Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

Bonnet, Crystel; Grati, M’hamed; Marlin, Sandrine; Levilliers, Jacqueline; Hardelin, Jean Pierre; Parodi, M.; Niasme-Grare, Magali; Zélénika, Diana; Délépine, Marc; Feldmann, Delphine; Jonard, Laurence; El-Amraoui, Aziz; Weil, Dominique; Delobel, Bruno; Vincent, C.; Dollfus, Hélène; Eliot, Marie Madeleine; David, Albert; Calais, C.; Vigneron, Jacqueline; Montaut-Verient, Bettina; Bonneau, Dominique; Dubin, J.; Thauvin, Christel; Duvillard, Alain; Francannet, Christine; Mom, T.; Lacombe, Didier; Duriez, Françoise; Drouin‐Garraud, Valérie; Thuillier-Obstoy, Marie Françoise; Sigaudy, Sabine; Frances, Anne Marie; Collignon, P.; Challe, Georges; Couderc, Rémy; Lathrop, Mark; Sahel, José‐Alain; Weissenbach, Jean; Petit, Christine; Denoyelle, Françoise

doi:10.1186/1750-1172-6-21

Cited by 93 publications

(99 citation statements)

References 83 publications

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“…Combined TES and Sanger-DNA direct sequencing determined that our overall mutation detection rate for the current cohort was 78.2%. This solving proportion is compatible with the reported rates in several previous studies using TES or Sanger-DNA direct sequencing 6,10,11,[26][27][28] ; however, it is still about 15% lower than the 92.7% rate reported recently by Bonnet et al 12 The mutation detection rate is related to the accuracy of the patients' clinical diagnoses. In our study, the mutation detection rate (85%) for USH1 patients was higher than that (76.8%) for USH2 patients.…”

Section: Discussionsupporting

confidence: 90%

“…Although traditional Sanger sequencing of all exons of the USH gene can solve more than 80% of USH families, 6,11 it is both time consuming and expensive due to the large sizes of most USH genes (435 coding exons), especially for a large study cohort. An array-based mutation screening (arrayed primer extension technology, APEX) is an efficient and rapid technique of identifying previously reported mutations; however, it results in a lower mutation detection rate due to the high proportion of the family-specific pathogenic mutations.…”

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confidence: 99%

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Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Sun

Ren

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations. METHODS.A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations. RESULTS.We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles. CONCLUSIONS.Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Sun

Ren

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…To this is added the further potential complexity of digenic inheritance which has been proposed in some cases of Usher syndrome and described in other retinal diseases 18 20 21. Although a major undertaking in terms of time and expense, we decided at the beginning of the study to sequence all the known Usher genes in all subjects, regardless of clinical subtype, in order to assess evidence for, and contribution of, digenic inheritance and the extent of polymorphic sequence variation within the genes.…”

Section: Discussionmentioning

confidence: 99%

“…Although a number of molecular studies of Usher cohorts have been published to date, only one smaller study has been designed in a way that would systematically detect digenic inheritance and whether or not this is a significant or recurring phenomenon 18. Bonnet et al described 10 (out of 54) USH patients with presumably pathogenic mutations in two different USH genes.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study

Stabej¹,

Saihan

Rangesh³

et al. 2011

J Med Genet

155

154

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BackgroundUsher syndrome (USH) is an autosomal recessive disorder comprising retinitis pigmentosa, hearing loss and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous with three distinctive clinical types (I–III) and nine Usher genes identified. This study is a comprehensive clinical and genetic analysis of 172 Usher patients and evaluates the contribution of digenic inheritance.MethodsThe genes MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98, WHRN, CLRN1 and the candidate gene SLC4A7 were sequenced in 172 UK Usher patients, regardless of clinical type.ResultsNo subject had definite mutations (nonsense, frameshift or consensus splice site mutations) in two different USH genes. Novel missense variants were classified UV1-4 (unclassified variant): UV4 is ‘probably pathogenic’, based on control frequency <0.23%, identification in trans to a pathogenic/probably pathogenic mutation and segregation with USH in only one family; and UV3 (‘likely pathogenic’) as above, but no information on phase. Overall 79% of identified pathogenic/UV4/UV3 variants were truncating and 21% were missense changes. MYO7A accounted for 53.2%, and USH1C for 14.9% of USH1 families (USH1C:c.496+1G>A being the most common USH1 mutation in the cohort). USH2A was responsible for 79.3% of USH2 families and GPR98 for only 6.6%. No mutations were found in USH1G, WHRN or SLC4A7.ConclusionsOne or two pathogenic/likely pathogenic variants were identified in 86% of cases. No convincing cases of digenic inheritance were found. It is concluded that digenic inheritance does not make a significant contribution to Usher syndrome; the observation of multiple variants in different genes is likely to reflect polymorphic variation, rather than digenic effects.

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“…Examples include SLC26A4 gene sequencing in individuals suspected of having Pendred syndrome, PAX3 gene sequencing in individuals with features of Waardenburg syndrome type I, MITF and SOX10 gene sequencing in individuals with features of Waardenburg syndrome type II, or sequencing of MYO7A or USH2A, the most common genes involved in Usher syndrome types I and II, respectively. 90,91 Such screening can also be cost effective in individuals with genetically heterogeneous hearing loss phenotypes when a single gene is responsible for a significant percentage of cases. For example, GJB2 gene sequencing can identify the underlying etiology for many individuals whose clinical presentation is consistent with autosomal recessive nonsyndromic hearing loss.…”

Section: Genetic Testing For the Etiologic Diagnosis Of Hereditary Hementioning

confidence: 99%

American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss

Alford

Arnos

Fox

et al. 2014

Genetics in Medicine

214

134

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DEFINITIONSDeaf: a community with a distinct culture and language shaped by the experience of being deaf or hard of hearing, which may include deaf, hard-of-hearing, and hearing individuals deaf: an auditory phenotype characterized by a total or neartotal loss of the ability to hear hard of hearing: an auditory phenotype characterized by a partial loss of the ability to hear hearing loss: an auditory phenotype characterized by any degree of loss of the ability to hear; depending on cause, hearing loss can be temporary or permanent-this guideline focuses on permanent hearing loss Hearing loss is a common and complex condition that can occur at any age, can be inherited or acquired, and is associated with a remarkably wide array of etiologies. The diverse causes of hearing loss, combined with the highly variable and often overlapping presentations of different forms of hearing loss, challenge the ability of traditional clinical evaluations to arrive at an etiologic diagnosis for many deaf and hard-of-hearing individuals. However, identifying the etiology of a hearing loss may affect clinical management, improve prognostic accuracy, and refine genetic counseling and assessment of the likelihood of recurrence for relatives of deaf and hard-of-hearing individuals. Linguistic and cultural identities associated with being deaf or hard of hearing can complicate access to and the effectiveness of clinical care. These concerns can be minimized when genetic and other health-care services are provided in a linguistically and culturally sensitive manner. This guideline offers information about the frequency, causes, and presentations of hearing loss and suggests approaches to the clinical evaluation of deaf and hard-of-hearing individuals aimed at identifying an etiologic diagnosis and providing informative and effective patient education and genetic counseling.

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Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

Cited by 93 publications

References 83 publications

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Comprehensive Molecular Screening in Chinese Usher Syndrome Patients

Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study

American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss

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