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.
1 UOA Otochirurgia Az, Ospedaliera di Padova,
of Medical Genetics, University of Antwerp, Belgium
University of Manchester, Department of Education Studies – Centre for Human
Communication and Deafness, UK
4 Department of
Audiology, Bispebjerg Hospital, Copenhagen, Denmark.
of ENT, Head & Neck Surgery and Communication disorders, University
Hospital Antwerp, Belgium
6 Department of
Audiology, University of Ferrara, Italy
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,
comparisons. Another problem that we have noted several times is the use of
incorrect nomenclature for gene loci, genes or mutations, sometimes leading
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
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: firstname.lastname@example.org), 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
2. Mutations that
produce the phenotype
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)
describe the protein function, and explain the change in function introduced by
3. Geographical origin
of the family
specify country and region from which the family originates as specific as
possible, and include the ethnicity of family (Asian/ Black/ White/ Other), if
4. Pattern of
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
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
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
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
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.
sloping: 15-29 dB HL difference between the mean of 0.5 and 1 kHz and the
mean of 4 and 8 kHz.
steeply sloping: >30 dB HL difference between the above
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
frequencies: < 0.5 kHz
frequencies: >0.5 kHz < 2 kHz
frequencies: >2 kHz < 8 kHz
frequencies: > 8 kHz
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
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).
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.
cases the timescale
and patient age should be specified.
(If present, use verbal descriptors: e.g. low or high tone pitch, noise, etc)
13. Vestibular symptoms
symptoms are present, describe in detail.
function: normal/abnormal. If abnormal, report vestibular testing results.
or interfamilial variability for the various points
Audiological terms. In “Definitions, protocols & guidelines in genetic
hearing impairment.” A. Martini, M. Mazzoli, D. Stephens, A. Read. (Eds.) Whurr
Mitelman, F. (ed.) Chromosomes:
An International System for Human Cytogenetic Nomenclature (ISCN). Karger,
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
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
1. Nomenclature and
product name (if gene identified)
5. Type of hearing
2. Mutations and
protein function (if known)
change introduced by the mutation (if known)
6. Severity of hearing
3. Origin of family
origin of the family
4. Pedigree and
8. Frequency ranges
10. Estimated age of
symptoms and function