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J Hum Genet (2005) 50:684–685 DOI 10.1007/s10038-005-0325-x

BOOK REVIEW

Atsuyoshi Takao Kieran C. Murphy, Peter J. Scambler (eds): Velo-cardio-facial : a model for understanding microdeletion disorders

Cambridge University Press, Cambridge, 2005, ISBN 0-521-82185-1

Published online: 9 November 2005 Ó The Japan Society of Human and Springer-Verlag 2005

Genetics- and etiology-minded physicians with a keen and a right aortic arch or conotruncal heart defect, observant eye may differentiate rarity from commonality presented with characteristic facial features forming a in clinical practice, despite only subtle changes in phe- syndrome that Shprintzen aptly called Velo-Cardio-Fa- notypic features. When a center for a specific is cial Syndrome. Takao, a pediatric cardiologist at the established for treatment or research purposes, patients Heart Institute of Japan in Tokyo was kept busy taking with the relevant morbid condition will be referred to care of blue babies and children with conditions such as specialists working at the center. With time, the patient tetralogy, , truncus, vascular anoma- load will increase, and out of the group will emerge rare lies, etc. Among them was a subset of children with cases with characteristic features that attract the atten- hypernasality of voice, and characteristic facial features tion of leading specialists. Thus begins a search for a [Kinouchi et al (1976) Pediatr Jpn 17:84–87]. These new disease entity or to find an underlying pathological features were so specific for the group that the name mechanism, eventually opening new fields of study. At Conotruncal Anomaly Face Syndrome (CAFS) was present, human features (phenotypes) are roughly cate- proposed to attract the attention of pediatricians and gorized genetically into one of several groups, including cardiologists in Japan. Several with this syn- single anomalies, polygenic environment-gene- drome had hypocalcemic seizures and thymic hypopla- interactions, chromosomal aberrations, microdeletions, sia. In 1965, in a discussion of a colleague’s paper as well as mitochondrially inherited conditions and relating to immune disorders in children, Angelo Di- uniparental dysomy or imprinting. Epigenetic and George described athymia and immune disorder in a environmental factors also play important roles in cau- child with a right aortic arch, and further experience of a sation. series of cases expanded the phenotype to include co- The fascinating story of the discovery and under- notruncal heart anomalies in the defect literature standing of the microdeletion-associated condition [DiGeorge (1965) J Pedatr 67(Suppl):907–909]. Fur- known as Velo-Cardio-Facial Syndrome (VCFS), from thermore, in both VCFS and CAFS, it was noticed that the first independent encounters by investigators in dif- a relatively high prevalence of schizophrenia became a ferent disciplines, in different countries, and with dif- real clinical problem for the patients and their families. ferent clinical backgrounds, has been well described in a The above three or sequences were de- historical overview by Shprintzen [Shprintzen et al scribed independently by clinicians and investigators in (1978) Cleft Palate J 15:56–62], who discovered and different disciplines. However, through the steady efforts named VCFS. The story can be summarized as follows: made toward elucidation of the pathogenetic mecha- in the 1960s–1970s, children with a nasal voice, speech nisms, especially with progress in molecular cytogenetic disorders and learning or behavioral problems analysis, it was found that all three syndromic pheno- were referred to a center for craniofacial and speech types are associated with deletions encompassing disorder at a hospital in New York City. These patients, mapped to 22q11. VCFS is a associated who had a cleft or palate (submucous cleft palate) with a of the long arm of , which is the most common interstitial deletion disorder found in man, affecting every major system in the body A. Takao with more than 100 physical and behavioral phenotypic Japan Research Promotion Society for Cardiovascular Disease, Tokyo Women’s Medical University, 8-1 Kawada-cho, features. Shinjuku-ku, Tokyo 162-8666, Japan Interstitial deletions occur within chromosomal seg- E-mail: [email protected] ments between the centromere and the telomeres. Im- 685 proved banding and fluorescent in situ hybridization cussed. Professionals studying or treating one aspect of (FISH) techniques allow us to detect interstitial mic- this deletion syndrome may be unaware of the involve- rodeletions that are too small to be visualized by routine ment of other systems—this book will assist them in karyotyping. These usually encompass multiple genes (in obtaining a more holistic view of patients with VCFS the case of VCFS, >30 due to a deletion of 1.5–3 Mb), (del 22q11.2). A phenotypic aggregate indicates the need causing aggregate phenotypes, which form syndromes for a multi-disciplinary holistic approach and for life- expressing the sum of phenotypes expected from the long follow-up of patients, during which new sequelae haplo-insufficiency of genes within the deletion region. may appear. Microdeletion syndromes (VCFS, Wil- Velo-cardio-facial syndrome: a model for understand- liams, Alagille and others) represent one aspect of ing microdeletion disorders summarizes recent progress in diversified human phenotypes in evolutionary history. the understanding and treatment of VCFS. The focus is VCFS may be seen as a paradigm for other less common on clinical issues, with chapters devoted to psychiatric microdeletion disorders, and experience with this syn- disorders, neuroimaging, speech and language disorders, drome may be most informative and thus help to direct as well as to cardiac, ENT, gastrointestinal, ophthalmic, research and treatment strategies. Clinicians and scien- and urological manifestations. Molecular genetics, tists of different disciplines will all enjoy and benefit immunodeficiency, and genetic counselling are also dis- from reading this book.