1. health and fitness
2. disease
3. deafness

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
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
2
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 genotypephenotype 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 makee 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: [email protected]),
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 (http://
www.gene.ucl.ac.uk/nomenclature/guidelines.html).
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 boneconduction 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.
Table 1
Checklist for description of genetic hearing impairment
Genetic aspects
1. Nomenclature and localisation
Audiological aspects
5. Type of hearing impairment
Locus name
6. Severity of hearing impairment
Chromosomal localization
7. Audiometric configuration
Gene name (if identified)
8. Frequency ranges
Gene product name (if gene identified)
9. Unilateral/bilateral
2. Mutations and function
10. Estimated age of onset
Mutations
11. Progression
Gene protein function (if known)
12. Tinnitus
Function change introduced by the mutation (if known)
13. Vestibular symptoms and function
3. Origin of family
Geographical origin of the family
Ethnicity of family
4. Pedigree and inheritance
Pedigree figure
Pattern of inheritance
Penetrance
Complicating factors
14. Intrafamilial/interfamilial variability
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
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
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.
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.