Mutation detection in FGFR2 craniosynostosis syndromes.

Five autosomal dominant craniosynostosis syndromes (Apert, Crouzon, Pfeiffer, Jackson-Weiss and Crouzon syndrome with acanthosis nigricans) result from mutations in FGFR genes. Fourteen unrelated patients with FGFR2-related craniosynostosis syndromes were screened for mutations in exons IIIa and IIIc of FGFR2. Eight of the nine mutations found have been reported, but one patient with Pfeiffer syndrome was found to have a novel G-to-C splice site mutation at-1 relative to the start of exon IIIc. Of those mutations previously reported, the mutation C1205G was unusual in that it was found in two related patients, one with clinical features of Pfeiffer syndrome and the other having mild Crouzon syndrome. This degree of phenotypic variability shows that the clinical features associated with a specific mutation do not necessarily breed true.

Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2.

The epilepsies comprise a group of syndromes that are divided into generalized and partial (focal) types. Familial occurrence has long been recognized but progress in mapping epilepsy genes has been slow except for rare cases where the inheritance is easily determined from classical genetic studies. Linkage is established for three generalized syndromes: the EBN1 and EBN2 genes for benign familial neonatal convulsions (BFNC) map to chromosomes 20q and 8q (refs 2-5), the EPM1 gene for Unverricht-Lundborg disease maps to 21q (ref. 6) and the gene for the northern epilepsy syndrome maps to 8p (ref. 7). A claim for linkage of the EJM1 gene for the common generalized syndrome of juvenile myoclonic epilepsy to 6p is currently in dispute. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was recently described in five families. We now report the chromosomal assignment, to 20q13.2, for the gene for ADNFLE in one large Australian kindred with 27 affected individuals spanning six generations.

Localization of craniosynostosis Adelaide type to 4p16.

Craniosynostosis Adelaide type is a rare autosomal dominant syndrome associated with digital abnormalities. Linkage mapping was carried out excluding allelism to Saethre-Chotzen syndrome at 7p21, craniosynostosis Boston type at 5q34-q35, Jackson-Weiss and Crouzon syndromes at 10q24-q25 and Pfeiffer syndrome mapping near 8cen. Exclusion mapping was extended to the entire genome until linkage to chromosome 4 was detected. A maximum two-point lod score of 6.2 (theta = 0.0) was obtained with D4S412. The gene responsible for craniosynostosis Adelaide type was localized to 4p16, telomeric to D4S394. This region contains two plausible candidate genes, the MSX1 (HOX7) homeobox gene and the FGFR3 fibroblast growth factor receptor gene.

Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1.

Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBN1, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uniformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible.