Scope for more genetic testing in learning disability: Case report of  an inherited duplication on the X-chromosome

Summary There have been major advances in the past few yearsin our understanding of the X-linked learning disabilities.The most common of these is the fragile-X syndrome, but thenumber of other gene defects that are now recognised to belinked with learning disability is increasing year on year. We describe one family displaying a family displaying a rareX-linked abnormality. Repeat genetic testing was requestedfor a family member with mild learning disability when, followingchromosomal analysis for her brother, it became known thathe had a genetic defect. The genetic defect 46, Xdup(X) (p22.13p22.31) was identified. To our knowledge this is the first timethis precise configuration has been demonstrated. We concludethat genetic testing for individuals with learning disabilityis worthwhile, even when there may be only a low index of suspicion.

INTRODUCTION

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INTRODUCTION

It is our aim to show that clinicians should have a high indexof suspicion regarding a genetic disorder when meeting someonewith a mild learning disability. It is already common practiceto carry out chromosomal analysis on patients with obviousdysmorphology. It is less common to carry out tests on peoplewith mild learning disabilities and no associated dysmorphological findings. It has been assumed that the intelligence level ofpeople with mild learning disabilities is merely the lowerend of the normal distribution and not associated with pathology(Lehrke, 1997); that this group of individuals was to be foundalmost exclusively among the lower social classes; and thattheir intelligence levels were accounted for by an interplaybetween the multifactorial genetic and environmental influencesthat account for intelligence in general. However, evidenceis now gathering from a number of sources to question this (Thapar et al, 1994). Crucially, much work has been done with regard to the roleof the X-chromosome in intelligence (Turner, 1996; Lehrke, 1997).Its contribution is now regarded as axial. Many different geneticdefects involving the X-chromosome have been described (seebelow), resulting in lowered intelligence. This topic has beenexplored further by Gecz & Mulley (2000) and Partingtonet al (2000). The incidence of chromosomal abnormalities hasconsistently been found to be higher in people with mild learningdisability than the general population. Gostason et al (1991)found chromosomal aberrations in 19.2% of a sample of 57 peoplewith mild learning disability compared with 1.9% of controls.It may be that many cases of mild disability are not owingto a culmination of polygenic inheritance and environment,but rather because of genetic defects of the X-chromosome which can be small and not necessarily associated with other obviousdysmorphology. These can then be passed from generation togeneration. The case study below illustrates some of the issues.

METHOD

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METHOD

Case study
Miss D was born when her mother was 29 years old, followingan unsuspected twin pregnancy. She was the firstborn twin andweighed 5lb 2oz. There were no immediate neonatal problems,but it soon became apparent that Miss D's development was fallingbehind that of her twin sister. She did, however, manage toattend mainstream school until the age of 9 years, when she transferred to a school for children with mild learning disabilities.Her IQ was tested in 1993 using subsets of the Wechsler AdultIntelligence Scale - Revised (WAIS-R; Wechsler, 1981) andverbal IQ of 65, performance IQ of 60 and full-scale IQ of62 were obtained.

Miss D presented to the learning disability service in 1993,following an epileptic seizure. She was a slim, dark-hairedyoung woman with no obvious dysmorphology apart from very slightclinodactyly. She had had epilepsy since childhood, at firstabsence type which later became tonic-clonic in nature. As partof routine assessment in 1993, chromosomal analysis had beencarried out. This was reported as a normal female karyotype46XX. Thus, Miss D was assigned to that large aetiologicalgroup designated `unknown'.

During the course of Miss D's investigations, it emerged thatshe had a brother with a more severe learning disability. Atthe request of one of the authors he attended for assessment.He was of a much more placid disposition than his sister, ofshort stature, had low-set ears, a high-arched palate, short,stubby fingers and, like his sister, clinodactyly. His facialfeatures were slightly coarse. There were no other abnormalfindings, he did not have epilepsy.

It also transpired that Miss D had two maternal cousins whodied at the ages of one year and 18 months respectively. Bothcousins had multiple handicaps and no diagnosis was establishedin either case. Lastly, Miss D had two maternal aunts withmultiple deformities. Again, no diagnosis was established;one died when a few days old, the other was stillborn.

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Fig. 1 Male dup(X)(p22.13p22.31). Extra chromosomal material on the short arm of the X-chromosome is also derived from X. The patient is disomic for this region.

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Fig. 2 Female dup(X)(p22.13p22.31). Extra chromosomal material on the short arm of the X-chromosome is also derived from X. The patient is trisomic for this region.

RESULTS

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RESULTS

Miss D's brother's chromosomes were analysed as part of hisassessment. His karyotype was 46,dup(X)(p22.13-p22.31),Y. Followingthis result it was decided to again examine Miss D's sampleand this time it was found to have the same configuration asbrother, i.e. 46,X,dup(X)(p22.13p22.31). In situ hybridisationstudies using probes specific for the X-chromosome established that the extra genetic material came from the X-chromosome(see data supplement to the online version of this paper).

Wider family studies were then undertaken where it was foundthat their mother had the same duplication on the X-chromosome.She has no learning disability. No other family members werefound to be affected.

DISCUSSION

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DISCUSSION

A brief glance at the literature surrounding the X-chromosomewill confirm the explosion of interest and information aboutits role in learning disability. It has long been known thatthe X-chromosome is important in the genesis of X-linked learningdisability, but the information around precise genetic mechanismsis increasing year on year.

Reports of similar genetic defects
We have been unable to find any reports in the literature ofduplications exactly the same as that of Miss D and her brother,although some similar abnormalities have been found. For example,Cianchetti et al (1992) described two brothers with the duplicateXp22-Xpter.

Martinez et al (1995) report linkage data in a Spanish familywith non-specific X-linked learning disability. They localised the gene to the area Xp22.2-p22.3, interestingly close to theduplicated area in this family. Reichenbach et al (1993) describedmultiple abnormalities in a male child owing to duplicationof the Xp21-Xp22 region. Tuck-Muller et al (1993) describedan inverted duplication of the short arm of the X-chromosomein a mother and daughter. In both these cases of duplication,the area concerned was larger than that implicated in our case. Telvi et al (1996) found a duplication of distal Xp associatedwith not only learning disability but also dysmorphic featuresand genital abnormalities, i.e. 46Y,invdup(X)(p22.11-p22.32).

Muroya et al (1999) cite the example of a boy with an interstitialdeletion at Xp.22.3. Boycott et al (2003) describe also afamilial contiguous gene deletion syndrome of Xp22.3. Kleefstraet al (2002) have localised a gene for non-specific learningdisability to Xp22.3-Xp21.3.

Whereas the above are all interesting in their own right, theoverall picture they create of the X-chromosome is even moreimportant. The above is only a small sample of the defectsreported concerning the distal Xp area. Learning disabilityis a consistent feature of such defects.

Syndromal and non-syndromal phenotypes
It is becoming more evident that the X-chromosome is implicatedin a sizeable proportion of cases of learning disability ofgenetic origin. It is now estimated that X-linked learningdisability has a prevalence of 2.6:1000 population, accountingfor over 10% of all cases of learning disability (Stevenson & Swartz, 2002).The most common of these disorders is fragile-X syndrome, witha prevalence of 1:4000 males and approximately 1:8000 females (Turner, 1996). Many other less prevalent gene defects, suchas that in our own case study, have now been identified. Morethan 150 genes associated with X-linked learning disability have now been identified.

Conventionally, the phenotypes associated with these genotypeshave been split into two groups: syndromal and non-syndromal.The syndromal types are characterised by external features,neurological signs and/or metabolic anomalies. The non-syndromaltypes do not show such specific features; here the X-linkedmode of inheritance is the only indicator (Tariverdian & Vogel, 2000).

However, recent findings have caused this distinction to becomeblurred, as mutations in some genes have been found in bothsyndromic and non-syndromic learning disability. Our case studyadds to the blurring of the groups. Whereas Miss D's brother'sphenotype undoubtedly falls within the syndromic group, hissister's only other physical manifestation, apart from her learning disability, was a very mild clinodactyly and epilepsy.

Clinical relevance
These findings are of great significance to both Miss D andher family. Should Miss D wish to have a family of her ownthen this result will enable a genetic counsellor to give hermore accurate advice. It has to be realised, however, thata degree of uncertainty about the severity of the disability associated with the phenotype must exist, since Miss D's mother,herself and her brother all have the same genotype but varygreatly in their degrees of expression.

There are a number of ethical factors to be considered. MissD and her mother consented to blood tests after counselling.Miss D's brother does not have the capacity to understand theissues involved. Moreover, other family relatives who werenot involved in the original decision may also have the particulargenetic defect and will now be faced with difficult decisions.

On a wider scale, the case adds to the momentum for even furtherresearch into the causes of learning disability. When the defectshave been fully elucidated at the gene level, it may be possibleto have gene therapy treatment which may be available in themedium to long term. This no doubt will bring its own ethical considerations.

REFERENCES

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