Recommendations for the description of genetic and audiological data for families with nonsyndromic hereditary  hearing impairment

 

Composed by the GENDEAF study group on genotype phenotype correlations:

M. Mazzoli1, G. Van Camp2, V. Newton3, N. Giarbini4, F. Declau5, A. Parving6

 

1 UOA Otochirurgia Az, Ospedaliera di Padova, Italy

2 Department. of Medical Genetics, University of Antwerp, Belgium

3 Victoria University of Manchester, Department of Education Studies – Centre for Human Communication and Deafness, UK

4 Department of Audiology, Bispebjerg Hospital, Copenhagen, Denmark.

5 Department of ENT, Head & Neck Surgery and Communication disorders, University Hospital Antwerp, Belgium

6 Department of Audiology, University of Ferrara, Italy

 

 

Introduction

Over the last decade, we have seen a tremendous growth in the localisation and identification of genes for nonsyndromic hearing impairment. It has become clear that this condition is extremely genetically heterogeneous. Currently (mid 2003), close to 100 different locus names for nonsyndromic hearing impairment have been assigned, and more than 30 of the responsible genes residing at these loci have been identified. A continuously updated overview of the field can be found in the Hereditary Hearing loss Homepage (http://www.uia.ac.be/dnalab/hhh/). Even in nonsyndromic hearing impairment, different phenotypical subtypes exist, and several genotype-phenotype correlations between specific (sub)phenotypes and certain loci, genes or mutations are being described. However, the delineation of these correlations is hampered by the lack of information observed in papers reporting gene localisations or identifications. In addition, the terminology used to describe phenotypes is sometimes ambiguous and not uniform, resulting in difficulties to accumulate these and to make comparisons. Another problem that we have noted several times is the use of incorrect nomenclature for gene loci, genes or mutations, sometimes leading to confusion.

These recommendations are intended for researchers, including audiologists and geneticist, who report families with nonsyndromic deafness, in order to help them making appropriate descriptions of both genetic and audiological aspects of hearing impairment. Terminology and definitions are briefly outlined, and a checklist is provided for the authors to make sure that the description is as complete as possible.

 

Recommendation for description of genetic aspects

1.      Nomenclature and localisation.

The localization of a new gene for hereditary hearing impairment by genetic linkage analysis, requires an official locus name that has to be obtained from the Human Genome Organisation (HUGO) nomenclature committee (http://www.gene.ucl.ac.uk/nomenclature/). A locus name refers to a specific location on a certain human chromosome where the responsible gene resides.

     Note that in principle locus names do not refer to phenotypes. Locus names consist of a prefix, followed by a number. Autosomal dominant loci get the prefix DFNA, autosomal recessive get DFNB, and X-linked DFN. (e.g. DFNB1: the first autosomal recessive locus for nonsyndromic hearing impairment)  However, do not assign a name yourself, but contact the committee (e-mail: nome@galton.ucl.ac.uk), providing the following information on your gene localisation: inheritance pattern, chromosomal localisation, flanking markers, and maximum LOD score.

When publishing a gene localisation, report the chromosomal localization as accurate as possible, on the basis of known locations of flanking or linked markers. Use the ISCN nomenclature, as described by Mitelman in 1995 (e.g. 14q12-q13: on the long arm of chromosome 14, in band q12 or q13).

     If you identify a new, previously unknown gene, obtain a gene name and gene product name from HUGO. Guidelines for Human Gene Nomenclature can be found in the paper by Wain et al (2002), or on the HUGO nomenclature committee website


      Note that human gene names and loci should be italicised, and that protein products are not italicised.

 

2. Mutations that produce the phenotype

Mutations need to be specified on the DNA level as well as on the protein level, according to the terminology and nomenclature system described by den Dunnen and Antonarakis (2001). This paper is also available on the web (http://archive.uwcm.ac.uk/uwcm/mg/docs/mut_nom.html). Note that there are differences between the DNA level and the protein level. On the DNA level, the position precedes the change (e.g. 35delG: a deletion of a G at position 35, or 269T>C: a change of T into C at position 269), while on the protein level the wild type amino acid precedes the position, and the mutant amino acid follows (e.g. L90P, the Leucine at position 90 is mutated into Proline)

If known, describe the protein function, and explain the change in function introduced by the mutation.

 

3. Geographical origin of the family

Please specify country and region from which the family originates as specific as possible, and include the ethnicity of family (Asian/ Black/ White/ Other), if known.

 

4. Pattern of inheritance

A pedigree should always be given in a figure. The most likely mode of transmission should be indicated (e.g. autosomal dominant/ autosomal recessive/ X-linked dominant/X-linked recessive/ mitochondrial/ complex). Indicate whether penetrance is most likely to be complete or incomplete. If there are indications for incomplete penetrance, estimate the penetrance of the mutant gene in the family (percentage). If there is evidence for other factors complicating the pedigree pattern, discuss these.

 

Recommendation for description of audiological aspects

Describe the audiological findings according to the following terms and definitions, based on the recommendations of the EU HEAR project, as described by Stephens (2001).

 

5. Type of  hearing impairment

Conductive: related to disease or deformity of outer/middle ear. Audiometrically there are normal bone-conduction thresholds (<20 dB HL) and an air-bone gap >15 dB HL averaged over 0.5, 1 and 2 kHz.

Sensorineural: related to disease/deformity of the inner ear/cochlear nerve with an air/bone gap < 15 dB HL averaged over 0.5, 1 and 2 kHz. If known, specify the site of lesion (e.g. inner hair cells, outer hair cells, stria vascularis, spiral ganglion or auditory pathways)

Mixed: related to combined involvement of the outer/middle ear and the inner ear/cochlear nerve. Audiometrically >20 dB HL in the bone conduction threshold together with >15 dB HL air-bone gap averaged over 0.5, 1 and 2 kHz.

 

6. Severity of hearing impairment

The severity of hearing impairment should be applied to the better hearing ear, averaged over 0.5, 1, 2 and 4 kHz.

Mild: 20-40 dB HL

Moderate: 41-70 dB HL

Severe: 71-95 dB HL

Profound: in excess of 95 dB HL

 

7. Audiometric configuration

Low frequency ascending: >15 dB HL from the poorer low frequency thresholds to the higher frequencies.

Mid frequency U-shaped: >15 dB HL difference between the poorest thresholds in the mid-frequencies, and those at higher and lower frequencies.

High frequency

a.      gently sloping: 15-29 dB HL difference between the mean of 0.5 and 1 kHz and the mean of 4 and 8 kHz.

b.      steeply sloping: >30 dB HL difference between the above frequencies.

Flat: <15 dB HL difference between the mean of 0.25, 0.5 kHz thresholds, the mean of 1 and 2 kHz and the mean of 4 and 8 kHz.

 

8. Frequency ranges

Low frequencies: < 0.5 kHz

Mid frequencies: >0.5 kHz < 2 kHz

High frequencies: >2 kHz < 8 kHz

Extended high frequencies: > 8 kHz

 

9. Unilateral/bilateral

Please specify if the bilateral hearing impairment is symmetrical/asymmetrical i.e. > 10 dB HL difference between the ears in at least two frequencies. (The average over 0.5, 1 and 2 kHz  of the better ear should be worse than 20 dB HL.)

 

10. Estimated age of onset

Congenital/ births to 10 years/11 to 30 years/ 31 to 50 years/ >50 years/ uncertain ( specify if estimated age at onset varies within the family).

 

11. Progression

Hearing impairment is called progressive if there is a deterioration of >15 dB HL in the average over the frequencies of 0.5, 1, and 2 kHz within a 10 year period. Results in those aged over 50 years should be treated with some caution, as the progression may be the consequence of age-related hearing impairment, rather than the specific genetic defect in the family. In specific cases the timescale and patient age should be specified.

 

12. Tinnitus

Absent/present (If present, use verbal descriptors: e.g. low or high tone pitch, noise, etc)

 

13. Vestibular symptoms and function

If vestibular symptoms are present, describe in detail.

Vestibular function: normal/abnormal. If abnormal, report vestibular testing results.

 

14. Intrafamilial/interfamilial variability

Specify intrafamilial or interfamilial variability for the various points.

 

References

 

Stephens, D. Audiological terms. In “Definitions, protocols & guidelines in genetic hearing impairment.” A. Martini, M. Mazzoli, D. Stephens, A. Read. (Eds.) Whurr publishers, 2001

 

Mitelman, F. (ed.) Chromosomes: An International System for Human Cytogenetic Nomenclature (ISCN). Karger, Basel, 1995

 

Wain, H.M., Bruford, E.A., Lovering, R.C., Lush, M.J., Wright, M.W., Povey S. Guidelines for Human Gene Nomenclature. Genomics  79: 464-470, 2002.

 

den Dunnen, J.T., Antonarakis, S.E. Nomenclature for the description of sequence variations. Hum. Genet. 109: 121-124, 2001

 

 

Acknowledgement: Published with the support of the European Commission, Fifth Framework programme, Quality of Life Management of Living Resources programme. The authors are solely responsible for this publication. It does not represent the opinion of the Community and the community is not responsible for any use that might be made of data appearing therein.

 

 
Table 1: Checklist for description of genetic hearing impairment

 

Genetic aspects

Audiological aspects

1. Nomenclature and localisation

Locus name

Chromosomal localization

Gene name (if identified)

Gene product name (if gene identified)

5. Type of  hearing impairment

2. Mutations and function

Mutations

Gene protein function (if known)

Function change introduced by the mutation (if known)

6. Severity of hearing impairment

 

3. Origin of family

Geographical origin of the family

Ethnicity of family

7. Audiometric configuration

 

4. Pedigree and inheritance

Pedigree figure

Pattern of inheritance

Penetrance

Complicating factors

8. Frequency ranges

 

 

9. Unilateral/bilateral

 

10. Estimated age of onset

 

11. Progression

 

12. Tinnitus

 

13. Vestibular symptoms and function

 

14. Intrafamilial/interfamilial variability

 

 

 

 

 



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