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Genetic Heterogeneity of Usher Syndrome Type II

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Genetic Heterogeneity of Usher Syndrome Type II J7Med Genet 1996;33:753-757 753 Genetic heterogeneity of Usher syndrome type II in a Dutch population J Med Genet: first published as 10.1136/jmg.33.9.753 on 1 September 1996. Downloaded from S Pieke-Dahl, A van Aarem, A Dobin, C W R J Cremers, W J Kimberling Abstract In 1959, Hallgren' laid the foundation for the The Usher syndromes are a group ofauto- clinical definition of US in a study of 172 US somal recessive disorders characterised patients from Sweden. Hallgren' showed sig- by retinitis pigmentosa (RP) with con- nificant phenotypic heterogeneity of US by genital, stable (non-progressive) sen- describing two clinically distinct forms, Usher sorineural hearing loss. Profound deaf- syndrome type I and Usher syndrome type II. ness, RP, and no vestibular responses are Profound congenital deafness, RP, and absent features of Usher type I, whereas moder- vestibular responses was defined as Usher I, ate to severe hearing loss and RP with while those exhibiting a congenital moderate to normal vestibular function describe severe hearing loss, RP, and no associated ves- Usher type II. The gene responsible for tibular problems was defined as Usher II.2 3 most cases ofUsher II, USH2a, is on chro- Although the existence of a type of US with mosome 1q41; at least one other Usher II progressive hearing loss had been proposed,4 gene (as yet unlinked) is known to exist. there was no firm genetic evidence for a Usher III presents with a progressive separate Usher III phenotype until a group of hearing loss that can mimic the audiomet- Finnish families with a phenotype of progres- ric profile seen in Usher II. A gene causing sive hearing loss and RP were observed with Usher III in a group of Finnish families, linkage to a genetic marker on 3q.6 There is USH3, resides on chromosome 3q. Since extensive genetic heterogeneity of Usher syn- the phenotypes for Usher II and III drome. Usher II was originally found to be overlap, it is important to determine how linked to markers on chromosome 1.7 8 The frequently Usher IIa, Usher ITb, and exclusion of Usher I families from the USH2a Usher III occur in a clinical population of region locus showed that Usher I and II were non-Usher I patients. DNA was collected non-allelic.7 9 The discovery of three Usher I from 29 Dutch families and genotyped genes followed: a group of French families with with six DNA markers known to flank the Usher I exhibited linkage to 1 4q whose locus is USH2a gene closely, and with five markers now called USHIa,'0 the most common form that flank USH3. Results of haplotype and of Usher I (USHlb) was shown to be linked to linkage analysis were consistent with link- 1 1 q,"I and a set of Acadian families with Usher http://jmg.bmj.com/ age to the USH2a locus in 26 of these 29 I (USHic) displayed linkage to 1 'p.12 The spe- Dutch families. Three families displayed cific mutation responsible for USHlb has no linkage to 1q41 markers, and one of recently been shown to be in myosin VIIa.'3 these three families appeared unlinked to The remaining Usher genes have not been 3q markers as well; current haplotypes of identified, but the location of USH2a has been the other two families are inconclusive for narrowed down to a region of about 400 kb.'4 linkage with the USH3 locus without Heterogeneity was shown for Usher II by the on October 3, 2021 by guest. Protected copyright. further genotyping. While an A test for identification of a family with a phenotype heterogeneity of USH2a was statistically typical of Usher II not linked to USH2a, indi- Genetics Department, significant, no convincing evidence of cating the existence of at least one other Usher Boys Town National linkage to USH3 was found in this Dutch II gene.'5 The proportion of non-USH2a Research Hospital, 555 sample. Consequently, the frequency of linked families has been estimated at 12.5%.16 North 30th Street, Omaha, NE 68131, the unlinked variety of Usher IIa (Usher As noted above, Usher III has shown linkage to USA Ilb) in The Netherlands was estimated as 3q,6 bringing the number of genetic loci S Pieke Dahl 0.104. To determine ifmarker alleles could involved in various subtypes of US to at least A Dobin W J Kimberling be used to differentiate Usher type Ila six. from Usher IIb, parental chromosomes of Subtle phenotypic variations within the clas- Department of the 26 Usher IIa families were analysed for sic Usher II phenotype were observed within a Otolaryngology, significant non-random association of University Hospital group of 23 affected Dutch patients from 10 Nijmegen, Philips van specific alleles from flanking loci with different families (all included in this study). LeydenLaan 15, USH2a, but no linkage disequilibrium was Serial audiograms were available for 13 of the Postbus 9101, 6500 HB observed in this Dutch population. 23 and Nijmegen, The patients, subsequent analysis showed Netherlands (C Med Genet 1996;33:753-757) three of these 13 patients with a mild but defi- A van Aarem nite progression of hearing loss'7; however, C W R J Cremers Key words: genetic heterogeneity; Usher syndrome type these families showed linkage to USH2a. II; Dutch population. Correspondence to: Given that these Usher II patients had progres- Dr Kimberling. sive loss (presumably owing to allelic differ- ences at the USH2a locus), it would be equally Received 26 February 1996 Revised version accepted for Usher syndrome (US) is defined as hearing possible that some Usher III patients showing publication 12 April 1996 loss or deafness with retinitis pigmentosa (RP). linkage to USH3 could show a stable congeni- 754 Pieke-Dahl, van Aarem, Dobin, Cremers, Kimberling tal hearing deficit. This would necessitate the brainstem auditory evoked potentials (BAEP). use of both genotypic and audiological evalua- Recent audiograms from patients examined at tions to make accurate diagnoses of Usher syn- the University Hospital of Nijmegen were drome type and subsequent prognoses for measured with an Interacoustic AC5 audiom- J Med Genet: first published as 10.1136/jmg.33.9.753 on 1 September 1996. Downloaded from affected patients. eter calibrated following the ISO 389 proce- Here we report the results of linkage analysis dure according to the ISO 8253-1 stand- of 29 Usher II families collected from various ard.'8 19 The ISO 7029 method was used to regions throughout The Netherlands to deter- establish individual P50 threshold values for mine (1) whether genetic heterogeneity of presbyacusis.20 Usher II exists in the Dutch population and (2) if any observed genetic heterogeneity of Usher GENOTYPING II can be explained as resulting from mutations Blood samples were collected and genomic at the USH3 locus. Given the probable DNA was extracted from lymphocytes using an existence of genetic heterogeneity of Usher II Applied Biosystem 340A nucleic acid extrac- in the Dutch population, we then proceeded to tion machine. STRP genotyping was done evaluate the 1q41 linked families for linkage according to standard protocols. Six chromo- disequilibrium with regard to the different alle- some 1 q markers were chosen based on locus les at the linked loci. If present, disequilibrium order as follows: cen - DlS419 - (0.2) - could be a useful adjunct to estimate any D1S237 - (1.0) - D1S474 - (0.65) - AFM144 - specific family's likelihood of being one or the (0.65) - DlS490 - (0.5) - DlS229 - tel. other Usher type. Distances (in centimorgans) approximated from our total database of Usher II families are Methods presented in parentheses between adjacent SUBJECTS AND CLINICAL STUDIES markers. The approximate location of USH2a Families with clinical diagnoses of Usher II is 1 q41; DNA markers D 1 S474 and AFM144 from different areas throughout the Nether- are known to flank the USH2a gene. 6 lands were ascertained by referral from the Chromosome 3q marker order and genetic dis- Foundation of the Deaf-Blind, the Kalorama tances were assumed as follows: cen - Institute for deaf-blind adults, and from the D3S 1555 - (1.0) - D3S 1308(2.0) - D3S 1299 - Nijmegen University Hospital Register. (2.5) - D3S1279 - (2.0) - D3S1280 - tel. Twenty-nine families with 56 affected subjects Marker D3S1299 shows no recombination were chosen as suitable for this study from a with Usher III and D3S 1308 and D3S 1279 are total of 36 Usher II families. Seven families the nearest established flanking markers.6 proved too small or incomplete to provide suf- ficient linkage information. The results of pre- ANALYSES vious audiological, vestibular, and visual tests Linkage analyses were performed with geno- and general medical reports of affected sub- typic data from the 29 informative Dutch jects and of first degree relatives with reported families. US was assumed to be an autosomal hearing or vision problems were available for recessive disorder, fully penetrant in the confirmation of an Usher II diagnosis and at affected homozygote, with a gene frequency of http://jmg.bmj.com/ least one affected subject from each family was 1/140.' No sporadic cases were assumed. The examined at the Nijmegen University Hospital. LINKAGE 5.03 program2' was used to obtain A diagnosis of Usher II required (1) retinitis two point and multipoint analyses. For the pigmentosa shown by retinal examination and chromosome lq analysis, D1S474 was arbi- by extent of night blindness and tunnel vision, trarily chosen as the origin, and lod scores were (2) intact vestibular responses, (3) a "sloping" calculated at approximately 0.4 cM intervals hearing loss, mild to moderate in the low for each family, with estimated interlocus on October 3, 2021 by guest.
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