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A female patient presented with features atypical of Friedreich ataxia(FA). For many years she was considered to have inflammatory demyelination rather than a pure cerebellar syndrome. Presenting in her late 20's, she has no scoliosis and no evidence for peripheral neuropathy or pes cavus. When testing for a series of SCA mutations proved negative, a diagnosis of FA was considered and she tested positive for the GAA expansion mutation within the frataxin gene. No normal sized allele was present and hence she was considered to be homozygous for the expansion and this was reported as being the underlying cause of her clinical symptoms. Surprisingly, later tests showed that her biological daughter, and therefore, an obligate carrier, did not have an expanded allele. Further studies have demonstrated that this apparent non-maternity is explained by the presence of a deletion on one of the mother's alleles and this has been passed to the daughter. This case illustrates that hemizygous deletions within the frataxin gene may be associated with atypical FA. Caution should, therefore, be observed when counselling and testing relatives if the index case in a FA family appears to be homozygous for a GAA expansion mutation. [ABSTRACT FROM AUTHOR]

Currarino syndrome is an autosomal dominant form of sacral agenesis, that is caused by mutation of the homeobox gene, MNX1 (previously HLXB9). The pathology shows variability, with some patients being clinically asymptomatic with partial sacral dysgenesis. This involves the formation of a hemisacrum with preservation of the 1st sacral vertebrae. Severe cases have the hemisacrum together with a presacral mass and anorectal stenosis. Previous studies at the Institute of Human Genetics, University of Newcastle upon Tyne, identified 22 families with likely pathogenic mutations in the MNX1 gene. A variety of nonsense, frameshift, missense, deletion and insertion mutations, spread throughout the three exons of the gene, were described. The aim of this study was to develop a robust molecular diagnostic service for patients with Currarino syndrome. This has involved confirmation of the mutations identified in the research project by sequencing and other mutation specific tests such as primer extension, and the use of known mutation controls to make a comparison between standard SSCP and DHPLC as mutation detection tools. A clinical questionnaire has been designed to help clinicians determine the appropriateness of their referrals and to filter referrals. The results of this study have been used to establish a diagnostic protocol for this syndrome. [ABSTRACT FROM AUTHOR]

We describe a female patient with non-syndromic mental retardation who carries an apparently balanced de novo X;autosome translocation. She has profound intellectual disability and developmental delay. Molecular analysis at the androgen receptor (AR) locus shows that the patient has a 100% skewed X-inactivation pattern in blood. Analysis of the X chromosome translocation breakpoint by FISH shows that the translocation is balanced and that the X chromosome breakpoint lies within the 5'UTR of the Dent's disease gene, CLCN5. No gene appears to be disrupted by the chromosome 3 translocation breakpoint. Complete absence of the CLCN5 transcript in a lymphoblastoid cell line from the patient was found whereas the transcript was present in normal controls. The patient, however, does not as yet show any clinical signs of Dent's disease. This discrepancy between the lymphoblastoid findings and the clinical picture could be explained by the presence of alternative transcription in the kidney from the published internal CLCN5 promoter that lies downstream from the translocation breakpoint or because there is an aberrant Xinactivation pattern in kidney. These investigations are presented. [ABSTRACT FROM AUTHOR]

Purpose: Advances in technology have enabled genetic testing to become part of mainstream clinical practice. However, little data is available on the number of tests that are performed and the cost of testing to the NHS. We performed an audit to examine these issues in our centre. Method: Questionnaire completed by the clinician for 250 consecutive consultations covering all types of genetics clinic. Data on diagnosis, availability of testing and whether testing was discussed and/or arranged was obtained. Results: 100 consultations resulted in a test being performed. From this representative cohort, we estimate that a minimum of 588 tests per million population will be performed per year. Of the 250 families seen the diagnosis had already been confirmed in a family member by a molecular genetic or cytogenetic test in 120 cases. 76% of these tests had been performed in our centre and 11% in other NHS laboratories. A diagnosis was made or suspected in 96 of the remaining cases and a diagnostic test was available in 63 of these (24 available in our centre and 39 elsewhere). Assuming an average cost of 200 per test, an external budget of 46,000 per million population would be required to offer testing to all families and avoid indiscriminate rationing. Conclusion: In over 70% of consultations a molecular or cytogenetic test is now available to confirm the diagnosis and this figure is likely to increase. This has implications for rationing limited resources within departments. [ABSTRACT FROM AUTHOR]

The aetiology of microphthalmia is poorly understood but it is likely that both environmental and genetic mechanisms are involved. Recently interest has focussed on polygenic inheritance as an explanation for variable expressivity of a number of genetic disorders. We present a family with a combination of NF1 and PAX6 mutation where microphthalmia was identified and we suggest that this is due to the two genes acting either additively or synergistically. Case 1 was noted at birth to have a small right eye and a fixed dilated left pupil. Ophthalmological examination revealed significant microphthalmos of the right eye. The left eye was of normal size but had an absent iris sphincter. Her mother had neurofibromatosis 1 (NF1) and her father had Leber's amaurosis. Over the first year of life she developed multiple cafe au lait macules and axilliary freckling. Case 2 is the mother of case 1. Manifestations of NF1 included cafe au lait macules, neurofibromas, spinal tumour, optic glioma and cataracts. Ophthalmological examination of KJs eyes demonstrated bilateral reduction in corneal diameter, iris stromal hypoplasia and foveal hypoplasia. DNA sequencing of the PAX6 gene revealing a cytosine to thiamine transition in exon 5 of the gene causing a missense mutation (R38W). It is clear that both RJ and KJ carry mutations in PAX6 and NF1. Microphthalmia is not commonly associated PAX6 or NF1 mutations and it is hypothesised that the two mutations combine to produce the observed phenotype. [ABSTRACT FROM AUTHOR]