Miller-Dieker syndrome

Small chromosomal rearrangements may be behind idiopathic learning disability

Learning disability affects about 3% of the population, yet the cause remains unknown in about 40% of people with moderate to severe learning disability (IQ [is less than] 50) and in 70% of people with mild developmental delay (IQ 50-75).[1] It is estimated that between 30% and 50% of cases of undiagnosed learning disability may be genetic in origin.[2] Mapping and sequencing the human genome have provided new ways of looking for chromosomal abnormalities. The standard investigation for learning disability is to stain chromosomes to reveal their unique banding pattern and then to look for any anomalies using light microscopy. However, the resolution of this routine cytogenetic approach is limited since very small rearrangements are not visible and larger abnormalities escape notice if they occur in regions where the banding pattern is not distinctive. There have been many attempts to increase reliability and resolution, but there is still no practical way to screen the entire human genome for rearrangements, regardless of size or chromosomal location. However, an alternative to whole genome screening, which has transformed our diagnostic capabilities, is to focus on specific chromosomal regions, in particular the chromosome ends, known as telomeres.

Some years ago molecular investigation of the chromosomal disorders implicated in learning disability established that cytogenetically undetectable rearrangements involving telomeres could give rise to Wolf-Hirschhorn syndrome (chromosome 4p), cri du chat syndrome (chromosome 5p), Miller-Dieker syndrome (chromosome 17p), and [Alpha] thalassaemia with learning disability (ATR-16 chromosome 16p).[3-7] However, only recently has the full extent of the involvement of small telomeric rearrangements in learning disability been appreciated. A novel method of molecular screening that looks at every chromosome end was used on over 400 children with idiopathic learning disability and established that 7.4% of those with moderate to severe learning disability had subtle abnormalities of chromosome ends.[8 9] If we take into account all known causes of disability in children with moderate to severe learning disability, then rearrangements of chromosome ends account for a total of 3% and are the second most common cause after Down's syndrome.

Making a diagnosis is important in caring for the child and it is important for the family and society. There is a need for a straightforward, cost effective service for screening for telomeres provided by clinical diagnostic laboratories, and for guidelines on who should be screened. The cost of the Chromoprobe T System (Cytocell Ltd) seems acceptable at 125 [pounds sterling] ($168) for a full telomeric screening test, but the budget of many clinical genetics centres is not enough to cover the potential demand if every child with idiopathic learning disability were to be screened. Although increased demand may encourage companies to lower prices, the burden of cost can also be relieved by better defining who should be investigated for small chromosomal deletions.

In half the cases the disorder is familial--that is, one parent is found to be carrying a balanced chromosomal rearrangement. Thus, although the hit rate for finding a telomeric abnormality is 8% when the test is used for routine screening, subsequent investigation of first and second degree relatives increases the number of diagnoses to about 25% of people tested.[9]

A more cost effective strategy would be to identify a clinical subgroup in which small rearrangements at telomeres occur at a much higher frequency. Unfortunately, however, there are no characteristic clinical features that would help. In a study by Knight et al a combination of facial dysmorphism, minor physical abnormalities of hands or feet, small stature, and microcephaly were present in almost all those found to have chromosomal rearrangement. However, this constellation of features is common to many people with developmental delay.[9] One definite indication for testing is the observation of either a similar, or dissimilar, phenotype in a relative; a normal parent with a balanced translocation between two different chromosomes may pass on different unbalanced chromosomes to his or her affected children, thus creating the possibility of dissimilar features in related individuals. Until further studies are reported and clinical subcategories better defined, we advocate investigating telomeres in all patients with moderate to severe learning disability who have the clinical features described, especially those who have other affected family members.

[1] Flint J, Wilkie AO. The genetics of mental retardation. Br Med Bull 1996; 52:453-64.

[2] Fryns JP, Volcke PH, Haspeslagh M, Beusen L, Van Den Berghe H. A genetic diagnostic survey of an institutionalized population of 262 moderately retarded patients: the Borgerstein experience. J Ment Defic Res 1990;34:29-40.

[3] Lamb J, Wilkie AOM, Harris PC, Buckle VJ, Lindenhaum RH, Barton NJ, et al. Detection of breakpoints in submicroscopic chromosomal translocation, illustrating an important mechanism for genetic disease. Lancet 1989;ii:819-24.

[4] Overhauser J, Bengtsson U, McMahon J, Ulm J, Butler MG, Santiago L, et al. Prenatal-diagnosis and carrier detection of a cryptic translocation by using DNA markers from the short arm of chromosome 5. Am J Hum Genet 1989;45:296-303.

[5] Altherr MR, Bengtsson U, Elder FFB, Ledbetter DH, Wasmuth JJ, McDonald ME, et al. Molecular confirmation of Wolf-Hirschhorn syndrome with a subtle translocation of chromosome 4. Am J Hum Genet 1991;49:1235-42.

[6] Flint J, Wilkie AO, Buckle VJ, Winter, RM, Holland AJ, McDermid HE. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet 1995;9:132-40.

[7] Kuwano A, Ledbetter SA, Dobyns WB, Emanuel BS, Ledbetter DH. Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. Am J Hum Genet 1991;49:707-14.

[8] Knight SJL Horsley SW, Regan R, Lawrie NM, Maher EJ, Cardy DLN, et al. Development and clinical application of an innovative fluorescence in situ hybridization technique which detects submicroscopic rearrangements involving telomeres. Eur J Hum Genet 1997;5:1-8.

[9] Knight SJL, Regan R, Nicod A, Horsley SW, Kearney L, Homfray T, et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 1999;354:1676-81.

Samantha J L Knight Wellcome Trust research fellow

Jonathan Flint consultant psychiatrist

Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS

BMJ 2000;321:1240

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