Syndromic Hearing Loss Panel

Last modified: Mar 21, 2018


  • Is a 89 gene panel that includes assessment of non-coding variants
  • Is ideal for patients suspected to have a syndromic form of hearing loss. The genes on this panel are included on the Comprehensive Hearing Loss and Deafness Panel.

    Is not ideal for patients suspected to have non-syndromic hearing loss. Please refer to our Non-Syndromic Hearing Loss Panel or our Comprehensive Hearing Loss and Deafness Panel.

Analysis methods

  • PLUS
  • SEQ


3-4 weeks

Number of genes


Test code


CPT codes

SEQ 81404
SEQ 81405
SEQ 81408
DEL/DUP 81479


The Blueprint Genetics Syndromic Hearing Loss Panel (test code EA0401):

  • Is a 89 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) 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

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • 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.

Hearing loss is a genetically heterogenous group of phenotypes varying in severity and causes. In syndromic hearing loss, one or more organ systems are also affected in addition to the hearing impairment 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 1-2:10,000. The most common syndromic causes of hearing loss include Alport syndrome, branchio-oto-renal (BOR) syndrome, Pendred syndrome, Stickler syndrome, Usher syndrome and Waardenburg syndrome.

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, Febrile seizures, familial, 4 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
ATP6V1B2 Deafness, congenital, with onychodystrophy, autosomal dominant, Zimmermann-Laband syndrome 2 AD 5 2
BCS1L Bjornstad syndrome AR 32 37
BSND Sensorineural deafness with mild renal dysfunction, Bartter syndrome AR 10 19
BTD Biotinidase deficiency AR 183 235
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome AR 37
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
CEP78 Cone rod dystrophy and hearing loss 7 8
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
CLPP Deafness AR 3 13
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, Hematuria, benign familial 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
DCAF17 Woodhouse-Sakati syndrome AR 12 13
DFNB31 Deafness, Usher syndrome AR 11 30
DLX5 Split-hand/foot malformation with sensorineural hearing loss AR 3 8
DNMT1 Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsy AD 10 19
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
FDXR Auditory neuropathy and optic atrophy AR 4
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
GJA1* Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3 AD/AR 28 105
HARS* Usher syndrome, Charcot-Marie-Tooth disease, axonal, type 2W AR 5 9
HARS2 Perrault syndrome AR 7 3
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
KIT Gastrointestinal stromal tumor AD 73 109
LARS2 Perrault syndrome AR 11 11
LRP2 Donnai-Barrow syndrome, Faciooculoacousticorenal syndrome AR 22 27
MAN2B1 Mannosidosis, alpha B, lysosomal AR 34 142
MANBA Mannosidosis, lysosomal AR 12 18
MGP Keutel syndrome AR 5 7
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
PEX1 Heimler syndrome AR 77 130
PEX6 Heimler syndrome AR 25 105
PEX26 Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorder AR 11 24
POLR1C Treacher Collins syndrome AR 16 20
POLR1D Treacher Collins syndrome AD/AR 7 26
SALL1* Townes-Brocks syndrome 1 AD 24 83
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
SLC52A2 Brown-Vialetto-Van Laere syndrome AR 22 19
SLC52A3 Fazio-Londe disease, Brown-Vialetto-Van Laere syndrome AR 33 30
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, Retinitis pigmentosa 39 AR 225 1001
VCAN Wagner disease AD 11 19
WFS1 Wolfram syndrome, Deafness AD/AR 65 343

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ANKH Chr5:14871567 c.-11C>T NM_054027.4
BCS1L Chr2:219524871 c.-147A>G NM_004328.4
BCS1L Chr2:219525123 c.-50+155T>A NM_004328.4 rs386833855
BTD Chr3:15687154 c.*159G>A NM_000060.2 rs530872564
CDH23 Chr10:73403617 c.1135-1G>T NM_022124.5
CDKN1C Chr11:2905209 c.*5+20G>T NM_000076.2 rs760540648
CHD7 Chr8:61734568 c.2836-15C>G NM_017780.3
CHD7 Chr8:61757794 c.5051-15T>A NM_017780.3
CHD7 Chr8:61763035 c.5405-17G>A NM_017780.3 rs794727423
COL11A1 Chr1:103488576 c.1027-24A>G NM_080629.2
COL11A1 Chr1:103386637 c.3744+437T>G NM_080629.2
COL11A1 Chr1:103491958 c.781-450T>G NM_080629.2 rs587782990
COL2A1 Chr12:48379984 c.1527+135G>A NM_001844.4
COL4A3 Chr2:228145145 c.2224-11C>T NM_000091.4
COL4A3 Chr2:228168708 c.4028-27A>G NM_000091.4
COL4A3 Chr2:228173092 c.4462+457C>G NM_000091.4
COL4A3 Chr2:228176114 c.4929-388G>T NM_000091.4
COL4A4 Chr2:227875240 c.4334-23A>G NM_000092.4
COL4A5 ChrX:107838719 c.1424-20T>A NM_033380.2 rs281874668
COL4A5 ChrX:107849958 c.2245-14T>A NM_033380.2
COL4A5 ChrX:107852872 c.2395+2750A>G NM_033380.2
COL4A5 ChrX:107813924 c.385-719G>A NM_033380.2 rs104886396
COL4A5 ChrX:107933678 c.4529-2300T>G NM_033380.2
COL4A5 ChrX:107935633 c.4529-345A>G NM_033380.2
COL4A5 ChrX:107816792 c.466-12G>A NM_033380.2 rs104886414
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
EDN3 Chr20:57875743 c.-125G>A NM_000114.2
EDN3 Chr20:57875849 c.-19C>A NM_000114.2 rs375594972
EYA1 Chr8:72156939 c.1051-12T>G NM_000503.4
EYA1 Chr8:72211483 c.640-15G>A NM_000503.4
KCNJ10 Chr1:160039811 c.-1+1G>T NM_002241.4 rs796052606
MYO7A Chr11:76839534 c.-48A>G NM_000260.3
MYO7A Chr11:76893448 c.3109-21G>A NM_000260.3
NDP ChrX:43818099 c.-207-1G>A NM_000266.3
NDP ChrX:43832549 c.-208+1G>A NM_000266.3
NDP ChrX:43832548 c.-208+2T>G NM_000266.3
NDP ChrX:43832545 c.-208+5G>A NM_000266.3
PAX3 Chr2:223085913 c.958+28A>T NM_181459.3
PCDH15 Chr10:56560684 c.-29+1G>C NM_001142763.1
PEX6 Chr6:42933952 c.2300+28G>A NM_000287.3 rs267608237
PEX6 Chr6:42933858 c.2301-15C>G NM_000287.3 rs267608236
SLC26A4 Chr7:107301201 c.-103T>C NM_000441.1 rs60284988
SLC26A4 Chr7:107301301 c.-4+1G>C NM_000441.1
SLC26A4 Chr7:107301305 c.-4+5G>A NM_000441.1 rs727503425
SLC26A4 Chr7:107301244 c.-60A>G NM_000441.1 rs545973091
SLC26A4 Chr7:107334836 c.1264-12T>A NM_000441.1
SLC26A4 Chr7:107336364 c.1438-7dupT NM_000441.1 rs754734032
SOX10 Chr22:38412215 c.-31954C>T NM_006941.3 rs606231342
SOX10 Chr22:38379877 c.-84-2A>T NM_006941.3
TIMM8A ChrX:100601671 c.133-23A>C NM_004085.3 rs869320666
TYR Chr11:88960973 c.1037-18T>G NM_000372.4
USH2A Chr1:216596610 c.-259G>T NM_206933.2
USH2A Chr1:215821092 c.14583-20C>G NM_206933.2
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
USH2A Chr1:215967783 c.9959-4159A>G NM_206933.2
WFS1 Chr4:6271704 c.-43G>T NM_006005.3

Added and removed genes from the panel

Genes added Genes removed

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • 1479 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

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

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.

The Blueprint Genetics syndromic hearing loss panel covers classical genes associated with Waardenburg syndrome, Alport syndrome, Pendred syndrome, Usher syndrome, Stickler syndrome, Jervell and Lange-Nielsen syndrome, Mohr-Tranebjaerg syndrome, Norrie disease, Treacher Collins syndrome, CHARGE syndrome and Branchio-oto-renal (BOR) syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics' Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient's phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%


The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. 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. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.