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Molecular characterisation of a proximal chromosome 18q deletion

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Editor—Deletion of the proximal end of 18q is uncommon. It has been associated with mild facial dysmorphism, hypotonia, ataxia, seizures, mental retardation, and behavioural abnormalities. Phenotypic variability has been noted. We describe a 4 year old boy with del(18)(q11.2q12.2), defined by G banding, comparative genomic hybridisation (CGH), and molecular genetic analysis. The typical facial dysmorphism was absent, but he did manifest hyperactivity, distractibility, and moderate mental retardation. This patient falls into the milder end of the spectrum of phenotypes associated with proximal 18q deletions. His case emphasises the value of performing cytogenetic analysis in children with mild global developmental delay and behavioural problems without dysmorphism. This report represents the first molecular characterisation of chromosomal breakpoints in a proximal 18q deletion case.

Proximal 18q deletion is uncommon, but is associated with a recognisable phenotype and pattern of behaviour.1-8Dysmorphic features include prominent forehead, short nose, midfacial recession, deep set eyes, and high arched palate. There is also an association with ataxia and a risk of seizures. Moderate to severe mental retardation in association with hyperactivity, distractibility, and aggressive behaviour is commonly described. A number of authors have suggested that proximal deletion of 18q represents a distinct clinical entity, although there is some degree of phenotypic variability in previously reported proximal chromosome 18q deletion cases.1 2 4 The phenotypic variability could be the result of subtle differences in the chromosomal breakpoints. The proximal chromosome 18q region at a 550 band resolution contains two identical dark G bands, q12.1 and q12.3, making precise delineation of the deleted region difficult. Authors must often define the deleted region as either q12.1 or q12.3.

We present here the clinical details of a de novo del(18)(q11.2q12.2) case to define further the range of variability in phenotypes for deletion of the proximal end of chromosome 18q, as well as to provide more precise definition of chromosomal breakpoints.

A 4 year old boy was referred for evaluation of global developmental delay and behavioural problems. He is the second child of healthy unrelated parents and there is no significant family history. Birth was at term by normal delivery. There was a transient neonatal stridor. Recurrent otitis media and upper respiratory infections necessitated bilateral grommet insertion, tonsillectomy, and adenoidectomy. Five febrile convulsions occurred between 2 and 3 years of age.

There was significant axial hypotonia during the first year. Developmental milestones were delayed in all areas. The patient did not sit up unsupported until 10 months and walked at 2 years. Physical examination at 3 years showed clumsiness without any neurological signs. EEG was normal. A single palmar crease was noted on the right hand and an extra transverse crease was noted on the left hand. No facial dysmorphism was noted. Language development was delayed and he did not speak phrases until the age of 3 years. There were behavioural difficulties including poor concentration and hyperactivity. Distractibility and learning difficulties were noted in pre-school. Formal cognitive assessment using the Stanford-Binet Intelligence Scale (4th edition) showed a full scale IQ of 61 across four areas of verbal reasoning, abstract/visual reasoning, quantitative reasoning, and short term memory. This may have been an underestimate of his true potential because of limited cooperation. At 5 years he attends a special school.

G band cytogenetic evaluation showed an apparent deletion of the proximal end of the q arm of chromosome 18, karyotype 46,XY,del(18)(q11.2q12.2) (fig 1A). The deletion occurred de novo since no abnormality involving chromosome 18 was detected in either parent. Comparative genomic hybridisation (CGH) analysis was performed by previously described methods9 in order to confirm the position of the breakpoints defined by G banding. The CGH results were evaluated with Applied Imaging equipment and software. As shown in fig1B, the green to red fluorescence ratio falls below 0.75 in the region q11.2, and for a portion of the q12 region. CGH analysis indicated that none of band q21 was deleted, consistent with the G band cytogenetic analysis.

Figure 1

(A) G banded chromosomes 18 from the proband. The normal chromosome 18 is on the left and the deleted chromosome 18 on the right. Chromosomes are at the 550 band resolution. (B) CGH profile of chromosome 18 showing decrease in green to red fluorescence ratio (FR) over the region q11.2 to q12. The FR value over the q21 region was ∼1.0 (not deleted). The ideogram used for CGH analysis is at the 400 band resolution. The CGH analysis provides molecular cytogenetic confirmation of the G band analysis.

Fluorescent genotyping analysis of microsatellite markers of the proband and both parents using a Pharmacia ALF DNA sequencer was informative for seven proximal chromosome 18 loci (table 1). A maternally derived deletion was detected at four loci, D18S36, D18S34, D18S67, and D18S535. This places the deletion breakpoints distal to the position of 52.86 cM and proximal to 66.66 cM on the sex averaged linkage map described by Broman et al.10 The proximal breakpoint would map somewhere between D18S66 at 52.86 cM and D18S36 at 58.45 cM. The map position of 52.86 cM is close to the centromere since the locus D18S480, at linkage position 51.21 cM, is on the p arm. The molecular genetic analysis is therefore consistent with a more proximal breakpoint in band q11.2 and provides an initial set of reference loci for more precise mapping of deletion breakpoints in other cases.

Table 1

Results of genotyping analysis at seven informative chromosome 18 loci

This case represents the only case out of the 13 previously described cases1-8 of proximal 8q deletion to have breakpoints defined at the molecular level. The majority of previously described cases of proximal 18q deletion were de novo in origin, as in the present case. Four affected subjects were identified in two generations of one family resulting from an insertional translocation.3 Some of the more consistent phenotypic abnormalities in previously described cases included moderate to severe mental retardation, prominent forehead with a short nose and midfacial recession, deep set eyes, high arched palate, ear anomalies, a tendency to obesity, ataxia, and a risk of seizure. Hyperactivity, aggressive behaviour, and distractibility were common.

Our patient falls into the milder end of the spectrum of phenotypes resulting from proximal 18q deletion. He did not have the typical dysmorphic facial features, but his hyperactive behaviour, distractibility, and mild to moderate mental retardation are consistent with descriptions of previous cases. Our result leads us to suggest that the typical facial dysmorphism associated with other proximal 18q deletion cases may be more associated with loss of band q12.3, which was not deleted in our case. Furthermore, the behavioural phenotype associated with proximal 18q deletion may be more a consequence of loss of the more proximal bands q11.2 and/or q12.1. Only more precise identification of deletion breakpoints in additional cases of proximal 18q deletion will allow us to determine if this hypothesis is correct.

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