MYO3A Deafness AR 6 18
MYO6 Deafness AR 14 47
MYO7A Deafness, Usher syndrome AR 125 402
MYO15A Deafness AR 48 209
NARS2 Combined oxidative phosphorylation deficiency AR 3 6
OSBPL2 Deafness AD 2 3
OTOA* Deafness AR 12 24
OTOF Neuropathy, Deafness AR 94 153
OTOG Deafness AR 5 3
OTOGL Deafness AR 10 17
P2RX2 Deafness AD 2 3
PCDH15 Deafness, Usher syndrome AR/Digenic 28 97
PNPT1* Deafness AR 12 4
POU3F4 Deafness XL 19 66
POU4F3 Deafness AD 6 14
PRPS1* Deafness, Phosphoribosylpyrophosphate synthetase I superactivity, Arts syndrome XL 22 26
PTPRQ Deafness AR 5 27
RDX* Deafness AR 5 7
SERPINB6 Deafness AR 1 3
SIX1 Deafness, Branchiootic syndrome, Branchiootorenal syndrome AD 9 15
SLC17A8 Deafness AD 1 5
SLC26A4 Deafness, Pendred syndrome, Enlarged vestibular aqueduct AR 98 521
SLC26A5 Deafness AR 2 7
SLITRK6 Deafness and myopia AR 3 3
SMPX Deafness XL 5 9
STRC* Deafness AR 24 71
SYNE4 Deafness AR 4 1
TBC1D24 Deafness, Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome AD/AR 27 41
TECTA Deafness AD/AR 17 97
TJP2 Cholestasis, progressive familial intrahepatic, Hypercholanemia, familial AR 15 15
TMC1 Deafness AR 23 84
TMC2 Hearing loss AD/AR
TMEM132E Hearing loss AD/AR 1
TMIE Deafness AR 8 10
TMPRSS3 Deafness AR 20 66
TNC Deafness AD 2 5
TPRN Deafness AR 5 10
TRIOBP Deafness AR 13 32
TSPEAR Deafness AR 1 8
USH1C Deafness, Usher syndrome AR 13 45
WFS1 Wolfram syndrome AR 59 343

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number Comment Reference
HGF Chr7:81384517–81384519 c.482+1986_1988delTGA NM_000601.4
HGF Chr7:81384505–81384514 c.482+1991_2000delGATGATGAAA NM_000601.4

Blueprint Genetics offers a comprehensive Non-Syndromic Hearing Loss Panel that covers classical genes associated with Baraitser-Winter syndrome, branchio-oto-renal (BOR) syndrome, non-syndromic genetic deafness, sensorineural hearing loss, unilateral and bilateral and Usher syndrome. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ81430
DEL/DUP81431


ICD codes

Commonly used ICD-10 codes when ordering the Non-Syndromic Hearing Loss Panel

ICD-10 Disease
H90.5 Sensorineural hearing loss, unilateral and bilateral

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

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