Valerie Newton

A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.

A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000. In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.

Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2.

Waardenburg syndrome (WS) is a combination of deafness and pigmentary disturbances, normally inherited as an autosomal dominant trait. The pathology involves neural crest derivatives, but WS is heterogeneous clinically and genetically. Some type I WS families show linkage with markers on distal 2q and in three cases the disease has been attributed to mutations in the PAX3 gene. PAX3 encodes a paired domain, a highly conserved octapeptide and probably also a paired–type homeodomain. Here we describe a further three PAX3 mutations which cause WS; one alters the octapeptide motif plus the presumed homeodomain; a second alters all three elements and the third alters the paired box alone. The latter occurs in a family with probable type 2 WS, a clinical variant usually considered not to be allelic with type 1 WS.

Global burden of childhood hearing impairment and disease control priorities for developing countries

The World Bank has published disease-control priorities setting out cost-eff ective interventions for international resource mobilisation and allocation to the developing world. This list was compiled amidst the worldwide health priorities of many agencies, for attainment of the Millennium Development Goals (MDGs). Many of the disease-control priorities were based on a complementary report about the global burden of disease, which ranked communicable and non-communicable diseases and injuries according to their associated mortality and disability-adjusted life years (DALYs). Lopez and colleagues’ report attempts to fairly assess the burden of diverse fatal and non-fatal diseases worldwide. The report included adult-onset hearing impairment, but excluded permanent childhood hearing impairment and all other hearing impairment of childhood-onset in the quantifi cation of the burden of disease of this disability. This Viewpoint reviews the implications of this approach in light of the emerging trend toward early detection of childhood hearing impairment as an essential public-health service and in the context of equity, which underpins the global burden of disease initiative. WHO defi nes disabling hearing impairment as having permanent unaided hearing threshold in the better ear of more than 30 dB in children aged up to 15 years, or more than 40 dB in adults at frequencies of 0·5, 1, 2, and 4 kHz. This defi nition is commonly associated with sensorineural hearing impairment and tends to exclude conductive hearing loss of any severity or duration. Additionally, it overlooks unilateral permanent hearing impairment of any severity as well as slight or mild bilateral hearing impairment in the range of 16–30 dB in children or 16–40 dB in adults. However, these categories of hearing impairment have adverse consequences for speech, language, and cognitive development and educational attainment. The use of the terms slight, mild, or moderate might not adequately depict the degree of disability in children with hearing impairment, within the WHO framework for classifi cation of functioning and health (table 1), especially for school-age children in developing countries. Similarly, adults with unilateral or mild hearing impairment could encounter diffi culties with speech discrimination and comprehension in noisy environments or at social gatherings resulting in substantial activity limitation and participation restrictions. Therefore, the disease burden for adult-onset hearing impairment would have been understated in the global burden of disease report by the exclusion of unilateral or mild hearing impairment. Of special interest is the exclusion of hearing impairment in the early years, which can aff ect optimum childhood development. For example, in 1995, the World Health Assembly passed a resolution on the prevention and control of major causes of avoidable hearing impairment and for early detection of hearing loss in “babies, toddlers, and children, as well as in the elderly, within the framework of primary health care”. This resolution was predicated on concerns about the growing problem of disabling but largely preventable hearing impairment worldwide (aff ecting an estimated 120 million people in 1995) and the recognition of its adverse Lancet 2007; 369: 1314–17

A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling.

The major defining features, age at onset of symptoms, and survival in 150 patients with type 2 neurofibromatosis (NF2) have been studied. The mean age at onset was 21.57 years (n = 110) and no cases presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumours. In 97 cases studied personally by the authors, skin and eye examination were found to be useful to detect early signs of the condition. Examination of the skin is likely to assist in early diagnosis in at least 10% of cases and examination of the eye for a lens opacity or cataract in at least as many again. There are marked interfamilial differences in disease severity and tumour susceptibility. Vestibular schwannomas are not fully penetrant, but the condition is usually expressed in another way. Alteration to the current diagnostic criteria is advocated to cover the lack of provision for new mutations. A screening protocol is proposed and the effect of disease heterogeneity on management is discussed.

Mutations in the Myosin VIIA Gene Cause a Wide Phenotypic Spectrum, Including Atypical Usher Syndrome

This work was supported by the Medical Research Council (U.K.), Defeating Deafness—the Hearing Research Trust, and SENSE and by European Community grant CT96-1324. C.H. acknowledges support from the British Retinitis Pigmentosa Society and the Birmingham Eye Foundation.

Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population

Usher syndrome type I (USH1), the most severe form of this syndrome, is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. At least seven USH1 loci, USH1A-G, have been mapped to the chromosome regions 14q32, 11q13.5, 11p15, 10q21-q22, 21q21, 10q21-q22, and 17q24-25, respectively. Mutations in five genes, including MYO7A, USH1C, CDH23, PCDH15 and SANS, have been shown to be the cause of Usher syndrome type 1B, type 1C, type 1D, type 1F and type 1G, respectively. In the present study, we carried out a systematic mutation screening of these genes in USH1 patients from USA and from UK. We identified a total of 27 different mutations; of these, 19 are novel, including nine missense, two nonsense, four deletions, one insertion and three splicing defects. Approximatelly 35–39% of the observed mutations involved the USH1B and USH1D genes, followed by 11% for USH1F and 7% for USH1C in non-Acadian alleles and 7% for USH1G. Two of the 12 MYO7A mutations, R666X and IVS40-1G>T accounted for 38% of the mutations at that locus. A 193delC mutation accounted for 26% of CDH23 (USH1D) mutations, confirming its high frequency. The most common PCDH15 (USH1F) mutation in this study, 5601-5603delAAC, accounts for 33% of mutant alleles. Interestingly, a novel SANS mutation, W38X, was observed only in the USA cohort. The present study suggests that mutations in MYO7A and CDH23 are the two major components of causes for USH1, while PCDH15, USH1C, and SANS are less frequent causes.

Congenital non-syndromal sensorineural hearing impairment due to connexin 26 gene mutations — molecular and audiological findings

We screened DNA from 72 sibships and 138 sporadically affected individuals with congenital non-syndromal sensorineural hearing impairment (NSSNHI) for mutations in the 26 (CX26) gene. A total of 20 (27.8%) of the sibships and 11 (7.9%) of the sporadically affected individuals were homozygous or compound heterozygotes for CX26 mutations. A total of 11 (17.2%) of 64 individuals with severe and 30 (30%) of 100 with profound NSSNHI compared to eight (8.7%) of 92 persons with moderate and none (0%) of 19 individuals with mild hearing impairment were homozygous or compound heterozygotes for CX26 mutations (chi2 test, 3 df, P = 0.000). CX26 mutation status bad no effect on the symmetry of the hearing impairment or configuration of the audiogram. In addition, serial audiograms showed no evidence of progression of the hearing impairment or differences in the severity of the hearing impairment in affected siblings in persons whether or not due to CX26 mutations. Sporadically affected individuals with congenital NSSNHI should be routinely tested for mutations in CX26, especially if the hearing impairment is severe or profound in severity, since identification of a mutation in CX26 allows use of Mendelian recurrence risks.

Hearing loss and Waardenburg's syndrome: implications for genetic counselling.

Ten families in which there were 79 individuals affected by Waardenburgs syndrome were examined for penetrance of sensorineural hearing loss and expressivity of the gene. There were 47 with Waardenburg syndrome Type 1 and 32 with Waardenburg syndrome Type II. Penetrance of senorineural hearing loss was calculated after exclusion of the probands and was found not to be significantly different between each syndrome type but to show marked interfamilial variation. A bilateral sensorineural hearing loss was present more frequently than unilateral with the proportion varying between families. Certain audiometric shapes were found to recur in the syndrome but, apart from possibly one asymmetric configuration, seem to have been described also in other conditions. The degree of hearing loss was very variable within and between families. The implications for genetic counselling are discussed and the advantages of basing risk factors upon individual families rather than syndrome types emphasized.

A new locus for non-syndromal, autosomal recessive, sensorineural hearing loss (DFNB16) maps to human chromosome 15q21-q22.

Non-syndromal, recessive deafness (NSRD) is the most common form of inherited deafness or hearing impairment in humans. NSRD is genetically heterogeneous and it has been estimated that as many as 35 different loci may be involved. We report the mapping of a novel locus for autosomal recessive, non-syndromal deafness (DFNB16) in three consanguineous families originating from Pakistan and the Middle East. Using multipoint analysis (HOMOZ/MAPMAKER) a maximum combined lod score of 6.5 was obtained for the interval D15S1039-D15S123. Recombination events and haplotype analysis define a 12-14 cM critical region between the markers D15S1039 and D15S155 on chromosome 15q15-q21.

Evaluation of the use of a questionnaire to detect hearing loss in Kenyan pre-school children

In developing countries, there is a lack of trained personnel and testing equipment to facilitate the early detection of hearing impairment in children. A questionnaire offers a low cost option and the value of this for detecting hearing impairment in pre-school children was determined in several districts in Kenya. The questionnaire was completed by either teachers, parents/carers or community nurses. The children were subsequently tested using pure tone audiometry and visual examination of the ear by ENT Clinical Officers, who were not given prior access to the results of the questionnaire. A total of 757 (88%) questionnaires were completed. Of the 735 children, who could be tested using pure tone audiometry, four were found to have a unilateral hearing impairment and one was detected by the questionnaire. A total of 13 children had a bilateral hearing impairment >40 dB HL. All were detected using the questionnaire. There were eight males and five females with ages ranging from 4.2 to 6.9 years, mean age 5.7 years and median age 5.8 years. Eight had a sensorineural hearing impairment and two a mixed hearing impairment. Three of the children with a sensorineural hearing loss had a family history of hearing impairment. No question detected all children with a hearing impairment and some questions were more discerning than others. There was 100% sensitivity for the questionnaire when a hearing loss of >40 dB was considered, but specificity was lower at 75%. Negative predictive value was 100%, but the positive predictive value was low, 6.75%. It was concluded that a questionnaire of this nature could be usefully applied at Primary Health Care level for detecting hearing impairment at the pre-school stage. There would be need for services available for diagnosis, treatment and habilitation before a screening programme was introduced.