title: Four-year follow-up of diagnostic service in USH1 patients.
abstract: OBJECTIVE
  The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes.
  
  
  METHODS
  To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements.
  
  
  RESULTS
  Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene.
  
  
  CONCLUSIONS
  Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.
authors: Laboratoire de Génétique Moléculaire, Montpellier, France. anne-francoise.roux@inserm.fr
authors: Anne-Françoise
authors: AF
authors: Roux
authors: Valérie
authors: V
authors: Faugère
authors: Christel
authors: C
authors: Vaché
authors: David
authors: D
authors: Baux
authors: Thomas
authors: T
authors: Besnard
authors: Susana
authors: S
authors: Léonard
authors: Catherine
authors: C
authors: Blanchet
authors: Christian
authors: C
authors: Hamel
authors: Michel
authors: M
authors: Mondain
authors: Brigitte
authors: B
authors: Gilbert-Dussardier
authors: Patrick
authors: P
authors: Edery
authors: Didier
authors: D
authors: Lacombe
authors: Dominique
authors: D
authors: Bonneau
authors: Muriel
authors: M
authors: Holder-Espinasse
authors: Umberto
authors: U
authors: Ambrosetti
authors: Hubert
authors: H
authors: Journel
authors: Albert
authors: A
authors: David
authors: Geneviève
authors: G
authors: Lina-Granade
authors: Sue
authors: S
authors: Malcolm
authors: Mireille
authors: M
authors: Claustres
mesh_terms: D002874:Chromosome Mapping; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005500:Follow-Up Studies; D005602:France; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D009154:Mutation; D020125:Mutation, Missense; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics; D052245:Usher Syndromes / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D009218:Myosins