Development and co-construction of a therapeutic patient education program for albinism.

BACKGROUND: Long-term and ongoing support in accordance with the changing needs of patients and their families is one of the main components of patient care, including therapeutic patient education (TPE). OBJECTIVE: To co-construct a TPE program for albinism with all those involved in the management of albinism patients. METHODS: Eight steps have been defined for the co-construction process: 1) identify all the relevant experts and invite them to participate in the construction of a TPE program to improve care for and support of patients with albinism, 2) review and analyse all publications regarding TPE for albinism, 3) conduct semi-structured interviews with the patients' parents, 4) conduct brainstorming meetings with the participating experts for an exchange of experience and expertise, 5) elaborate the program's concrete content with the experts, 6) draw up a TPE skills checklist, 7) create TPE educational tools to facilitate learning, 8) review and summarize each step of the co-construction protocol. RESULTS: Co-construction of a TPE program for children, adolescents, and young adults with albinism, and their parents. CONCLUSION: Strengths and advantages of the co-construction process include: i) highlighting of the experiential knowledge mentioned in the repository, ii) multiplicity of points of view and perspectives, iii) rapid improvement in TPE training both for the association and the patients, iv) awareness of the shift caregivers' position with regards to TPE and recognition of the polysemy of their discourse. The TPE program for albinism has been authorized since 2018.

BOR and BO syndromes are allelic defects of EYA1.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disease characterized by varying combinations of branchial, otic and renal anomalies. By positional cloning, a candidate gene, EYA1, homologous to the drosophila eyes absent gene, has recently been identified at 8q13.3 and shown to underlie this syndrome. The name branchio-oto (BO) syndrome has been used to describe a similar combination of branchial and otic anomalies, without the association of renal anomalies. Whether BOR and BO syndromes involve the same gene was unknown. To address this question, we analyzed two large independent families for which each of the 8 affected members present exclusively with BO syndrome. In both families, linkage analysis mapped the causative gene to the same chromosomal region as EYA1. A search for mutations in 9 of the EYA1 coding exons identified a 2-bp insertion segregating in one family and an 8-bp deletion segregating in the other. These results demonstrate that EYA1 also underlies BO syndrome, and that BOR and BO syndromes are allelic defects of this gene.

A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family.

A candidate gene for Branchio-Oto-Renal (BOR) syndrome was identified at chromosome 8q13.3 by positional cloning and shown to underlie the disease. This gene is a human homologue of the Drosophila eyes absent gene (eya), and was therefore called EYA1. A highly conserved 271-amino acid C-terminal region was also found in the products of two other human genes (EYA2 and EYA3), demonstrating the existence of a novel gene family. The expression pattern of the murine EYA1 orthologue, Eya1, suggests a role in the development of all components of the inner ear, from the emergence of the otic placode. In the developing kidney, the expression pattern is indicative of a role for Eya1 in the metanephric cells surrounding the 'just-divided' ureteric branches.

Clustering of mutations responsible for branchio-oto-renal (BOR) syndrome in the eyes absent homologous region (eyaHR) of EYA1.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder, characterised by the association of branchial, otic and renal anomalies with variable degrees of severity. We have recently identified EYA1 , a human homologue of the Drosophila eyes absent gene, as the gene underlying this syndrome. The products of both genes share a highly conserved 271 amino acid C-terminal region (eyaHR). The eyaHR was also found in the products of two other human genes (EYA2 and EYA3), demonstrating the existence of a novel gene family. We report here on the complete genomic structure of EYA1. This gene consists of 16 coding exons and extends over 156 kb. It encodes various alternatively spliced transcripts differing only in their 5' regions. Sequence analysis of the entire EYA1 coding region was performed for 20 unrelated patients affected by BOR syndrome, and six novel mutations were identified. Among these mutations, two are missense mutations, highlighting amino acid residues essential for the function of the EYA1 protein, and one mutation comprises a de novo Alu insertion into an exon. This insertion presumably occurs by retrotransposition, and the mobile Alu element has a poly(A) tail that is unstable throughout generations. To date, 14 mutations have been detected in BOR patients, all of which are different. However, all the mutations are located within or in the immediate vicinity of the eyaHR; the significance of this clustering is discussed.

Characterization of a translocation-associated deletion defines the candidate region for the gene responsible for branchio-oto-renal syndrome.

Fluorescence in situ hybridization analysis of an 8q translocation breakpoint, dir ins(8)(q24.11;q13.3;q21.13), carried by an individual presenting with Branchio-Oto-Renal (BOR) syndrome, resulted in the identification of an associated deletion. The generation of a YAC contig and the isolation of overlapping recombinant P1 and lambda phage clones from the region allowed further characterization of this deletion. Its size was estimated to be between 470 and 650 kb, and it was flanked by the two polymorphic markers D8S1060 and D8S1807. This mapping led us to reevaluate the localization of the gene responsible for BOR syndrome and has now focused the search for the BOR gene to within the limits of this deletion.

A proposed new contiguous gene syndrome on 8q consists of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, a dominant form of hydrocephalus and trapeze aplasia; implications for the mapping of the BOR gene.

The analysis of a de novo 8q12.2-q21.2 deletion led to the identification of a proposed previously undescribed contiguous gene syndrome consisting of Branchio-Oto-Renal (BOR) syndrome, Duane syndrome, hydrocephalus and trapeze aplasia. This is the first reported localization of the genes responsible for Duane syndrome and this dominant form of hydrocephalus. In contrast, we report a new localization for the gene responsible for BOR syndrome which is more telomeric to an initial placement. Linkage analysis of affected families consistently mapped the gene responsible for BOR and Branchio-Oto (BO) syndromes to within the deletion. Using new algorithms, a YAC contig was constructed and used to localize the breakpoint of another chromosomal rearrangement associated with BO syndrome to a 500 kb interval within the deletion. The 8q12.2-q21.2 deletion suggests that reduced dosage of the relevant genes is sufficient to cause Duane syndrome, BOR syndrome and this dominant form of hydrocephalus.

Construction of a yeast artificial chromosome contig spanning the pseudoautosomal region and isolation of 25 new sequence-tagged sites.

Thirty-one yeast artificial chromosomes (YACs) from the human pseudoautosomal region were identified by a combination of sequence-tagged site (STS) screenings and colony hybridizations, using a subtelomeric interspersed repetitive element mapping predominantly to the pseudoautosomal region. Twenty-five new pseudoautosomal STSs were generated, of which 4 detected restriction fragment length polymorphisms. A total of 33 STSs were used to assemble the 31 YACs into a single contiguous set of overlapping DNA fragments spanning at least 2.3 megabases of the pseudoautosomal region. In addition, four pseudoautosomal genes including hydroxyindole O-methyltransferase have been positioned on this set of fragments.

X chromosome-linked Kallmann syndrome: stop mutations validate the candidate gene.

Kallmann syndrome represents the association of hypogonadotropic hypogonadism with anosmia. This syndrome is from a defect in the embryonic migratory pathway of gonadotropin-releasing hormone synthesizing neurons and olfactory axons. A candidate gene for the X chromosome-linked form of the syndrome was recently isolated by using a positional cloning strategy based on deletion mapping in the Xp22.3 region. With the PCR, two exons of this candidate gene were amplified on the genomic DNAs from 18 unrelated patients affected with the X chromosome-linked Kallmann syndrome. Three different base transitions--all leading to a stop codon--and one single-base deletion responsible for a frameshift were identified. We thus conclude that the candidate gene is the actual KAL gene responsible for the X chromosome-linked Kallmann syndrome. Furthermore, unilateral renal aplasia in two unrelated patients carrying a stop mutation indicates that the KAL gene is itself responsible for this Kallmann syndrome-associated anomaly. The gene is, therefore, also involved in kidney organogenesis. Additional neurologic symptoms in Kallmann patients are also discussed.

The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules.

Kallmann syndrome associates hypogonadotropic hypogonadism and anosmia and is probably due to a defect in the embryonic migration of olfactory and GnRH-synthesizing neurons. The Kallmann gene had been localized to Xp22.3. In this study 67 kb of genomic DNA, corresponding to a deletion interval containing at least part of the Kallmann gene, were sequenced. Two candidate exons, identified by multiparameter computer programs, were found in a cDNA encoding a protein of 679 amino acids. This candidate gene (ADMLX) is interrupted in its 3' coding region in the Kallmann patient, in which the proximal end of the KAL deletion interval was previously defined. A 5' end deletion was detected in another Kallmann patient. The predicted protein sequence shows homologies with the fibronectin type III repeat. ADMLX thus encodes a putative adhesion molecule, consistent with the defect of embryonic neuronal migration.