We have localized the DNA sequences required for mitotic centromere function on the human Y chromosome. Analysis of 33 rearranged Y chromosomes allowed the centromere to be placed in interval 8 of a 24-interval deletion map. Although this interval is polymorphic in size, it can be as small as approximately 500kb. It contains alphoid satellite DNA and approximately 300kb of adjacent Yp sequences. Chromosomes with rearrangements in this region were analysed in detail. Two translocation chromosomes and one monocentric isochromosome had breakpoints within the alphoid array. Of 12 suppressed Y centromeres on translocation chromosomes and dicentric isochromosomes that were also analysed two showed deletions one of which only removed alphoid DNA. These results indicate that alphoid DNA is a functional part of the Y chromosome centromere.

Split hand/foot malformation (SHFM) with long bone deWciency (SHFLD) is a distinct entity in the spectrum of ectrodactylous limb malformations characterised by associated tibial a/hypoplasia. Pedigrees with multiple individuals aVected by SHFLD often include nonpenetrant intermediate relatives, making genetic mapping diYcult. Here we report a sporadic patient with SHFLD who carries a de novo chromosomal translocation t(2;18)(q14.2;p11.2). Characterisation of the breakpoints revealed that neither disrupts any known gene; however, the chromosome 2 breakpoint lies between GLI2 and INHBB, two genes known to be involved in limb development. To investigate whether mutation of a gene in proximity to the chromosome 2 breakpoint underlies the SHFLD, we sought independent evidence of mutations in GLI2, INHBB and two other genes (RALB and FLJ14816) in 44 unrelated patients with SHFM, SHFLD or isolated long bone deWciency. No convincing pathogenic mutations were found, raising the possibility that a long-range cis acting regulatory element may be disrupted by this translocation. The previous description of a translocation with a 2q14.2 breakpoint associated with ectrodactyly, and the mapping of the ectrodactylous Dominant hemimelia mouse mutation to a region of homologous synteny, suggests that 2q14.2 represents a novel locus for SHFLD.

A case of prenatally detected cri du chat syndrome (5p-) is reported. Amniocentesis was performed following an abnormal ultrasound finding of isolated moderate bilateral ventriculomegaly. The karyotype showed a terminal deletion of the short arm of chromosome 5 including the critical region 5p15 for cri du chat syndrome. This was confirmed by fluorescence in situ hybridisation (FISH). Isolated mild ventriculomegaly may be a non-specific marker for cri du chat syndrome.

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Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a birth incidence of 1/3,500. Around 50% of cases are due to new mutations. The NF1 gene maps to 17q11.2 and encodes neurofibromin. NF1 is a "classical" tumor suppressor gene. Congenital disseminated NF1 is rare with just two cases previously reported. We present a deceased baby with congenital disseminated NF1 in whom we performed molecular studies. A germline mutation (R461X) in exon 10a of the NF1 gene was found. A 2 bp deletion (3508delCA) in codon 1170 of exon 21 was identified in DNA derived from some tumor tissue. Loss of heterozygosity in NF1 and TP53 was observed in other tumor samples. No microsatellite instability was observed in the tumor samples. This is the first report of molecular analysis of the NF1 locus in a patient with disseminated congenital neurofibromatosis. This case had a de novo germline mutation in NF1 and three documented somatic mutations in the NF1 and TP53 genes in tumor specimens.