Syndromic Hearing Loss Panel

89 gene panel that includes assessment of non-coding variants

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 Availability Number of genes Test code CPT codes
4 weeks 89 GHC0048 SEQ 81404
SEQ 81405
SEQ 81408
DEL/DUP 81479


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.

Panel Content

Genes in the Syndromic Hearing Loss Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABHD12Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataractAR1418
ACTG1Deafness, Baraitser-Winter syndromeAD2543
ADGRV1Usher syndrome, Febrile seizures, familial, 4AR/Digenic69207
ALMS1Alström syndromeAR64295
ANKHCalcium pyrophosphate deposition disease (familial chondrocalcinosis type 2), Craniometaphyseal dysplasia autosomal dominant typeAD1220
ATP6V1B1Renal tubular acidosis with deafnessAR1156
ATP6V1B2Deafness, congenital, with onychodystrophy, autosomal dominant, Zimmermann-Laband syndrome 2AD62
BCS1LBjornstad syndrome, GRACILE syndrome, Leigh syndrome, Mitochondrial complex III deficiency, nuclear type 1AR3337
BSNDSensorineural deafness with mild renal dysfunction, Bartter syndromeAR1019
BTDBiotinidase deficiencyAR180236
C10ORF2Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3AR3677
CACNA1DPrimary aldosteronism, seizures, and neurologic abnormalities, Sinoatrial node dysfunction and deafnessAD/AR77
CD151Raph blood group, Nephropathy with pretibial epidermolysis bullosa and deafnessBG12
CDH23Deafness, Usher syndromeAR/Digenic90351
CDKN1CBeckwith-Wiedemann syndrome, IMAGE syndromeAD2881
CEP78Cone rod dystrophy and hearing lossAR79
CHD7Isolated gonadotropin-releasing hormone deficiency, CHARGE syndromeAD244813
CHSY1Temtamy preaxial brachydactyly syndromeAR611
CIB2Deafness, Usher syndromeAR515
CLRN1Retinitis pigmentosa, Usher syndromeAR1739
COL2A1Avascular 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 1AD166544
COL4A3Alport syndrome, Hematuria, benign familialAD/AR49245
COL4A4Alport syndromeAD/AR42199
COL4A5Alport syndromeXL683976
COL4A6Deafness, with cochlear malformationXL114
COL9A1Stickler syndrome recessive type, Multiple epiphyseal dysplasia type 6 (EDM6)AR95
COL9A2Stickler syndrome, Multiple epiphyseal dysplasia type 2 (EDM2)AD/AR712
COL9A3Multiple epihyseal dysplasia type 3 (EDM3)AD/AR1015
COL11A1Marshall syndrome, Fibrochondrogenesis, Stickler syndrome type 2AD/AR3086
COL11A2Weissenbacher-Zweymuller syndrome, Deafness, Otospondylomegaepiphyseal dysplasia, Fibrochondrogenesis, Stickler syndrome type 3 (non-ocular)AD/AR2855
DCAF17Woodhouse-Sakati syndromeAR1213
DFNB31Deafness, Usher syndromeAR1131
DLX5Split-hand/foot malformation with sensorineural hearing lossAR38
DNMT1Neuropathy, hereditary sensory, Cerebellar ataxia, deafness, and narcolepsyAD919
EDN3Hirschsprung disease, Central hypoventilation syndrome, congenital, Waardenburg syndromeAD/AR621
EDNRBHirschsprung disease, ABCD syndrome, Waardenburg syndromeAD/AR866
EYA1Otofaciocervical syndrome, Branchiootic syndrome, Branchiootorenal syndromeAD44203
FDXRAuditory neuropathy and optic atrophyAR517
FGF3Deafness, congenital with inner ear agenesis, microtia, and microdontiaAR1320
FOXI1Pendred syndrome, Enlarged vestibular aqueductAR19
GATA3Hypomagnesemia, renalAD2281
GJA1*Oculodentodigital dysplasia mild type, Oculodentodigital dysplasia severe type, Syndactyly type 3AD/AR32106
HARS*Usher syndrome, Charcot-Marie-Tooth disease, axonal, type 2WAR49
HARS2Perrault syndromeAR73
HOXB1Facial paresis, hereditary congenitalAR36
KCNE1Long QT syndrome, Jervell and Lange-Nielsen syndromeAD/AR/Digenic745
KCNJ10Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SESAME syndrome), Pendred syndrome, Enlarged vestibular aqueductAR/Digenic1425
KCNQ1Short QT syndrome, Long QT syndrome, Atrial fibrillation, Jervell and Lange-Nielsen syndromeAD/AR/Digenic285604
KITGastrointestinal stromal tumor, PiebaldismAD75110
LARS2Perrault syndrome, Hydrops, lactic acidosis, and sideroblastic anemia (HLASA)AR1411
LRP2Donnai-Barrow syndrome, Faciooculoacousticorenal syndromeAR2330
MAN2B1Mannosidosis, alpha B, lysosomalAR37144
MANBAMannosidosis, lysosomalAR1218
MGPKeutel syndromeAR57
MITFTietz albinism-deafness syndrome, Waardenburg syndromeAD/AR2855
MYH9Sebastian syndrome, May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Macrothrombocytopenia and progressive sensorineural deafness, Deafness, autosomal dominant 17AD23117
MYO7ADeafness, Usher syndrome, Deafness, autosomal dominant 11AD/AR165491
NDPExudative vitreoretinopathy, Norrie diseaseXL31165
NLRP3Neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, Chronic infantile neurologic cutaneous articular (CINCA) syndrome, Familial cold-induced autoinflammatory syndrome 1AD22129
PAX3Craniofacial-deafness-hand syndrome, Waardenburg syndromeAD/AR33138
PCDH15Deafness, Usher syndromeAR/Digenic73116
PDZD7Usher syndromeDigenic118
PEX1Heimler syndrome, Peroxisome biogenesis factor disorder 1A, Peroxisome biogenesis factor disorder 1BAR80132
PEX6Heimler syndrome, Peroxisome biogenesis disorder 4A, Peroxisome biogenesis disorder 4BAR32106
PEX26Adrenoleukodystrophy, neonatal, Zellweger syndrome, Peroxisome biogenesis disorderAR1327
POLR1CTreacher Collins syndromeAR1620
POLR1DTreacher Collins syndromeAD/AR826
SALL1Townes-Brocks syndrome 1AD2784
SIX1Deafness, Branchiootic syndrome, Branchiootorenal syndromeAD1117
SIX5Branchiootorenal syndromeAD310
SLC19A2Thiamine-responsive megaloblastic anemia syndromeAR1349
SLC26A4Deafness, Pendred syndrome, Enlarged vestibular aqueductAR151535
SLC52A2Brown-Vialetto-Van Laere syndromeAR2622
SLC52A3Fazio-Londe disease, Brown-Vialetto-Van Laere syndromeAR3440
SLITRK6Deafness and myopiaAR34
SMAD4Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Polyposis, juvenile intestinal, Myhre dysplasia, Hereditary hemorrhagic telangiectasiaAD162141
SNAI2Waardenburg syndrome, PiebaldismAR24
SOX10Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung diseaseAD41136
TCOF1Treacher Collins syndromeAD42320
TFAP2ABranchiooculofacial sydromeAD1241
TIMM8AMohr-Tranebjaerg syndrome, Jensen syndrome, Opticoacoustic nerve atrophy with dementiaXL1021
TYRAlbinism, oculocutaneousAR77391
USH1CDeafness, Usher syndromeAR2151
USH1GUsher syndromeAR1031
USH2AUsher syndrome, Retinitis pigmentosa, Retinitis pigmentosa 39AR2571127
VCANWagner diseaseAD1119
WFS1Wolfram syndrome, Deafness, Wolfram-like syndrome, autosomal dominant, Deafness, autosomal dominant 6/14/38, Cataract 41AD/AR68351

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number

Panel Update

Genes added

  • ATP6V1B2
  • C10ORF2
  • CEP78
  • CLPP
  • DCAF17
  • DNMT1
  • FDXR
  • GJA1
  • HARS2
  • KIT
  • LARS2
  • MAN2B1
  • MGP
  • PEX1
  • PEX26
  • PEX6
  • SALL1
  • SLC52A2
  • SLC52A3

Genes removed

Test strength and Limitations

The strengths of this test include:

  • CAP and ISO-15189 accreditations covering all operations at GHC 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
  • ~1,500 non-coding disease causing variants in GHC 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 The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *PPA2* (11, 12). 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 GHC Genetics.

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

Test Performance

The GHC Genetics panel covers classical genes associated with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac arrest underlying cardiac condition, cardiac arrest cause unspecified, syncope and collapse, abnormal ECG, Long QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Short QT 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. GHC 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 GHC 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%

Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Detection of Del/Dup of several genes is by MLPA analysis (MS Holland). All genes are performed by CNV analysis through the genome depending on exon size, sequencing coverage and sequence content. We have validated the assays for different starting materials including isolated DNA from EDTA blood that provide high-quality results.

Bioinformatics & clinical interpretation

The sequencing data generated in our laboratory is analysed by our bioinformatic pipeline, integrating state-of-the art algorithms and industry-standard software solutions. We use also JSI medical systems software for sequencing data analysis. JSI medical systems is a certified system offering sophisticated bioinformatic software solutions covering a wide field of sequencing techniques.

Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results.

Every pathogenic or probably pathogenic variant is confirmed by the Sanger sequencing method. 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. The analysis of detected variants was performed on the basis of the reference database of polymorphisms and international mutation databases: UMD, LOVD and ClinVar.

The consequence of variants in coding and splice regions are estimated using Alamut software. The Alamut database contains more than 28000 coding genes, non-protein coding genes and pseudogenes. This database (shared with the high throughput annotation engine for NGS data, Alamut Batch) is frequently updated. Information comes from different public databases such as NCBI, EBI, and UCSC, as well as other sources including gnomAD, ESP, Cosmic, ClinVar, or HGMD and CentoMD (for those a separate subscription from Qiagen/Biobase and Centogene respectively is required). Alamut Visual finds information about nucleotide conservation data through many vertebrates’ species, with the phastCons and phyloP scores, amino acid conservation data through orthologue alignments and information on protein domains.

Moreover, we integrate several missense variant pathogenicity prediction tools and algorithms such as SIFT, PolyPhen, AlignGVGD or MutationTaster. It also offers a window dedicated to the in silico study of variants’ effect on RNA splicing, allowing the assessment of their potential impact on splice junctions and visualization of cryptic or de novo splice sites. Impact on splicing regulation is also assessed.

Clinical interpretation

At GHC 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 report. We recommend an interpretation of the findings of this molecular genetic analysis, including subsequent oncological consultation for the patient in the context of genetic counselling for the patient.

We strive to continuously monitor current genetic literature identifying new relevant information and findings and adapting them to our diagnostics. This enables relevant novel discoveries to be rapidly translated and adopted into our ongoing diagnostics development without delay. The undertaking of such comprehensive due diligence ensures that our diagnostic panels and clinical statements are the most up-to-date on the market.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. 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 analysed at our laboratories enables 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 three times at GHC Genetics. Reported variants of uncertain significance (VUS) 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 GHC 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, 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 counselling.

Our Clinical interpretation team analyses 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 laboratories are therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by GHC Genetics is re-classified, our laboratories will issue a follow-up statement to the original ordering health care provider at no additional cost.