Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing.

Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS.

Tetrasomy 12p (Pallister-Killian syndrome): difficulties in prenatal diagnosis.

PURPOSE: We report a rare case of Pallister-Killian syndrome diagnosed prenatally with increased nuchal translucency during screening for trisomy 21. MATERIALS AND METHODS: Echografic and postmortem examination of the fetus, G-banded chromosome and FISH analysis on short- and long-term chorion villous sampling (CVS) culture. RESULTS AND DISCUSSION: Cytogenetic analysis revealed a supernumerary isochromosome 12p after long-term culture whereas a normal cell line was detected in short-term culture only. Sonografic examination in 17-weeks' gestation showed further increase of the NT and the additional presence of brachymelia, diaphragmatic hernia and a marked dextroposition of the heart. Termination of the pregnancy was performed. The cases of PKS karyotypically confirmed on CVS are reviewed, and cytogenetic and sonographic aspects of the prenatal diagnosis of PKS are discussed.

A disease causing deletion of 29 base pairs in intron 15 in the MKS1 gene is highly associated with the campomelic variant of the Meckel-Gruber syndrome.

Meckel-Gruber syndrome (MKS) is an autosomal recessive disorder causing severe defects in the developing central nervous system and other organs. Recently, mutations in the MKS1 gene have been identified as disease causing in individuals of Finnish MKS families. The primary aim of the present study was to assess the frequency of the 'Finnish founder mutation' (29 bp IVS15-7_35) in the MKS1 gene in 20 aborted fetuses with a diagnosis of MKS. The secondary aim was to screen for novel mutations in the coding sequence of the MKS1 gene of MKS fetuses and to obtain genotype-phenotype correlations where possible. Furthermore, we evaluated the carrier rate of a deletion of 29 bp in intron 15 of the MKS1 gene in a German population. To identify and characterize mutations in the MKS1 gene, sequence analyses and quantitative real time polymerase chain reaction studies were performed. We could identify the same type of mutation, a deletion of 29 bp in intron 15 of the MKS1 gene, in 8 out of the 20 cases studied. Six out of the eight cases with such a mutation displayed the campomelic variant of MKS. The carrier frequency among 519 healthy German individuals was 1:260. This deletion in the MKS1 gene is highly associated with a distinct subtype of the MKS, namely the campomelic variant. In individuals of European origin suffering from the campomelic MKS variant, the described deletion is highly likely to be causative. Regarding the results of our study, the incidence of MKS in Germany can be estimated as 1:135,000. In families with a known mutation in the MKS1 gene, it is now possible to offer an early prenatal testing, for example with chorionic villus sampling and mutation analysis.

[Fulminant course of falciparum malaria]. / Foudroyanter Verlauf einer Malaria tropica.

HISTORY AND ADMISSION FINDINGS: A 57-year-old white man had been travelling in Kenya for vacation until 14 days before admission. Due to apprehension about side effects, the patient had refused any malaria prophylaxis. Ten days before admission he developed low grade temperatures and suffered from pain in the limbs, from nausea and vomiting. A new episode of tachyarrhythmia was diagnosed two days before admission and was treated by his general practitioner. Finally he was admitted to our hospital because of high temperatures, chills and progressive clinical deterioration. Autopsy revealed prominent congestion of liver, spleen and cerebral vessels as well as subdural and subarachnoidal hemorrhage. INVESTIGATIONS: In both thin and thick peripheral blood smears Plasmodium parasites were demonstrated in approximately 30% of the eryhthrocytes and the diagnosis of Plasmodium falciparum was immediately confirmed by an immunological test. TREATMENT AND COURSE: Due to the fulminant clinical and neurological deterioration with progressive hypoxaemia, the patient required ventilator therapy already one hour after admission. Therapy with chinine and doxycycline was initiated and exchange transfusion was considered. However, due to hyperkalaemia and cardiac arrest, the patient died 4 hours after admission due to parasitic hemolysis. CONCLUSIONS: Severe Plasmodium falciparum infection in non-immunized patients is a medical emergency and requires immediate diagnosis and treatment. Malaria should always be considered in the differential diagnosis in persons who have travelled to endemic areas and presenting not only with temperatures, but also with non-specific clinical signs, like cardiac arrhythmias. Although never entirely effective, chemoprophylaxis is highly recommended.