- Email: [email protected]
Genetic resources for the neonatologist
Seminars in Fetal & Neonatal Medicine (2005) 10, 291e298
www.elsevierhealth.com/journals/siny
Genetic resources for the neonatologist Louise Kaufman a,*, Mark Herbert b a
Department of Clinical Genetics, Churchill Hospital, Headington, Oxford OX3 7JL, UK Neonatal Unit, Department of Paediatrics, Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK b
KEYWORDS Books; Databases; Websites; Genetic resources
Summary Diagnosing genetic disorders and counselling the parents of babies with possible genetic conditions takes up a significant proportion of a neonatologist’s clinical time. This article provides a guide to establishing genetic tools and a reference library on a neonatal unit. The availability of good resources may heighten staff awareness of genetic aetiologies in babies with subtle features, and enable possible diagnoses to be considered and a genetics consultation sought. In addition, when a diagnosis is made, information is then readily available to guide the neonatologist in his or her consultations with parents. It is not intended that the tools outlined here should be a replacement for the genetics consultation; their role is merely to facilitate the interaction of neonatologists with geneticists, to the benefit of the parents and the baby. Ó 2005 Published by Elsevier Ltd.
Introduction The three main genetics resources are textbooks, databases and websites (Table 1); examples of each are summarised in this article. Textbooks usually have a chapter structure or an index that allows the book to be used to help make a diagnosis; these include Smith’s Recognizable Patterns of Human Malformation1 and Clinical Genetics: An Essential Guide.2 Several textbooks * Corresponding author. Neonatal Unit, Department of Paediatrics, Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. E-mail address: [email protected] (L. Kaufman). 1744-165X/$ - see front matter Ó 2005 Published by Elsevier Ltd. doi:10.1016/j.siny.2005.02.002
give more detailed information, useful for when a diagnosis has been made, such as Syndromes of the Head and Neck,3Bone Dysplasias,4,5Management of Genetic Syndromes5 and the Catalogue of Unbalanced Chromosome Aberrations in Man.6 Perhaps the best resources for making preliminary diagnoses are, however, web-based and CDROM genetic databases, such as Online Mendelian Inheritance in Man (OMIM)7,8 and the Wintere Baraitser Dysmorphology Database.9 These databases are specifically designed for searching syndromes on the basis of the phenotype. They are limited by users’ experience in the hierarchical classification of the signs and their ability to recognize features and describe them with genetic
292
Table 1
Genetic resources
Resources Books
Databases
Websites
Smith’s Recognizable Patterns of Human Malformation Clinical Genetics: An Essential Guide Syndromes of the Head and Neck Bone Dysplasias Management of genetic syndromes
References
Notes
1
Useful overview of Mendelian inherited and chromosomal disorders
2 3 4 5
A handbook of clinical genetics One of the most useful books in clinical genetics An excellent reference with illustrations for bone disorders A trove of valuable clinical information on 30 of the most common genetic syndromes The definitive textbook for syndromes arising from chromosomal anomalies
Catalogue of Unbalanced Chromosome Aberrations in Man
6
WintereBaraitser Dysmorphology Database
9
POSSUM SynDiag (Syndrome Diagnosis)
12 13
Online Mendelian Inheritance in Man Genomics and Disease Prevention Clinical Genetics Computer Resources GeneClinics and GENEReviews European Directory of DNA Diagnostic Laboratories Online Searchable Directory of Genetic Resources from the Genetic Alliance Database of Chromosomal Variation in Man ORPHANET Cambridge Genetics Knowledge Park
www.ncbi.nlm.nih.gov/ www.cdc.gov/genomics/info/database.htm www.kumc.edu/gec/prof/genecomp.html www.geneclinics.org/ www.eddnal.com/ www.geneticalliance.org
An excellent resource containing information on over 3400 syndromes and over 12 500 photographs
L. Kaufman, M. Herbert
www.wiley.com/legacy/products/subject/life/borgaonkar/access.html http://www.orpha.net/ http://www.cgkp.org.uk/biglinks.html
Genetic resources for the neonatologist terminology (e.g. ‘telecanthus’). Although helpful to the practising neonatologist for making preliminary diagnoses, gaining the confidence to seek a genetics consultation or gaining some idea of a condition prior to the arrival of a geneticist, these databases yield better results in the hands of the experienced. The web-based databases tend not to show pictures of syndromes, whereas the CD-ROM databases have the advantage that they do. Most of the genetic books, websites and databases listed here deal with Mendelian inherited disorders (autosomal recessive, dominant and Xlinked conditions) and do not comprehensively cover chromosomal aberrations (triploidies, aneuploidies, rearrangements, translocations and deletions). Thus, for example, an OMIM search using the typical features of Down, Edward or Patau syndrome will not identify these conditions. One of the best resources for understanding chromosomal aberrations is the Catalogue of Unbalanced Chromosome Aberrations in Man.6 It is a superb reference once a diagnosis has been made, or even suspected, but is not easy to use to help make a diagnosis when a syndrome is not immediately recognized by Gestalt processes. Hence the value of a cytogenetic chromosomal study on any patient with a suspected genetic disorder, especially if the features do not suggest a Mendelian inherited condition.
Genetic reference books Smith’s Recognizable Patterns of Human Malformation1 is a compact textbook organized so that it is searchable on features. Making a diagnosis solely with this book can, however, be laborious, and the databases are perhaps better for this role. Once a diagnosis has been made, ‘Smith’s’ covers most of the common genetic conditions, a double-page spread being given over to each syndrome, with a brief synopsis and images. For many conditions, this book provides some information for a neonatologist to discuss the condition in an informed manner with parents, as an addition to a genetics consultation, but it contains limited information on the genetic basis of the disorder. Clinical Genetics: An Essential Guide2 is one of the Oxford Handbook series pocket texts and promises to be an estimable book, perhaps to be carried in every neonatologist’s pocket. Gorlin et al.’s Syndromes of the Head and Neck3 is one of the most useful books in clinical genetics, rivalled perhaps only by OMIM. As most genetic syndromes have head or neck involvement, this book covers many of the syndromes one is likely to encounter on a neonatal unit. The chapters are
293 divided by aetiology and by major features; there are, for example, chapters on syndromes with contractures, and on short stature syndromes, as well as on osteogenesis imperfecta and chondrodysplasias. It is a definitive textbook aimed at the clinical geneticist but a wonderful book to have on a neonatal unit, especially for finding out more detail on a condition when a diagnosis has been made and for subsequently following up the child. Bone Dysplasias4 is also organized by features, such as lethal syndromes, syndromes with predominant metaphyseal, epiphyseal or diaphyseal involvement, and dysostosis multiplex. The book contains numerous photographs and radiographs, and is a fascinating source of information for the neonatologist once a diagnosis has been made. Because of its layout, it is also very helpful for considering likely diagnoses in advance of a genetics opinion. Management of Genetic Syndromes5 is a trove of valuable clinical information on 30 of the most common genetic syndromes. The chapters are arranged alphabetically, starting with achondroplasia, Angelman syndrome, BeckwitheWiedemann syndrome, CHARGE association, Cornelia de Lange syndrome, Down syndrome, etc. It is directed at the clinician who is not a geneticist, with an emphasis on clinical evaluation and management. Each chapter deals with a different condition and covers incidence, diagnostic criteria, aetiology and pathogenesis, diagnostic testing, differential diagnosis and the nature, evaluation and treatment of major disease manifestations. Many genetic disorders seen on a neonatal unit are caused by chromosome deletions or duplications rather than point mutations, and these are comprehensively covered in the Catalogue of Unbalanced Chromosome Aberrations in Man6. Don’t be put off by the title: the book is well organized. Each of the main chapters covers disorders of one chromosome, and each is divided into sections covering monosomy of that chromosome, deletions, ring chromosomes, duplications, trisomies and uniparental disomy. It is an outstanding textbook for gaining knowledge after a diagnosis has been made. Victor McKusick’s book Mendelian Inheritance in Man10 is a textbook version of OMIM and contains over 9000 entries. It is designed for those with knowledge of genetics and will be found on the shelves of many geneticists. The usefulness of this textbook on a neonatal unit is, however, limited, especially with the availability of OMIM, which is continuously updated. Mendelian Inheritance in Man was last updated in 1998. Chromosome Abnormalities and Genetic Counseling11 is a small but extremely detailed
294
L. Kaufman, M. Herbert
textbook, really designed for the geneticist or genetics counsellor. If you want to know how to calculate the recurrence risk of having abnormal offspring from a heterologous Robertsonian translocation carrier, this is the book for you.
Genetic databases The WintereBaraitser Dysmorphology Database is a fantastic searchable resource that has been developed over 25 years. It currently contains information on over 3400 dysmorphic, multiple congenital anomaly and mental retardation syndromes, and includes single-gene disorders, sporadic conditions and those caused by environmental agents. Although the database mainly contains information about non-chromosomal multiple congenital anomaly syndromes, it also includes information about distinctive microdeletion syndromes and those resulting from uniparental disomy. It contains over 35 000 fully searchable references, linked to the appropriate syndromes, and a Photo Library of over 12 500 photographs that show the main dysmorphic features of the syndrome and other relevant images, such as skeletal radiographs. There are two components to the database e dysmorphology and neurogenetics e both of which are available on a single CD-ROM. The CD-ROM contains 400 MB of .jpg images that can (space permitting) be downloaded to the user’s computer. The database can be searched by syndrome, such as achondroplasia (Fig. 1). Double-clicking a syndrome name produces a ‘syndrome description’ window (Fig. 2) giving the location of the gene in the genome (in this case 4p16), a reference code
Figure 1
for the syndrome in OMIM (McKusick reference 100800), the gene(s) involved (FGFR3), synonyms and mode of inheritance (autosomal dominant). A detailed Abstract of the syndrome (Fig. 2), as well as Features, References and Photos (Fig. 3), can be browsed. The most useful aspect of the database is ‘Search Syndromes on Features’, in which up to nine characteristics can be searched as being mandatory, or otherwise, to the condition. Other similar databases exist, such as POSSUM12 and SynDiag (Syndrome Diagnosis).13
Websites Online resources divide into (1) searchable databases, of which OMIM7,8 is probably the best known, and (2) websites containing reviews of genetic and rare conditions, the latter often having links to research tools and clinical laboratories. Two useful gateways to the wealth of websites that are available on the Internet are the Genomics and Disease Prevention (http://www.cdc.gov/genomics/info/ database.htm) and the Clinical Genetics Computer Resources (http://www.kumc.edu/gec/prof/ genecomp.html) websites. These provide links to all the websites reviewed in this article and many others. However, many of these sites are mostly relevant to geneticists and researchers, although they are worth a browse, especially for the budding clinical geneticist. OMIM (accessible via http://www.ncbi.nlm.nih. gov/) is a continuously updated catalogue of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and a team of science writers
A list of syndromes searchable in the WintereBaraitser Dysmorphology Database.
Genetic resources for the neonatologist
Figure 2
The WintereBaraitser Dysmorphology Database ‘syndrome description’ window.
at Johns Hopkins University, Maryland, USA. OMIM focuses primarily on inherited, or heritable, genetic diseases. It is also considered to be a phenotypic companion to the Human Genome Project. Entries include a general description of each syndrome,
Figure 3 Database.
295
a phenotypic description, clinical features, biochemistry, mode of inheritance, diagnosis, management and a review of research publications, with numerous links to Medline articles (also accessible via http://www.ncbi.nlm.nih.gov/). OMIM
Photographs are included for most syndrome descriptions in the WintereBaraitser Dysmorphology
296
Figure 4
L. Kaufman, M. Herbert
Online Mendelian Inheritance in Man via the National Center for Biotechnology Information website.
is searchable by inputting any list of features (Fig. 4). Any combination of features can be entered, without the need for separators. The search result is a link to one or more inherited syndromes (Fig. 5). For example, entering the features ‘high-pitched cry’, ‘microcephaly’ and ‘micrognathia’ produces a link to cri-du-chat syndrome. Clicking on the link (i.e. a single click on #123450) then produces a review of the syndrome, including a general description, clinical features, the genetics of the condition and references with links to Pubmed (Fig. 6). Another attribute of OMIM is the ‘search gene map’ feature, which allows the browser to match a phenotype with a breakpoint of a translocation or identify the features that arise from a microdeletion. A second website useful for expert authored reviews is GeneClinics (http://www.geneclinics. org/) (Fig. 7). The GENEReviews cover single-gene disorders only and were created to aid healthcare professionals in applying new advances in genetic testing to the diagnosis, management and
Figure 5
counselling of patients and families with inherited disorders. A review does not exist for every condition on the site, but where they do exist they are generally very informative. Other websites that are also valuable include: The European Directory of DNA Diagnostic Laboratories (http://www.eddnal.com/) providing links to the laboratories in Europe that test for rare disorders, and the tests that are available. There are also links to other sites, such as GeneClinics. The Online Searchable Directory of Genetic Resources from the Genetic Alliance (http:// www.geneticalliance.org/diseaseinfo/search. html). This provides descriptions of over 150 disorders, and has links to other relevant websites for each disorder as well as American support groups. The database of Chromosomal Variation in Man (http://www.wiley.com/legacy/products/subject/ life/borgaonkar/access.html). It consists of key references of all common and rare chromosomal
Entering features into Online Mendelian Inheritance in Man.
Genetic resources for the neonatologist
Figure 6
297
A typical extract from Online Mendelian Inheritance in Man.
alterations, phenotypes and abnormalities in humans. The database is organized by chromosome variations and anomalies, numerical anomalies and chromosomal breakage syndromes, and users should be able to locate the literature on any given condition or topic. It contains over 24 000 entries that have been continuously updated since 1974. The database is intended for use primarily by cytogeneticists.
Figure 7
ORPHANET (http://www.orpha.net/) is a database dedicated to information on rare diseases and orphan drugs. The Dysmorphic Syndrome Features website (http://www.hgmp.mrc.ac.uk/DHMHD/view_ human.html), from the UK Human Genome Mapping Project Resource Centre, provides a concise list of features for hundreds of syndromes.
The GeneClinics website.
298 The Cambridge Genetics Knowledge Park (http://www.cgkp.org.uk/biglinks.html) provides links to other Genetics Knowledge Parks in England and Wales, Clinical Genetics in the UK, and Ethics sites, among others.
References 1. Jones KL. Smith’s recognizable patterns of human malformation. Philadelphia: WB Saunders; 1997. 2. Firth HV, Hurst JA, Hall JG. Clinical genetics: an essential guide. New York: Oxford University Press; 2004. 3. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the head and neck. New York: Oxford University Press; 2001. 4. Spranger JW, Brill PW, Poznanski A. Bone dysplasias. Oxford University Press; 2002. 5. Cassidy SB, Allanson JE. Management of genetic syndromes. New York: Wiley-Liss; 2001.
L. Kaufman, M. Herbert 6. Schinzel A. Catalogue of unbalanced chromosome aberrations in man. Berlin: Walter de Gruyter; 2001. 7. Hamosh A, Scott AF, Amberger J, Valle D, McKusick VA. Online Mendelian inheritance in man (OMIM). Hum Mutat 2000;15:57e61. 8. Hamosh A, Scott AF, Amberger J, Bocchini C, Valle D, McKusick VA. Online Mendelian inheritance in man (OMIM), a knowledgebase of human genes and genetic disorders. Nucleic Acids Res 2002;30:52e5. 9. Winter RM, Baraitser M. WintereBaraitser database. London: London Medical Databases; 2004. 10. McKusick VA. Mendelian inheritance in man. Baltimore: Johns Hopkins University Press; 1998. 11. Gardner RJM, Sutherland GR. Chromosome abnormalities and genetic counseling. Oxford: Oxford University Press; 2004. 12. Bankier A, Marquet J. POSSUM. Melbourne: Murdock Institute and Royal Children’s Hospital Research Institute; Launched 1987. 13. Ilyina H, Kolosov S. SynDiag. Minsk, Belarus: Belorussian Institute for Hereditary Diseases; 2004.
www.elsevierhealth.com/journals/siny
Genetic resources for the neonatologist Louise Kaufman a,*, Mark Herbert b a
Department of Clinical Genetics, Churchill Hospital, Headington, Oxford OX3 7JL, UK Neonatal Unit, Department of Paediatrics, Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK b
KEYWORDS Books; Databases; Websites; Genetic resources
Summary Diagnosing genetic disorders and counselling the parents of babies with possible genetic conditions takes up a significant proportion of a neonatologist’s clinical time. This article provides a guide to establishing genetic tools and a reference library on a neonatal unit. The availability of good resources may heighten staff awareness of genetic aetiologies in babies with subtle features, and enable possible diagnoses to be considered and a genetics consultation sought. In addition, when a diagnosis is made, information is then readily available to guide the neonatologist in his or her consultations with parents. It is not intended that the tools outlined here should be a replacement for the genetics consultation; their role is merely to facilitate the interaction of neonatologists with geneticists, to the benefit of the parents and the baby. Ó 2005 Published by Elsevier Ltd.
Introduction The three main genetics resources are textbooks, databases and websites (Table 1); examples of each are summarised in this article. Textbooks usually have a chapter structure or an index that allows the book to be used to help make a diagnosis; these include Smith’s Recognizable Patterns of Human Malformation1 and Clinical Genetics: An Essential Guide.2 Several textbooks * Corresponding author. Neonatal Unit, Department of Paediatrics, Women’s Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. E-mail address: [email protected] (L. Kaufman). 1744-165X/$ - see front matter Ó 2005 Published by Elsevier Ltd. doi:10.1016/j.siny.2005.02.002
give more detailed information, useful for when a diagnosis has been made, such as Syndromes of the Head and Neck,3Bone Dysplasias,4,5Management of Genetic Syndromes5 and the Catalogue of Unbalanced Chromosome Aberrations in Man.6 Perhaps the best resources for making preliminary diagnoses are, however, web-based and CDROM genetic databases, such as Online Mendelian Inheritance in Man (OMIM)7,8 and the Wintere Baraitser Dysmorphology Database.9 These databases are specifically designed for searching syndromes on the basis of the phenotype. They are limited by users’ experience in the hierarchical classification of the signs and their ability to recognize features and describe them with genetic
292
Table 1
Genetic resources
Resources Books
Databases
Websites
Smith’s Recognizable Patterns of Human Malformation Clinical Genetics: An Essential Guide Syndromes of the Head and Neck Bone Dysplasias Management of genetic syndromes
References
Notes
1
Useful overview of Mendelian inherited and chromosomal disorders
2 3 4 5
A handbook of clinical genetics One of the most useful books in clinical genetics An excellent reference with illustrations for bone disorders A trove of valuable clinical information on 30 of the most common genetic syndromes The definitive textbook for syndromes arising from chromosomal anomalies
Catalogue of Unbalanced Chromosome Aberrations in Man
6
WintereBaraitser Dysmorphology Database
9
POSSUM SynDiag (Syndrome Diagnosis)
12 13
Online Mendelian Inheritance in Man Genomics and Disease Prevention Clinical Genetics Computer Resources GeneClinics and GENEReviews European Directory of DNA Diagnostic Laboratories Online Searchable Directory of Genetic Resources from the Genetic Alliance Database of Chromosomal Variation in Man ORPHANET Cambridge Genetics Knowledge Park
www.ncbi.nlm.nih.gov/ www.cdc.gov/genomics/info/database.htm www.kumc.edu/gec/prof/genecomp.html www.geneclinics.org/ www.eddnal.com/ www.geneticalliance.org
An excellent resource containing information on over 3400 syndromes and over 12 500 photographs
L. Kaufman, M. Herbert
www.wiley.com/legacy/products/subject/life/borgaonkar/access.html http://www.orpha.net/ http://www.cgkp.org.uk/biglinks.html
Genetic resources for the neonatologist terminology (e.g. ‘telecanthus’). Although helpful to the practising neonatologist for making preliminary diagnoses, gaining the confidence to seek a genetics consultation or gaining some idea of a condition prior to the arrival of a geneticist, these databases yield better results in the hands of the experienced. The web-based databases tend not to show pictures of syndromes, whereas the CD-ROM databases have the advantage that they do. Most of the genetic books, websites and databases listed here deal with Mendelian inherited disorders (autosomal recessive, dominant and Xlinked conditions) and do not comprehensively cover chromosomal aberrations (triploidies, aneuploidies, rearrangements, translocations and deletions). Thus, for example, an OMIM search using the typical features of Down, Edward or Patau syndrome will not identify these conditions. One of the best resources for understanding chromosomal aberrations is the Catalogue of Unbalanced Chromosome Aberrations in Man.6 It is a superb reference once a diagnosis has been made, or even suspected, but is not easy to use to help make a diagnosis when a syndrome is not immediately recognized by Gestalt processes. Hence the value of a cytogenetic chromosomal study on any patient with a suspected genetic disorder, especially if the features do not suggest a Mendelian inherited condition.
Genetic reference books Smith’s Recognizable Patterns of Human Malformation1 is a compact textbook organized so that it is searchable on features. Making a diagnosis solely with this book can, however, be laborious, and the databases are perhaps better for this role. Once a diagnosis has been made, ‘Smith’s’ covers most of the common genetic conditions, a double-page spread being given over to each syndrome, with a brief synopsis and images. For many conditions, this book provides some information for a neonatologist to discuss the condition in an informed manner with parents, as an addition to a genetics consultation, but it contains limited information on the genetic basis of the disorder. Clinical Genetics: An Essential Guide2 is one of the Oxford Handbook series pocket texts and promises to be an estimable book, perhaps to be carried in every neonatologist’s pocket. Gorlin et al.’s Syndromes of the Head and Neck3 is one of the most useful books in clinical genetics, rivalled perhaps only by OMIM. As most genetic syndromes have head or neck involvement, this book covers many of the syndromes one is likely to encounter on a neonatal unit. The chapters are
293 divided by aetiology and by major features; there are, for example, chapters on syndromes with contractures, and on short stature syndromes, as well as on osteogenesis imperfecta and chondrodysplasias. It is a definitive textbook aimed at the clinical geneticist but a wonderful book to have on a neonatal unit, especially for finding out more detail on a condition when a diagnosis has been made and for subsequently following up the child. Bone Dysplasias4 is also organized by features, such as lethal syndromes, syndromes with predominant metaphyseal, epiphyseal or diaphyseal involvement, and dysostosis multiplex. The book contains numerous photographs and radiographs, and is a fascinating source of information for the neonatologist once a diagnosis has been made. Because of its layout, it is also very helpful for considering likely diagnoses in advance of a genetics opinion. Management of Genetic Syndromes5 is a trove of valuable clinical information on 30 of the most common genetic syndromes. The chapters are arranged alphabetically, starting with achondroplasia, Angelman syndrome, BeckwitheWiedemann syndrome, CHARGE association, Cornelia de Lange syndrome, Down syndrome, etc. It is directed at the clinician who is not a geneticist, with an emphasis on clinical evaluation and management. Each chapter deals with a different condition and covers incidence, diagnostic criteria, aetiology and pathogenesis, diagnostic testing, differential diagnosis and the nature, evaluation and treatment of major disease manifestations. Many genetic disorders seen on a neonatal unit are caused by chromosome deletions or duplications rather than point mutations, and these are comprehensively covered in the Catalogue of Unbalanced Chromosome Aberrations in Man6. Don’t be put off by the title: the book is well organized. Each of the main chapters covers disorders of one chromosome, and each is divided into sections covering monosomy of that chromosome, deletions, ring chromosomes, duplications, trisomies and uniparental disomy. It is an outstanding textbook for gaining knowledge after a diagnosis has been made. Victor McKusick’s book Mendelian Inheritance in Man10 is a textbook version of OMIM and contains over 9000 entries. It is designed for those with knowledge of genetics and will be found on the shelves of many geneticists. The usefulness of this textbook on a neonatal unit is, however, limited, especially with the availability of OMIM, which is continuously updated. Mendelian Inheritance in Man was last updated in 1998. Chromosome Abnormalities and Genetic Counseling11 is a small but extremely detailed
294
L. Kaufman, M. Herbert
textbook, really designed for the geneticist or genetics counsellor. If you want to know how to calculate the recurrence risk of having abnormal offspring from a heterologous Robertsonian translocation carrier, this is the book for you.
Genetic databases The WintereBaraitser Dysmorphology Database is a fantastic searchable resource that has been developed over 25 years. It currently contains information on over 3400 dysmorphic, multiple congenital anomaly and mental retardation syndromes, and includes single-gene disorders, sporadic conditions and those caused by environmental agents. Although the database mainly contains information about non-chromosomal multiple congenital anomaly syndromes, it also includes information about distinctive microdeletion syndromes and those resulting from uniparental disomy. It contains over 35 000 fully searchable references, linked to the appropriate syndromes, and a Photo Library of over 12 500 photographs that show the main dysmorphic features of the syndrome and other relevant images, such as skeletal radiographs. There are two components to the database e dysmorphology and neurogenetics e both of which are available on a single CD-ROM. The CD-ROM contains 400 MB of .jpg images that can (space permitting) be downloaded to the user’s computer. The database can be searched by syndrome, such as achondroplasia (Fig. 1). Double-clicking a syndrome name produces a ‘syndrome description’ window (Fig. 2) giving the location of the gene in the genome (in this case 4p16), a reference code
Figure 1
for the syndrome in OMIM (McKusick reference 100800), the gene(s) involved (FGFR3), synonyms and mode of inheritance (autosomal dominant). A detailed Abstract of the syndrome (Fig. 2), as well as Features, References and Photos (Fig. 3), can be browsed. The most useful aspect of the database is ‘Search Syndromes on Features’, in which up to nine characteristics can be searched as being mandatory, or otherwise, to the condition. Other similar databases exist, such as POSSUM12 and SynDiag (Syndrome Diagnosis).13
Websites Online resources divide into (1) searchable databases, of which OMIM7,8 is probably the best known, and (2) websites containing reviews of genetic and rare conditions, the latter often having links to research tools and clinical laboratories. Two useful gateways to the wealth of websites that are available on the Internet are the Genomics and Disease Prevention (http://www.cdc.gov/genomics/info/ database.htm) and the Clinical Genetics Computer Resources (http://www.kumc.edu/gec/prof/ genecomp.html) websites. These provide links to all the websites reviewed in this article and many others. However, many of these sites are mostly relevant to geneticists and researchers, although they are worth a browse, especially for the budding clinical geneticist. OMIM (accessible via http://www.ncbi.nlm.nih. gov/) is a continuously updated catalogue of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and a team of science writers
A list of syndromes searchable in the WintereBaraitser Dysmorphology Database.
Genetic resources for the neonatologist
Figure 2
The WintereBaraitser Dysmorphology Database ‘syndrome description’ window.
at Johns Hopkins University, Maryland, USA. OMIM focuses primarily on inherited, or heritable, genetic diseases. It is also considered to be a phenotypic companion to the Human Genome Project. Entries include a general description of each syndrome,
Figure 3 Database.
295
a phenotypic description, clinical features, biochemistry, mode of inheritance, diagnosis, management and a review of research publications, with numerous links to Medline articles (also accessible via http://www.ncbi.nlm.nih.gov/). OMIM
Photographs are included for most syndrome descriptions in the WintereBaraitser Dysmorphology
296
Figure 4
L. Kaufman, M. Herbert
Online Mendelian Inheritance in Man via the National Center for Biotechnology Information website.
is searchable by inputting any list of features (Fig. 4). Any combination of features can be entered, without the need for separators. The search result is a link to one or more inherited syndromes (Fig. 5). For example, entering the features ‘high-pitched cry’, ‘microcephaly’ and ‘micrognathia’ produces a link to cri-du-chat syndrome. Clicking on the link (i.e. a single click on #123450) then produces a review of the syndrome, including a general description, clinical features, the genetics of the condition and references with links to Pubmed (Fig. 6). Another attribute of OMIM is the ‘search gene map’ feature, which allows the browser to match a phenotype with a breakpoint of a translocation or identify the features that arise from a microdeletion. A second website useful for expert authored reviews is GeneClinics (http://www.geneclinics. org/) (Fig. 7). The GENEReviews cover single-gene disorders only and were created to aid healthcare professionals in applying new advances in genetic testing to the diagnosis, management and
Figure 5
counselling of patients and families with inherited disorders. A review does not exist for every condition on the site, but where they do exist they are generally very informative. Other websites that are also valuable include: The European Directory of DNA Diagnostic Laboratories (http://www.eddnal.com/) providing links to the laboratories in Europe that test for rare disorders, and the tests that are available. There are also links to other sites, such as GeneClinics. The Online Searchable Directory of Genetic Resources from the Genetic Alliance (http:// www.geneticalliance.org/diseaseinfo/search. html). This provides descriptions of over 150 disorders, and has links to other relevant websites for each disorder as well as American support groups. The database of Chromosomal Variation in Man (http://www.wiley.com/legacy/products/subject/ life/borgaonkar/access.html). It consists of key references of all common and rare chromosomal
Entering features into Online Mendelian Inheritance in Man.
Genetic resources for the neonatologist
Figure 6
297
A typical extract from Online Mendelian Inheritance in Man.
alterations, phenotypes and abnormalities in humans. The database is organized by chromosome variations and anomalies, numerical anomalies and chromosomal breakage syndromes, and users should be able to locate the literature on any given condition or topic. It contains over 24 000 entries that have been continuously updated since 1974. The database is intended for use primarily by cytogeneticists.
Figure 7
ORPHANET (http://www.orpha.net/) is a database dedicated to information on rare diseases and orphan drugs. The Dysmorphic Syndrome Features website (http://www.hgmp.mrc.ac.uk/DHMHD/view_ human.html), from the UK Human Genome Mapping Project Resource Centre, provides a concise list of features for hundreds of syndromes.
The GeneClinics website.
298 The Cambridge Genetics Knowledge Park (http://www.cgkp.org.uk/biglinks.html) provides links to other Genetics Knowledge Parks in England and Wales, Clinical Genetics in the UK, and Ethics sites, among others.
References 1. Jones KL. Smith’s recognizable patterns of human malformation. Philadelphia: WB Saunders; 1997. 2. Firth HV, Hurst JA, Hall JG. Clinical genetics: an essential guide. New York: Oxford University Press; 2004. 3. Gorlin RJ, Cohen MM, Hennekam RCM. Syndromes of the head and neck. New York: Oxford University Press; 2001. 4. Spranger JW, Brill PW, Poznanski A. Bone dysplasias. Oxford University Press; 2002. 5. Cassidy SB, Allanson JE. Management of genetic syndromes. New York: Wiley-Liss; 2001.
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