Syndromic Hearing Loss Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: EA0401

The Blueprint Genetics Syndromic Hearing Loss Panel is a 70 gene test for genetic diagnostics of patients with clinical suspicion of Alport syndrome, branchio-oto-renal (BOR) syndrome, Pendred syndrome, Stickler syndrome, Usher syndrome or Waardenburg syndrome.

Inheritance of syndromes characterized by hearing loss and deafness varies from autosomal recessive and dominant to X-linked forms. Clinical utility of this Panel varies between syndromes, and is estimated to be for example >50% for Pendred syndrome, 80%-90% for Usher syndrome, >80% for Alport syndrome and >40% for branchio-oto-renal syndrome. In addition to main phenotypes, this Panel can be used for differential diagnostics of other rare phenotypes such as Jervell and Lange-Nielsen syndrome, Mohr-Tranebjaerg syndrome, Norrie disease, Treacher Collins syndrome and CHARGE syndrome. This Panel includes the Waardenburg Syndrome Panel, Pendred Syndrome Panel, Usher Syndrome Panel, Stickler Syndrome Panel, Alport Syndrome Panel and Branchio-Oto-Renal (BOR) Syndrome Panel. This Panel is included in the Comprehensive Hearing Loss and Deafness Panel.

About Syndromic Hearing Loss

Hearing loss is a genetically very heterogenous group of phenotypes varying in severity and causes. In syndromic hearing loss, symptoms affecting other parts of the body occur interlinked with hearing impairnment or deafness. Altogether syndromic hearing loss accounts for 20% to 30% of congenital hearing loss and deafness and the combined prevalence of syndromic hearing loss is approximately 1-2:10000.

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

Genes in the Syndromic Hearing Loss Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ABHD12 Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract AR 12 18
ACTG1* Deafness, Baraitser-Winter syndrome AD 21 43
ADGRV1 Usher syndrome AR/Digenic 58 164
ALMS1* Alström syndrome AR 50 291
ANKH Calcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant type AD 12 20
ATP6V1B1 Renal tubular acidosis with deafness AR 9 54
BCS1L Bjornstad syndrome AR 32 37
BSND Sensorineural deafness with mild renal dysfunction, Bartter syndrome AR 10 19
BTD Biotinidase deficiency AR 183 235
CACNA1D Primary aldosteronism, seizures, and neurologic abnormalities, Sinoatrial node dysfunction and deafness AD/AR 6 5
CD151 Raph blood group BG 1
CDH23 Deafness, Usher syndrome AR/Digenic 69 332
CDKN1C Beckwith-Wiedemann syndrome, IMAGE syndrome AD 24 81
CHD7 Isolated gonadotropin-releasing hormone deficiency, CHARGE syndrome AD 192 784
CHSY1 Temtamy preaxial brachydactyly syndrome AR 6 11
CIB2 Deafness, Usher syndrome AR 4 15
CLRN1 Retinitis pigmentosa, Usher syndrome AR 17 34
COL2A1 Avascular necrosis of femoral head, Rhegmatogenous retinal detachment, Epiphyseal dysplasia, with myopia and deafness, Czech dysplasia, Achondrogenesis type 2, Platyspondylic dysplasia Torrance type, Hypochondrogenesis, Spondyloepiphyseal dysplasia congenital (SEDC), Spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, Spondyloperipheral dysplasia, Mild SED with premature onset arthrosis, SED with metatarsal shortening, Stickler syndrome type 1 AD 138 541
COL4A3 Alport syndrome AD/AR 34 229
COL4A4 Alport syndrome AD/AR 21 184
COL4A5 Alport syndrome XL 645 940
COL4A6 Deafness, with cochlear malformation XL 11 4
COL9A1 Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6) AR 7 5
COL9A2 Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2) AD/AR 7 12
COL9A3 Multiple epihyseal dysplasia type 3 (EDM3) AD/AR 6 15
COL11A1 Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2 AD/AR 22 81
COL11A2 Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular) AD/AR 23 54
DFNB31 Deafness, Usher syndrome AR 11 30
DLX5 Split-hand/foot malformation with sensorineural hearing loss AR 3 8
EDN3 Hirschsprung disease, Central hypoventilation syndrome, congenital, Waardenburg syndrome AD/AR 6 21
EDNRB Hirschsprung disease, ABCD syndrome, Waardenburg syndrome AD/AR 7 66
EYA1 Otofaciocervical syndrome, Branchiootic syndrome, Branchiootorenal syndrome AD 39 197
FGF3 Deafness, congenital with inner ear agenesis, microtia, and microdontia AR 13 20
FOXI1 Pendred syndrome, Enlarged vestibular aqueduct AR 1 9
GATA3 Hypomagnesemia, renal AD 20 77
HARS Usher syndrome AR 5 9
HOXB1 Facial paresis, hereditary congenital AR 1 5
KCNE1 Long QT syndrome, Jervell and Lange-Nielsen syndrome AD/AR/Digenic 8 45
KCNJ10 Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), Pendred syndrome, Enlarged vestibular aqueduct AR/Digenic 14 24
KCNQ1 Short QT syndrome, Long QT syndrome, Atrial fibrillation, Jervell and Lange-Nielsen syndrome AD/AR/Digenic 258 599
LRP2 Donnai-Barrow syndrome, Faciooculoacousticorenal syndrome AR 22 27
MANBA Mannosidosis, lysosomal AR 12 18
MITF Renal cell carcinoma with or without malignant melanoma, Tietz albinism-deafness syndrome, Waardenburg syndrome, Melanoma, cutaneous malignant AD 24 55
MYH9 Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness AD 21 113
MYO7A Deafness, Usher syndrome AD/AR 155 426
NDP Exudative vitreoretinopathy, Norrie disease XL 29 159
NLRP3 Neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, Chronic infantile neurologic cutaneous articular (CINCA) syndrome AD 19 127
PAX3 Craniofacial-deafness-hand syndrome, Waardenburg syndrome AD/AR 22 135
PCDH15 Deafness, Usher syndrome AR/Digenic 71 107
PDZD7 Usher syndrome Digenic 1 15
POLR1C Treacher Collins syndrome AR 16 20
POLR1D Treacher Collins syndrome AD/AR 7 26
SEMA3E CHARGE syndrome AD 1 4
SIX1 Deafness, Branchiootic syndrome, Branchiootorenal syndrome AD 11 16
SIX5 Branchiootorenal syndrome AD 3 9
SLC19A2 Thiamine-responsive megaloblastic anemia syndrome AR 11 49
SLC26A4 Deafness, Pendred syndrome, Enlarged vestibular aqueduct AR 137 535
SLITRK6 Deafness and myopia AR 3 3
SMAD4 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasia AD 139 132
SNAI2 Waardenburg syndrome AR 2 4
SOX10 Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease AD 34 133
TCOF1 Treacher Collins syndrome AD 31 320
TFAP2A Branchiooculofacial sydrome AD 9 41
TIMM8A* Mohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementia XL 10 21
TYR* Albinism, oculocutaneous AR 69 391
USH1C Deafness, Usher syndrome AR 18 48
USH1G Usher syndrome AR 9 26
USH2A Usher syndrome, Retinitis pigmentosa AR 225 1001
VCAN Wagner disease AD 11 19
WFS1 Wolfram syndrome, Deafness AD/AR 65 343

*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
BCS1L Chr2:219525123 c.-50+155T>A NM_004328.4 rs386833855
CHD7 Chr8:61763035 c.5405-17G>A NM_017780.3 rs794727423
COL11A1 Chr1:103491958 c.781-450T>G NM_080629.2 rs587782990
COL4A5 ChrX:107838719 c.1424-20T>A NM_033380.2 rs281874668
COL4A5 ChrX:107813924 c.385-719G>A NM_033380.2 rs104886396
COL4A5 ChrX:107816787 c.466-17T>G NM_033380.2 rs104886415
COL4A5 ChrX:107938272 c.4821+121T>C NM_033380.2 rs104886423
COL4A5 ChrX:107938346 c.4822-151_4822-150insT NM_033380.2 rs397515494
KCNJ10 Chr1:160039811 c.-1+1G>T NM_002241.4 rs796052606
SLC26A4 Chr7:107301201 c.-103T>C NM_000441.1 rs60284988
SLC26A4 Chr7:107301305 c.-4+5G>A NM_000441.1 rs727503425
TIMM8A ChrX:100601671 c.133-23A>C NM_004085.3 rs869320666
USH2A Chr1:216247476 c.5573-834A>G NM_206933.2
USH2A Chr1:216064540 c.7595-2144A>G NM_206933.2 rs786200928
USH2A Chr1:216039721 c.8845+628C>T NM_206933.2

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Blueprint Genetics offers a comprehensive Syndromic Hearing Loss Panel that covers classical genes associated with Alport syndrome, branchio-oto-renal (BOR) syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Mohr-Tranebjaerg syndrome, Norrie disease, Pendred syndrome, Stickler syndrome, treacher Collins syndrome, Usher syndrome and Waardenburg 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

SEQ 81479
DEL/DUP 81431


ICD codes

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

ICD-10 Disease
E70.30 Waardenburg syndrome
Q87.89 Alport syndrome
E07.1 Pendred syndrome
H35.50 Usher syndrome
Q89.8 Stickler syndrome
Q87.89 Branchio-oto-renal (BOR) syndrome

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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