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To: ADC Fetal and Neonatal Edition Letters and ADC Education and Practice Letters

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Leading articles: John P Osborne, Jane Merrifield, and Finbar J.K. O'Callaghan Tuberous sclerosis: what's new? Arch Dis Child 2008; 0: adc.2006.094938v2 [Abstract]

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Tuberous sclerosis: what's new...the role of gene testing

Maya Chopra, John Lawson, Meredith Wilson and David Mowat   (2 July 2008)

Tuberous sclerosis: what's new...the role of gene testing 2 July 2008
Maya Chopra, Fellow in Clinical Genetics Sydney Children's Hospital, John Lawson, Meredith Wilson and David Mowat Send letter to journal: Re: Tuberous sclerosis: what's new...the role of gene testing maya.chopra{at}sesiahs.health.nsw.gov.au Maya Chopra, et al.	Dear Editor, In regard to “Tuberous sclerosis: what’s new?” 1, we agree with the authors’ assertion that gene testing has limited diagnostic value (sensitivity of 75%2). Diagnosis of tuberous sclerosis (TSC) is based on established clinical and radiological criteria3. In our experience, TSC gene testing has an important adjunct role. Currently, parents of an index case are assessed for signs of TSC, including skin, renal and brain evaluation. TSC mutation testing the parents is a cost-effective and practical alternative, provided the mutation is known in the index case. The disadvantage is that parental somatic mosaicism may not be detected. In one series, five parents of 62 individuals with apparently sporadic TSC were proven to have somatic mosaicism; all five had cutaneous manifestations4. Therefore, Wood’s lamp examination combined with mutation testing may effectively rule out clinically relevant somatic mosaicism. In our experience, many couples with one affected child who are at low risk of recurrence (2-3%) are more willing to have further children if prenatal testing is available. Our practice is to undertake genetic testing in the index case if the parents are of reproductive age. Affected adults with a known mutation have had the option of prenatal testing for many years. More recently, pre-implantation genetic diagnosis (PGD) has become available for some couples. As for evaluation of siblings, we would argue that most parents want to know if their other children are affected, even if the health benefits have not been rigorously proven. Healthy siblings of children with TSC ought to have a clinical assessment including a Wood’s lamp examination. Mutation testing (if known) may be useful if there are equivocal clinical features. Screening for a previously identified mutation is inexpensive and somatic mosaicism is not an issue. Healthy siblings approaching adulthood may utilise mutation testing to restore reproductive confidence. Genetic testing is becoming cheaper and more widely available and may be usefully incorporated into the clinical management of patients with TSC and their families. References 1 Osborne JP, Merrifield, Callaghan F. Tuberous slcerosis: what’s new? Arch Dis Child.2008: published online 2 Au KS, Williams AT, Roach ES. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med 2007;9: 88-100 3 Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998; 13:624-628 4 Verhoef S, Bakker L, Tempealaars AM et al. High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genent. 1999; 1632-1637