Interactive e-learning courses in human genetics: usage and evaluation by science and medical students at the faculty of medicin.

INTRODUCTION: This study presents our online-teaching material within the k-MED project (Knowledge in Medical Education) at the university of Marburg. It is currently organized in five e-learning modules: cytogenetics, chromosomal aberrations, formal genetics, fundamentals of molecular diagnostics, and congenital abnormalities and syndromes. These are basic courses intended to do the educational groundwork, which will enable academic teachers to concentrate on more sophisticated topics during their lectures. METHODS: The e-learning modules have been offered to a large group of about 3300 students during four years at the Faculty of Medicine in Marburg. The group consists of science students (human biology) and medical students in the preclinical or the clinical period, respectively. Participants were surveyed on acceptance by evaluating user-tracking data and questionnaires. RESULTS AND CONCLUSION: Analysis of the evaluation data proofs the broad acceptance of the e-learning modules during eight semesters. The courses are in stable or even increasing use from winter term 2005/06 until spring term 2009. CONCLUSION: Our e-learning-model is broadly accepted among students with different levels of knowledge at the Faculty of Medicine in Marburg. If the e-learning courses are maintained thoroughly, minor adaptations can increase acceptance and usage even furthermore. Their use should be extended to the medical education of technical assistances and nurses, who work in the field of human genetics.

Cranial nerve palsy in Wegener's granulomatosis--lessons from clinical cases.

The problem of diagnosing vasculitic neuropathy is discussed based on case reports of two patients with Wegener's granulomatosis. One patient developed de novo 6(th) nerve palsy as an isolated relapse manifestation and the second patient a sequence of multiple cranial nerve palsies. Brain imaging with CT and MRI and the laboratory provided no clues suggesting active vasculitis. However, in both patients the neuropathies fully recovered in response to standard induction protocols of vasculitis. In the absence of organ-specific proof of vasculitis, these treatment decisions were guided by the overall clinical presentations. Cranial neuropathy may be the first obvious vasculitic manifestation preceding other organ disease, and since single reliable tests for its diagnosis are lacking, a multidisciplinary approach is advocated here to detect vasculitic manifestations in other organs.

Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome.

The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.

Situs ambiguus in a female fetus with balanced (X;21) translocation--evidence for functional nullisomy of the ZIC3 gene?

The human ZIC3 gene has been mapped to Xq26.2, the visceral heterotaxy locus HTX1, and has been shown to be mutated in X-linked situs ambiguus and/or complex heart defects. We report on a female fetus with situs ambiguus, asplenia and corrected transposition of the great arteries, displaying a (X;21) translocation. The balanced state of the t(X;21)(q26;p13) was verified by FISH on metaphase chromosomes of the fetus using DOP-PCR products of the microdissected der(21) and Xq-subtelomere specific sequences, and by PRINS with beta-satellite specific sequences. Examination with polymorphic markers flanking ZIC3 on DOP-PCR products of the microdissected der(21) chromosome evidenced that the complete copy of the ZIC3 gene was translocated to chromosome 21. Mutations in the fetal and parental ZIC3 genes were excluded by sequencing. Paternal origin of the der(X) and der(21) chromosomes was confirmed by use of polymorphic microsatellite markers from chromosome 21 and from the chromosomal region Xq26, respectively. X chromosome inactivation analysis using a PCR of a polymorphic (CAG)(n) repeat in the first exon of the androgen receptor gene showed a completely skewed X inactivation pattern with the paternal X as the active X chromosome, thus excluding functional disomy of distal Xq. A positional effect caused by the balanced (X;21) translocation may be responsible for functional nullisomy of ZIC3 and thus explain the situs and cardiac abnormalities in the fetus.

Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment.

Previously we confirmed linkage of autosomal dominantly inherited low-frequency sensorineural hearing impairment (LFSNHI) in a German family to the genetic locus DFNA6/DFNA14 on chromosome 4p16.3 close to the markers D4S432 and D4S431. Analysis of data from the Human Genome Project, showed that WFS1 is located in this region. Mutations in WFS1 are known to be responsible for Wolfram syndrome (DIDMOAD, MIM #606201), which follows an autosomal recessive trait. Studies in low-frequency hearing loss families showed that mutations in WFS1 were responsible for the phenotype. In all affected family members analysed, we detected a missense mutation in WFS1 (K705N) and therefore confirm the finding that the majority of mutations responsible for LFSNHI are missense mutations which localise to the C-terminal domain of the protein.

Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10.

Mutations in the connexin 26 gene (GJB2) are responsible for the major part of nonsyndromic autosomal recessive or apparently sporadic prelingual deafness in Caucasians (DFNB1). We screened 228 German hearing-impaired persons for mutations in the GJB2 gene by sequence analysis. Homozygous or compound heterozygous GJB2 mutations were detected in 38/228 (16.7%) of hearing impaired persons. The most frequently occurring mutation was the c.35delG mutation, which was found in 71.1% of the mutated alleles. The next frequent mutation detected in the group of hearing impaired persons was the c.101T>C mutation (9/76 alleles; 11.8%). One new mutation, c.567delA, was observed. We further studied the presence of a 10bp deletion in the 5' UTR of the GJB2 gene (c.-493del10) which was assumed to occur together with the c.101T>C mutation. Ten out of thirteen patients (76.9%) were found to be carriers of both the c.101T>C mutation and the 10bp variant and in 7/14 alleles a linkage disequilibrium between c.101T>C and the 10bp deletion was proven. In 4/14 alleles the linkage was ruled out and for the remaining 3 cases the phase determination was not possible. Seventy one controls were screened for the prevalence of Cx26 mutations and for the c.-493del10 variant. Heterozygosity frequency in the control group was for c.35delG 4.2%, for c.101T>C 1.4% and for c.-493del10 it was 5.6%.