http://repub.eur.nl/res/aut/4321/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/20845/ 2010-09-01T00:00:00Z Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic. We screened four known HPE genes in a Dutch cohort of 86 non-syndromic HPE index cases, including 53 family members. We detected 21 mutations (24.4%), 3 in SHH, 9 in ZIC2 and 9 in SIX3. Eight mutations involved amino-acid substitutions, 7 ins/del mutations, 1 frame-shift, 3 identical poly-alanine tract expansions and 2 gene deletions. Pathogenicity of mutations was presumed based on de novo character, predicted non-functionality of mutated proteins, segregation of mutations with affected family-members or combinations of these features. Two mutations were reported previously. SNP array confirmed detected deletions; one spanning the ZIC2/ZIC5 genes (approx. 100 kb) the other a 1.45 Mb deletion including SIX2/SIX3 genes. The mutation percentage (24%) is comparable with previous reports, but we detected significantly less mutations in SHH: 3.5 vs 10.7% (P=0.043) and significantly more in SIX3: 10.5 vs 4.3% (P=0.018). For TGIF1 and ZIC2 mutation the rate was in conformity with earlier reports. About half of the mutations were de novo, one was a germ line mosaic. The familial mutations displayed extensive heterogeneity in clinical manifestation. Of seven familial index patients only two parental carriers showed minor HPE signs, five were completely asymptomatic. Therefore, each novel mutation should be considered as a risk factor for clinically manifest HPE, with the caveat of reduced clinical penetrance. http://repub.eur.nl/res/pub/14282/ 2008-11-01T00:00:00Z SCO2 is a cytochrome c oxidase (COX) assembly gene. Mutations in the SCO2 gene have been associated with fatal infantile cardioencephalomyopathy. We report on the phenotype of a novel SCO2 mutation in two siblings with fatal infantile cardioencephalomyopathy. The index patient died of heart failure at 25 days of age. Muscle biopsy was performed for histology and biochemical study of the oxidative phosphorylation system complexes. The entire coding region of the SCO2 gene was sequenced. Autopsy was performed on the index patient and on a female sibling delivered at 23 weeks of gestation following termination of pregnancy during which amniocentesis and genetic testing had been performed. Muscle biopsy and biochemical analysis of heart and skeletal muscle detected a severe isolated COX-IV deficiency. Pathologic findings in both patients confirmed hypertrophic cardiomyopathy. Sequencing of the SCO2 gene showed compound heterozygous mutation; the common E140K mutation and a novel W36X nonsense mutation. Newborns with a combination of hypotonia and cardiomyopathy should be evaluated for multiple congenital anomaly syndromes, inborn errors of metabolism and mitochondrial derangements, and may require extensive diagnostic testing. Mutations in the SCO2 gene are a cause of prenatal-onset hypertrophic cardiomyopathy. http://repub.eur.nl/res/pub/3019/ 1990-01-01T00:00:00Z We report on the physical ordering of genes in a relatively small area of chromosome 19, segment q13, containing the locus for myotonic dystrophy (DM), the most frequent heritable muscular dystrophy of adulthood in man. DNAs from somatic cell hybrids with der 19q products that carry a breakpoint across the muscle-specific creatine kinase (CKMM) gene were analyzed by Southern blotting using probes for CKMM, APOC2, and the repair genes ERCC1 and ERCC2. Results were combined with data from CHEF and field inversion-gel-electrophoresis separation of large-sized DNA restriction fragments to establish a map localizing both DNA-repair genes and the CKMM gene within the same 250 kb of DNA, the order being cen-CKMM-ERCC2-ERCC1-ter, with APOC2 being at more than 260 kb proximal to CKMM. Transcriptional start sites of the CKMM and DNA-repair genes are all on the telomeric side of the genes. Our results provide a framework for the construction of a larger physical map of the area, which will facilitate the search for the DM gene.