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Dysmorphology
Dysmorpholog y 597 adjacent genes, perhaps by inducing inappropriate expression. Overall the pattern of inheritance is dominant and therefore the molecular pathways would appear to require gain-of-function properties although it is possible that dosage effects may contribute to the phenotype.
Conclusions Dynamic mutation involves a novel molecular mechanism with can account for the non-Mendelian phenomena, such as anticipation, exhibited by certain human genetic diseases. Dynamic mutation also represents the mechanism whereby one class of fragile site is generated from loci which normally exhibit copy number polymorphism of repeat sequences. The molecular pathway from genotype to phenotype is largely dependent upon the location of the expanded repeat with respect to any gene that it effects and can therefore result in either recessive, X-linked, or dominant inheritance characteristics.
Further Reading
Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW and Ranum LPW (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genetics 21: 379±384. Richards RI and Sutherland GR (1992) Dynamic mutations: A new class of mutations causing human disease. Cell 70: 709±712. Richards RI and Sutherland GR (1996) Repeat offenders: simple repeat sequences and complex genetic problems. Human Mutation 8: 1±7. Richards RI and Sutherland GR (1997) Dynamic mutation: possible mechanism and significance in human disease. Trends in Biochemical Sciences 22: 432±436. Sutherland GR and Richards RI (1995) Molecular basis of fragile sites in human chromosomes. Current Opinion in Genetics and Development 5: 323±327. Sutherland GR, Baker E and Richards RI (1998) Fragile sites still breaking. Trends in Genetics 14: 501±506. Warrick JM, Paulson HL, Gray-Board GL et al. (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93: 939±949.
References
Richards RI and Sutherland GR (1994) Simple repeat DNA is not replicated simply. Nature Genetics 6: 114±116. Weber JL (1990) Informativeness of human (dC-dA)n (dG-dT)n polymorphisms. Genomics 7: 524±530.
See also: Non-Mendelian Inheritance
Dysmorphology D Donnai Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0390
Dysmorphology is the medical and scientific discipline concerned with the study of birth defects and syndromes, and with diagnosis, investigation, and counseling of affected individuals and their families. Dysmorphologists have training in pediatrics and clinical genetics and work closely with their colleagues in diagnostic and research laboratories.
Making a Diagnosis When a baby is born with birth defects the parents have many questions: What is the problem?; What does it mean for our baby?; Why did it happen?; Will it happen again? In order to answer these questions properly and to manage and treat the baby appropriately a precise diagnosis is needed.
Approach to Diagnosis
A systematic approach to diagnosis includes: . History ± family, past obstetric and pregnancy history . Examination ± behavior, size and proportions, specific anomalies . Measurements . Investigations ± may include chromosomal or DNA analysis, metabolic studies, X-rays or scans . Photographs ± for record purposes. Once examination and investigations are complete a diagnostic synthesis can be made. Sometimes a clear diagnosis is suspected on clinical examination and then confirmed by investigations, e.g., by recognizing the poor tone and facial features of Down syndrome and then confirming the diagnosis by finding trisomy 21 on chromosomal analysis. In other situations there may not be a confirmatory laboratory test so diagnosis rests on clinical examination alone. As well as obvious structural malformations a child may have a subtle characteristic facial appearance or `gestalt' which can be recognized by those with appropriate aptitude and experience. Various computerized systems exist to help in syndrome identification and to provide rapid access to relevant literature.
Delineation of Newly Recognized Syndromes
There are over 1000 described dysmorphic syndromes and many more if syndromes due to small
598
Dystrophin
chromosomal duplications and deletions are included. However many children do not fit into previously reported syndromes and new patterns are being recognized all the time. Dysmorphologists have regular meetings where undiagnosed patients are discussed and new entities delineated. Dissemination of new findings is through scientific publications or meetings and increasingly through electronic networks.
Utility of a Diagnosis Establishing a precise diagnosis is important for the family, for clinical, social, and educational management, and for research. Once a diagnosis has been established the underlying cause of the problem (where known) can be discussed with the family and information given about prognosis and risks of recurrence including options for prenatal diagnosis. For many conditions there are family support groups. The provision of social and educational care for the special needs of a child with a syndrome is helped by knowledge of the precise condition a child has. A precise diagnosis aids early clinical management and anticipatory care. For example some syndromes may be associated with visual or hearing deficits which, if identified early, can be treated. Some malformation syndromes are lethal and early diagnosis may lead to a decision to encourage the parents and family to maximize their time with the child rather than surgical correction of structural malformations which will not affect the eventual outcome. For many conditions the underlying mechanism is not fully understood and research is continuing. The dysmorphologist, by making precise diagnoses and ensuring a group to be investigated is as homogeneous as possible, maximizes the chance for successful
research. Clinical observations may inform the research direction. See also: Clinical Genetics; Ethics and Genetics; Genetic Counseling
Dystrophin R L Somerville Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0391
Dystrophin is a flexible, rod-shaped protein of 3685 amino acid residues found predominantly in muscle tissue, in association with the inner surface of the plasma membrane. There are different isoforms of dystrophin located in brain cells, Schwann cells, and glial cells. In muscle,theprobablefunctionofdystrophinistoanchor specific membrane glycoproteins to the inner surface of the cell membrane. The dystrophin gene, situated at Xp21, is large (2400 kb) and complex (78 exons, multiple promoters), requiring about 16 h to be transcribed. Mutational alterations (usually deletions) in the dystrophin gene lead to the sex-linked diseases Becker and Duchenne muscular dystrophies. Muscle degeneration exceeds the rate of regeneration, and the life span of affected individuals rarely exceeds 20 years.
Further Reading
Kunkel LM, Monaco AP, Middlesworth W, Ochs HD and Lott SA (1985) Proceedings of the National Academy of Sciences, USA 82: 4778±4782.
See also: Duchenne Muscular Dystrophy (or Meryon's Disease); Muscular Dystrophies
Conclusions Dynamic mutation involves a novel molecular mechanism with can account for the non-Mendelian phenomena, such as anticipation, exhibited by certain human genetic diseases. Dynamic mutation also represents the mechanism whereby one class of fragile site is generated from loci which normally exhibit copy number polymorphism of repeat sequences. The molecular pathway from genotype to phenotype is largely dependent upon the location of the expanded repeat with respect to any gene that it effects and can therefore result in either recessive, X-linked, or dominant inheritance characteristics.
Further Reading
Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW and Ranum LPW (1999) An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genetics 21: 379±384. Richards RI and Sutherland GR (1992) Dynamic mutations: A new class of mutations causing human disease. Cell 70: 709±712. Richards RI and Sutherland GR (1996) Repeat offenders: simple repeat sequences and complex genetic problems. Human Mutation 8: 1±7. Richards RI and Sutherland GR (1997) Dynamic mutation: possible mechanism and significance in human disease. Trends in Biochemical Sciences 22: 432±436. Sutherland GR and Richards RI (1995) Molecular basis of fragile sites in human chromosomes. Current Opinion in Genetics and Development 5: 323±327. Sutherland GR, Baker E and Richards RI (1998) Fragile sites still breaking. Trends in Genetics 14: 501±506. Warrick JM, Paulson HL, Gray-Board GL et al. (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93: 939±949.
References
Richards RI and Sutherland GR (1994) Simple repeat DNA is not replicated simply. Nature Genetics 6: 114±116. Weber JL (1990) Informativeness of human (dC-dA)n (dG-dT)n polymorphisms. Genomics 7: 524±530.
See also: Non-Mendelian Inheritance
Dysmorphology D Donnai Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0390
Dysmorphology is the medical and scientific discipline concerned with the study of birth defects and syndromes, and with diagnosis, investigation, and counseling of affected individuals and their families. Dysmorphologists have training in pediatrics and clinical genetics and work closely with their colleagues in diagnostic and research laboratories.
Making a Diagnosis When a baby is born with birth defects the parents have many questions: What is the problem?; What does it mean for our baby?; Why did it happen?; Will it happen again? In order to answer these questions properly and to manage and treat the baby appropriately a precise diagnosis is needed.
Approach to Diagnosis
A systematic approach to diagnosis includes: . History ± family, past obstetric and pregnancy history . Examination ± behavior, size and proportions, specific anomalies . Measurements . Investigations ± may include chromosomal or DNA analysis, metabolic studies, X-rays or scans . Photographs ± for record purposes. Once examination and investigations are complete a diagnostic synthesis can be made. Sometimes a clear diagnosis is suspected on clinical examination and then confirmed by investigations, e.g., by recognizing the poor tone and facial features of Down syndrome and then confirming the diagnosis by finding trisomy 21 on chromosomal analysis. In other situations there may not be a confirmatory laboratory test so diagnosis rests on clinical examination alone. As well as obvious structural malformations a child may have a subtle characteristic facial appearance or `gestalt' which can be recognized by those with appropriate aptitude and experience. Various computerized systems exist to help in syndrome identification and to provide rapid access to relevant literature.
Delineation of Newly Recognized Syndromes
There are over 1000 described dysmorphic syndromes and many more if syndromes due to small
598
Dystrophin
chromosomal duplications and deletions are included. However many children do not fit into previously reported syndromes and new patterns are being recognized all the time. Dysmorphologists have regular meetings where undiagnosed patients are discussed and new entities delineated. Dissemination of new findings is through scientific publications or meetings and increasingly through electronic networks.
Utility of a Diagnosis Establishing a precise diagnosis is important for the family, for clinical, social, and educational management, and for research. Once a diagnosis has been established the underlying cause of the problem (where known) can be discussed with the family and information given about prognosis and risks of recurrence including options for prenatal diagnosis. For many conditions there are family support groups. The provision of social and educational care for the special needs of a child with a syndrome is helped by knowledge of the precise condition a child has. A precise diagnosis aids early clinical management and anticipatory care. For example some syndromes may be associated with visual or hearing deficits which, if identified early, can be treated. Some malformation syndromes are lethal and early diagnosis may lead to a decision to encourage the parents and family to maximize their time with the child rather than surgical correction of structural malformations which will not affect the eventual outcome. For many conditions the underlying mechanism is not fully understood and research is continuing. The dysmorphologist, by making precise diagnoses and ensuring a group to be investigated is as homogeneous as possible, maximizes the chance for successful
research. Clinical observations may inform the research direction. See also: Clinical Genetics; Ethics and Genetics; Genetic Counseling
Dystrophin R L Somerville Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0391
Dystrophin is a flexible, rod-shaped protein of 3685 amino acid residues found predominantly in muscle tissue, in association with the inner surface of the plasma membrane. There are different isoforms of dystrophin located in brain cells, Schwann cells, and glial cells. In muscle,theprobablefunctionofdystrophinistoanchor specific membrane glycoproteins to the inner surface of the cell membrane. The dystrophin gene, situated at Xp21, is large (2400 kb) and complex (78 exons, multiple promoters), requiring about 16 h to be transcribed. Mutational alterations (usually deletions) in the dystrophin gene lead to the sex-linked diseases Becker and Duchenne muscular dystrophies. Muscle degeneration exceeds the rate of regeneration, and the life span of affected individuals rarely exceeds 20 years.
Further Reading
Kunkel LM, Monaco AP, Middlesworth W, Ochs HD and Lott SA (1985) Proceedings of the National Academy of Sciences, USA 82: 4778±4782.
See also: Duchenne Muscular Dystrophy (or Meryon's Disease); Muscular Dystrophies