Oral-facial-digital type 1 syndrome (OFD1 [MIM 311200]) is transmitted as an X-linked dominant condition with lethality in males and is characterized by malformations of the face, oral cavity, and digits, and by a highly variable expressivity even within the same family. Malformation of the brain and polycystic kidneys are commonly associated with this disorder. The locus for OFD1 was mapped by linkage analysis to a 12-Mb interval, flanked by markers DXS85 and DXS7105 in the Xp22 region. To identify the gene responsible for this syndrome, we analyzed several transcripts mapping to the region and found mutations in OFD1 (formerly named "Cxorf5/71-7a"), encoding a protein containing coiled-coil alpha-helical domains. Seven patients with OFD1, including three with familial and four with sporadic cases, were analyzed. Analysis of the familial cases revealed a missense mutation, a 19-bp deletion, and a single base-pair deletion leading to a frameshift. In the sporadic cases, we found a missense (de novo), a nonsense, a splice, and a frameshift mutation. RNA in situ studies on mouse embryo tissue sections show that Ofd1 is developmentally regulated and is expressed in all tissues affected in OFD1 syndrome. The involvement of OFD1 in oral-facial-digital type I syndrome demonstrates an important role of this gene in human development.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/ CSA/ and www.umd.be/CSB/). Hum Mutat 31:113-126,

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Hereditary hemmorrhagic telangiectasia (HHT, or Osler-Rendu-Weber syndrome) is an autosomal dominant disease characterized by arteriovenous malformations, affecting 1 out of 10,000 individuals in France. The disease is caused by mutations of two genes: ENG and ALK1 (ACVRL1). We screened the coding sequence of ENG and ALK1 in 160 unrelated French index cases. A germline mutation was identified in 100 individuals (62.5%). A total of 36 mutations were found in ENG, including three nonsense mutations, 19 small insertions/deletions leading to a frameshift, two inframe deletions, seven missense mutations, and five intronic or splice-site mutations. Of the 36 mutations, 33 were novel mutations. A total of 64 mutations were found in ALK1, including six nonsense mutations, 28 small insertions/deletions leading to a frameshift, one inframe deletion, 27 missense mutations, and two intronic or splice-site mutations. Of the 64 mutations, 27 were novel mutations. Mutations were found in most parts of the coding sequence for both genes, except ALK1 exon 5 and ENG exons 12 to 14. Missense mutations in ALK1 were more frequent in exons 7, 8, and 10. ENG cDNA was sequenced for three intronic mutations: c.689+2T>C produced an abnormal transcript excluding exon 5, c.1103+3_1103+8del activated a cryptic splice site 22 bp upstream, and c.1428G>A produced two abnormal transcripts, one including intron 11 and the other excluding exon 10. Although most of the mutations were private, some recurrent mutations in ALK1 were of particular interest. Mutation c.1112_1113dupG (p.Gly371fsX391) was found in 17 unrelated individuals sharing a common haplotype, strongly suggesting a founder effect related to the concentration of patients previously reported in a specific French region (Rhône-Alpes). Three missense mutations involved the same codon: c.1231C>T (p.Arg411Trp), c.1232G>C (p.Arg411Pro), and c.1232G>A (p.Arg411Gln) were found in seven, two, and one patients, respectively. Haplotype analysis was in favor of both a founder effect and a mutation hot-spot.