Subtle chromosomal rearrangements in children with unexplained mental retardation

BACKGROUND No explanation for moderate to severe mental retardation is apparent in about 40% of cases. Although small chromosomal rearrangements may account for some undiagnosed cases, a lack of genome-wide screening methods has made it impossible to ascertain the frequency of such abnormalities. METHODS A fluorescence in-situ hybridisation (FISH) test was used to examine the integrity of chromosome ends in 284 children with unexplained moderate to severe retardation, and in 182 children with unexplained mild retardation. 75 normal men were also tested. When a chromosomal rearrangement was found, its size was estimated, and members of the child's family were investigated. FINDINGS Subtle chromosomal abnormalities occurred with a frequency of 7.4% in the children with moderate to severe mental retardation, and of 0.5% in the children with mild retardation. The abnormalities had an estimated population prevalence of 2.1 per 10,000, and were familial in almost half of cases. INTERPRETATION Once recognisable syndromes have been excluded, abnormalities that include the ends of chromosomes are the commonest cause of mental retardation in children with undiagnosed moderate to severe mental retardation. Owing to the high prevalence of familial cases, screening for subtle chromosomal rearrangements is warranted in children with unexplained moderate to severe mental retardation.

[1]  I. Temple,et al.  Distal 6p deletion syndrome: a report of a case with anterior chamber eye anomaly and review of published reports. , 1998, Journal of medical genetics.

[2]  A. Salisbury.  The National Foundation ‐ March of Dimes , 1974, Progress in clinical and biological research.

[3]  K. Davies,et al.  DNA testing for fragile X syndrome in schools for learning difficulties. , 1995, Archives of disease in childhood.

[4]  D. Ledbetter,et al.  A complete set of human telomeric probes and their clinical application , 1996, Nature Genetics.

[5]  M. Selikowitz,et al.  Chromosome testing in children with developmental delay in whom the aetiology is not evident clinically , 1993, Journal of paediatrics and child health.

[6]  P. Jacobs,et al.  Population studies of the fragile X: a molecular approach. , 1993, Journal of medical genetics.

[7]  S. Broman,et al.  Retardation in Young Children: A Developmental Study of Cognitive Deficit , 1987 .

[8]  A cytogenetic survey of an institution for the mentally retarded: I. Chromosome abnormalities , 1978 .

[9]  J. Flint,et al.  The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation , 1995, Nature Genetics.

[10]  N. Dennis,et al.  Aetiology of mild mental retardation. , 1988, Archives of disease in childhood.

[11]  A. Emery.  Human Genetic Diseases. A Practical Approach , 1987 .

[12]  S. Einfeld.  Clinical assessment of 4500 developmentally delayed individuals. , 2008, Journal of mental deficiency research.

[13]  J. Fryns,et al.  Sex chromatin and cytogenetic survey of 10417 adult males and 357 children institutionalized in Belgian institutions for mentally retarded patients , 1975, Human Genetics.

[14]  H. Nusbaum,et al.  Characterization of short tandem repeats from thirty-one human telomeres. , 1997, Genome research.

[15]  J. Elwood,et al.  Severe mental handicap in Northern Ireland. , 2008, Journal of mental deficiency research.

[16]  M. Taussig.  The Nervous System , 1991 .

[17]  K. Davies,et al.  Human genetic diseases : a practical approach , 1986 .

[18]  R. Regan,et al.  Development and Clinical Application of an Innovative Fluorescence in situ Hybridization Technique Which Detects Submicroscopic Rearrangements Involving Telomeres , 1997, European journal of human genetics : EJHG.

[19]  H. Birch,et al.  Book Reviews , 2006 .

[20]  Cécile Fizames,et al.  A comprehensive genetic map of the human genome based on 5,264 microsatellites , 1996, Nature.

[21]  S. Bundey,et al.  The recurrence risks for mild idiopathic mental retardation. , 1989, Journal of medical genetics.

[22]  J. Flint,et al.  Molecular-cytogenetic detection of a deletion of 1p36.3. , 1997, Journal of medical genetics.

[23]  M. Kohonen-Corish,et al.  Molecular characterization of patients with 18q23 deletions. , 1997, American journal of human genetics.

[24]  J. Morton,et al.  Fragile X syndrome is less common than previously estimated. , 1997, Journal of medical genetics.

[25]  J. Opitz,et al.  An etiological survey of the severely retarded Hertfordshire children who were born between January 1, 1965 and December 31, 1967. , 1977, American journal of medical genetics.

[26]  G. Hagberg,et al.  Severe Mental Retardation in a Swedish County – II. Etiologic and Pathogenetic Aspects of Children Born 1959–1970 , 1977, Neuropadiatrie.

[27]  D. Ledbetter,et al.  Molecular confirmation of Wolf-Hirschhorn syndrome with a subtle translocation of chromosome 4. , 1991, American journal of human genetics.

[28]  J. Dumanski,et al.  Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. , 1994, American journal of human genetics.

[29]  M. Rutter,et al.  Education, Health and Behaviour , 1970 .

[30]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[31]  V. P. Johnson,et al.  Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs. , 1997, American journal of medical genetics.

[32]  J. Opitz,et al.  Diagnostic/genetic studies in severe mental retardation. , 1978, Birth defects original article series.

[33]  J. Lamb,et al.  DETECTION OF BREAKPOINTS IN SUBMICROSCOPIC CHROMOSOMAL TRANSLOCATION, ILLUSTRATING AN IMPORTANT MECHANISM FOR GENETIC DISEASE , 1989, The Lancet.

[34]  H. Sambrook.  Molecular cloning : a laboratory manual. Cold Spring Harbor, NY , 1989 .

[35]  A. D. McDonald,et al.  Severely retarded children in Quebec: prevalence, causes, and care. , 1973, American journal of mental deficiency.

[36]  J. Burn,et al.  A submicroscopic translocation, t(4;10), responsible for recurrent Wolf-Hirschhorn syndrome identified by allele loss and fluorescent in situ hybridisation. , 1992, Journal of medical genetics.