Severe phenotypes in two Tunisian families with novel XPA mutations: evidence for a correlation between mutation location and disease severity

Abstract

Xeroderma pigmentosum (XP) is a rare disorder characterized by a high skin sun-sensitivity predisposing to skin cancers at an early age. Among Tunisian XP patients with an intermediate skin phenotype, 92% presented neurological abnormalities related to XPA gene deficiency. Clinical variability of the XP-A phenotype is associated with a mutational heterogeneity. In the present study, two Tunisian families with severe dermatological and neurological XP phenotypes were investigated in order to determine clinical characteristics and genetic basis. Two Tunisian families with four XP affected children were examined in the Dermatology Department. Clinical features showed severe presentation of the disease. Coding regions of the XPA gene were analysed by direct sequencing. Results showed the presence of a novel mutation, p.E111X, in three patients belonging to the same family and presenting a very severe phenotype i.e. development of skin lesions and neurological signs before 1 year age. For the other patient, we identified a nonsense mutation, p.R207X, already identified in a Palestinian XP-A patient. Identification of novel causing mutations in Tunisian XP-A patients shows the genetic and mutational heterogeneity of the disease in Tunisia. Despite a relatively homogenous mutational spectrum, mutational heterogeneity for rare cases is observed because of the high rate of consanguinity.

The Experience of a Tunisian Referral Centre in Prenatal Diagnosis of <b><i>Xeroderma pigmentosum</i></b>

“…In family XPA90, the mother was pregnant at the time we conducted the genetic inquiry. In this case, the rapid molecular analysis allowed not only the identification of a novel mutation in the XPA gene, p.E111X [6], but also obtaining the PND result on time.…”

“…Screening for mutations was performed by direct sequencing as previously described [3,4,6] and maternal-foetal contamination was checked by genotyping using the Identifiler Kit (Applied Biosystems). Genotyping for 16 polymorphic microsatellite markers (15 autosomal and 1 located on the X chromosome) were determined for the mother, the father and the foetus.…”

“…Nevertheless, the emergence of private mutations has also been noted [5,6]. Identifying the genetic basis of XP provided the crucial information for DNA-based PND.…”

Specific Aspects of Consanguinity: Some Examples from the Tunisian Population

“…The same situation is encountered for the founder mutation p.R228X, encountered in more than 80% of XP group A patients. Most XP group A cases additionally are concentrated in the same geographical area of Central Tunisia [24,25] . The third example is illustrated by the p.W1327X mutation responsible for glycogenosis type III that is frequently observed in the homozygous state and mainly occurs in a coastal region of Central Tunisia [26,27] .…”

“…Allelic heterogeneity within the same families has been observed for several diseases including ataxia telangiectasia, Stargardt disease [unpubl. data] and XP group A [30] . For the latter, a previously undescribed clinical presentation was observed due to the combination of a founder mutation and a new mutation that had arisen in one of the family branches [31] .…”