Genetic variation in ICF syndrome: evidence for genetic heterogeneity.

ICF syndrome is a rare autosomal recessive immunoglobulin deficiency, sometimes combined with defective cellular immunity. Other features that are frequently observed in ICF syndrome patients include facial dysmorphism, developmental delay, and recurrent infections. The most diagnostic feature of ICF syndrome is the branching of chromosomes 1, 9, and 16 due to pericentromeric instability. Positional candidate cloning recently discovered the de novo DNA methyltransferase 3B (DNMT3B) as the responsible gene by identifying seven different mutations in nine ICF patients. DNMT3B specifically methylates repeat sequences adjacent to the centromeres of chromosome 1, 9, and 16. Our panel of 14 ICF patients was subjected to mutation analysis in the DNMT3B gene. Mutations in DNMT3B were discovered in only nine of our 14 ICF patients. Moreover, two ICF patients from consanguineous families who did not show autozygosity (i.e. homozygosity by descent) for the DNMT3B locus did not reveal DNMT3B mutations, suggesting genetic heterogeneity for this disease. Mutation analysis revealed 11 different mutations, including seven novel ones: eight different missense mutations, two different nonsense mutations, and a splice-site mutation leading to the insertion of three aa's. The missense mutations occurred in or near the catalytic domain of DNMT3B protein, indicating a possible interference with the normal functioning of the enzyme. However, none of the ICF patients was homozygous for a nonsense allele, suggesting that absence of this enzyme is not compatible with life. Compound heterozygosity for a missense and a nonsense mutation did not seem to correlate with a more severe phenotype.

Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia.

Spinocerebellar ataxia type 7 (SCA7) is a neuro-degenerative disorder characterised by progressive cerebellar ataxia and macular degeneration. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias (ADCAs) in the world (4.5 to 11.6%), but in Sweden and Finland SCA7 is the most commonly identified form of ADCA. In an inventory of hereditary ataxias in Scandinavia (Sweden, Norway, Denmark and Finland) we identified 15 SCA7 families, eight in Sweden and seven in Finland, while no cases of SCA7 could be found in Norway or Denmark. We examined whether the relatively high frequency of SCA7 families in Sweden and Finland was the result of a common founder effect. Only two out of 15 families could be connected genealogically. However, an extensive haplotype analysis over a 10.2 cM region surrounding the SCA7 gene locus showed that all 15 families studied shared a common haplotype over at least 1.9 cM. This strongly suggests that all Scandinavian SCA7 families originate from a common founder pre-mutation.

Maternal isodisomy of chromosome 9 with no impact on the phenotype in a woman with two isochromosomes: i(9p) and i(9q).

We describe a 34-year-old healthy woman with isochromosomes for the short and long arm of chromosome 9 who was ascertained because of repeated spontaneous abortions. Molecular analysis demonstrated maternal uniparental isodisomy for the whole chromosome 9, thus the origin of the isochromosomes was maternal. Because the patient had a normal phenotype, the maternal isodisomy supports the previous assumption that there are no maternally imprinted genes on chromosome 9.

Early prenatal diagnosis of the ICF syndrome.

The ICF syndrome (immunodeficiency, (para)centromeric instability and facial abnormalities) is a rare autosomal recessive disorder with characteristic cytogenetic aberrations of chromosomes 1, 9 and 16 in lymphocytes. Previously, only one case has been diagnosed prenatally in the second trimester of pregnancy by fetal blood sampling. We report the first early prenatal exclusion of the ICF syndrome by chorionic villous sampling (CVS) and linkage analysis in a family with a previous affected child. The fetus was heterozygous for marker D20S850 closely linked to the ICF locus. The family was counselled of a probability of over 90% that the fetus would be unaffected. Postnatal chromosome analysis on peripheral blood was normal and thus confirmed the prenatal diagnosis.