Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-ofthe-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8 -16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease. copy number variants ͉ genomic structural variation ͉ human genome ͉ congenital heart disease ͉ leukemia F or over two decades trisomy 21 has represented a prototype disorder for the study of human aneuploidy and copy-number variation (1, 2), but the genes responsible for most Down syndrome (DS) phenotypes are still unknown. The analysis of several overlapping segmental trisomies 21 has led to the suggestion that dosage alteration through duplication of an extended region on chromosome 21 (HSA21) is associated with DS features (2-5, 42). However, humans with segmental trisomy 21 are rare, and thus humanbased DS-phenotypic maps have been of low resolution, far beyond the level of few or single genes, or even exons. Consequently, gene-disease links have often been based on indirect evidence from cellular or animal models (6, 7). Moreover, current hypotheses argue for the existence of a critical region, the DS consensus region (DSCR), responsible for most severe DS features (6, 8, 9), or presume the causative role of a small set of genes including DSCR1 and DYRK1A, or APP, for these phenotypes (6, 7).By using state-of-the-art genomics together with a large panel of partially trisomic individuals, we present the highest resolution DS phenotype map to date and identify distinct genomic regions that likely contribute to the manifestation of 8 DS features. Four of these phenotypes have never been associated with a particular region of HSA21. The map also enables us to rule out the necessary contribution of other HSA21 regions, thus pr...

Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II-like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed-54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.

Cockayne syndrome (CS) is a genetic disorder characterized by developmental abnormalities and photodermatosis resulting from the lack of transcription-coupled nucleotide excision repair, which is responsible for the removal of photodamage from actively transcribed genes. To date, all identified causative mutations for CS have been in the two known CS-associated genes, ERCC8 (CSA) and ERCC6 (CSB). For the rare combined xeroderma pigmentosum (XP) and CS phenotype, all identified mutations are in three of the XP-associated genes, ERCC3 (XPB), ERCC2 (XPD), and ERCC5 (XPG). In a previous report, we identified several CS cases who did not have mutations in any of these genes. In this paper, we describe three CS individuals deficient in ERCC1 or ERCC4 (XPF). Remarkably, one of these individuals with XP complementation group F (XP-F) had clinical features of three different DNA-repair disorders--CS, XP, and Fanconi anemia (FA). Our results, together with those from Bogliolo et al., who describe XPF alterations resulting in FA alone, indicate a multifunctional role for XPF.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a relatively common, underdiagnosed autosomal-dominant disorder of arteriovenous malformations and telangiectases. DNA testing for hereditary hemorrhagic telangiectasia has recently become available in North America, making presymptomatic screening available to relatives with a positive molecular diagnosis. This now enables practitioners to prevent catastrophic complications of undiagnosed pulmonary and CNS arteriovenous malformations and eliminates the need to radiographically screen all at-risk relatives shown to be unaffected by molecular testing. We review the clinical aspects of hereditary hemorrhagic telangiectasia, describe the indications, benefits, and limitations of molecular diagnostic testing for hereditary hemorrhagic telangiectasia, and provide a molecular genetics summary to facilitate genetic counseling before and after DNA testing for this complex disorder. Genet Med 2004:6(4): [175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191].

Fibular aplasia and/or hypoplasia is documented as a developmental field defect and the extent of the fibular developmental field is delineated. The term fibular a/hypoplasia denotes the clinical spectrum of fibular deficiency in different patients and also implies that aplasia can be present in one limb and hypoplasia in the other. Causal heterogeneity of fibular a/hypoplasia is demonstrated, thereby defining it as a developmental field defect. Most cases of fibular a/hypoplasia are isolated, sporadic events. An autosomal dominant form of isolated fibular a/hypoplasia with ankle joint anomaly is reviewed. Fibular a/hypoplasia may be part of more complex sporadic dysostoses; sporadic syndromes, an aneuploidy syndrome; several autosomal dominant and autosomal recessive conditions. Fibular a/hypoplasia is also postulated to occur as a result of disruption or teratogenic insult; in animals, fibular development can be disturbed by radiation, busulfan, and retinoic acid. Clinical data allow evaluation of the extent of the fibular developmental field of the lower limb. This appears to include the pubic portion of the pelvis, proximal femur (distal half being apparent tibial developmental territory), patella, anterior cruciate ligament, and lateral and/or axial foot rays (but “never” the hallux and almost never associated with polydactyly). The rare cases of fibuloulnar dimelia allow confirmation of the well known homology of mesomelic limb segments responsible for concordant ulnar and fibular (and radial and tibial) defect, if both upper and lower limbs are involved in a given condition. Because fibular a/hypoplasia is the commonest of the mesomelic paraxial hemimelias, is usually nonsyndromal, and in most cases is apparently nongenetic (ie, with negligible recurrence risk), we propose that in humans, as in several other tetrapods, the fibula is undergoing regressive evolution and hence is developmentally especially labile.