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The aim of this study was to describe the changing pattern of mutational spectrum of -thalassemia (-thal) in the Lazio region (Central Italy), as consequence of recent demographic variations. From 1994 until present, 256 immigrant subjects with hemoglobin disorders (including 191 heterozygotes and 65 homozygotes or compound heterozygotes) coming from 44 different foreign countries, have been molecularly characterized. 14 -globin gene mutations were identified and their frequencies reflect different ethnic origins: 8 of these mutations account for 76.97% of all molecular defects, while 6 of them are much rare, representing less than 2% of the total. These data differ, both in type and percentage, from the mutational spectrum detected in the native population in 1995. Since a few defects are prevalent in each country, a proper strategy for the identification of mutations in immigrant individuals relies on the prior knowledge of their frequency in native ethnic group.

The authors describe the case of a family in which two siblings affected by cleft palate and cheiloschisis were diagnosed as suffering from van der Woude's syndrome (VWS). The diagnosis was largely determined by the finding of mucous cysts (lip-pits) on the lower lip of the two patients and their mother. Classification as VWS enabled genetic counseling as to the risk of recurrence to be modified from multifactorial to autosomal dominant. The authors also consider aspects of differential diagnosis among van der Woude syndrome, pterygo -popliteal syndrome and labio or palatoschisis syndrome with filiform fusion of the eyelids.

From 1975 to 1979 the Rome Microcythaemia Centre carried out four health education campaigns and thalassaemia screenings among students of the intermediate schools throughout Latium, under the auspices and with the financial support of the Health Authorities of the Latium region. This project is aimed at avoiding reproduction by pairs of thalassaemia carriers and the birth of homozygous children. During the four campaigns 138 501 students were examined, that is, 70 to 76% of those enrolled. Of these 3343 were found to be thalassaemic. Thus the overall prevalence of thalassaemia in Latium is 2.41%, with minor fluctuations from one province to another and, above all, a slight, though definite, trend towards higher values in the southern part of Latium bordering on Campania. The screening was welcomed by the population and the thalassaemic families, there were no detectable negative side-effects, and it resulted in an increased awareness of the problem of the thalassaemias.

Since 1975 the Rome Microcythaemia Centre has carried out every year, under the auspices of the health authorities of the Latium region, a screening of thalassaemics among intermediate schoolchildren of Latium. From these campaigns, knowledge about thalassaemias among the young adult population has grown which, in its turn, has resulted in screening of these young adults. Through screening in schools between 1975 and 1982, of 289 763 students examined, 6838 thalassaemics were identified, 6045 of whom were beta- or delta beta-thalassaemics. The total number of young thalassaemics who are identified at present in the Centre through screenings of schoolchildren and young adults is about 3300 per year. Furthermore, from January 1980 to April 1983, 110 prospective couples of child-bearing age at risk (94 of whom originated from Latium) were identified at the Centre, and five homozygous fetuses (three of which originated from Latium) were diagnosed. These data derive from an area in which the frequency of thalassaemia is only 2.4%, and they show that the programme in Latium for the prevention of Mediterranean anaemia has been successful.

Because the spectrum of anorectal malformations is wide, genetic investigations of these anomalies should include the study of multigenic models presenting variable penetrance and expressivity. Current knowledge in clinical genetics, cytogenetics, and molecular genetics of anorectal anomalies are reviewed. The analysis of associated anomalies (that are found in more than 60% of anorectal malformations) is an important aspect of the molecular study, because the association of anomalies with mendelian transmission or with a recognized causative gene can be an essential starting point for further investigations. In the present study, the authors focus on associated sacral anomalies, urethral malformations, and intestinal dysganglionoses. In particular, associated sacral anomalies could be a partial expression of the Currarino syndrome, which represents the only association for which genetic evidence has been demonstrated by linkage analysis. The authors studied a four-generation pedigree with recurrence of the Currarino syndrome, and the haplotype reconstruction confirmed that the gene segregating in this family is located in the 7q36 region. The collection and study of families with multiple cases of anorectal malformations could show whether different phenotypes are caused by single genes.

SummaryWe have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.

TLX2 (also known as HOX11L1, Ncx and Enx) is a transcription factor playing a crucial role in the development of the enteric nervous system, as confirmed by mice models exhibiting intestinal hyperganglionosis and pseudo-obstruction. However, congenital defects of TLX2 have been excluded as a major cause of intestinal motility disorders in patients affected with intestinal neuronal dysplasia (IND) or pseudo-obstruction. After demonstrating the direct regulation of TLX2 expression by the homeoprotein PHOX2B, in the present work, we have focused on its paralogue PHOX2A. By co-transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation, we have demonstrated that PHOX2A, like PHOX2B, is involved in the cascade leading to TLX2 transactivation and presumably in the intestinal neuronal differentiation. Based on the hypothesis that missed activation of the TLX2 gene induces the development of enteric nervous system defects, PHOX2A and PHOX2B have been regarded as novel candidate genes involved in IND and pseudo-obstruction and consequently analyzed for mutations in a specific set of 26 patients. We have identified one still unreported PHOX2A variant; however, absence of any functional effect on TLX2 transactivation suggests that regulators or effectors other than the PHOX2 genes must act in the same pathway, likely playing a non redundant and direct role in the pathogenesis of such enteric disorders.

The molecular characterization of balanced chromosomal rearrangements has often been a powerful tool for the positional identification of genes associated with specific diseases. In some instances, these rearrangements may be associated with a variety of different phenotypes, and thus establishing a genotype-phenotype correlation may be a complex process. However, molecular characterization of the rearrangement remains a useful tool for diagnoses or prognoses, or for identifying new genes and establishing a gene-to-function relationship. In this work we describe the characterization of a de novo balanced translocation t(2;6)(q24.3;q22.31) found in a patient with a complex phenotype. The major clinical finding was a severe neurological involvement. Thanks to the molecular characterization of this translocation we found that the rearrangement led to the truncation of the TCBA1 gene on chromosome 6q. We found that the gene is transcribed in different splice variants and is highly specific for the central nervous system. TCBA1 does not show any similarity with other known genes, and no information is available about its function. However, the gene appears to be well conserved among species, and we were able to infer the sequence of a putative mouse homolog of TCBA1. This allowed us to perform a more detailed expression study in mice, thus confirming its specificity for the nervous system. This finding is of particular interest because it suggests that TCBA1 may be correlated with the neurological phenotype of our patient, and possibly mutated in genetic diseases with a neurological phenotype. Hum Mutat 26(5), 426-436, 2005. (c) 2005 Wiley-Liss, Inc.

Anorectal malformations (ARMs) are common congenital anomalies that account for 1:4 digestive malformations. ARM patients show different degrees of sacral hypodevelopment while the hemisacrum is characteristic of the Currarino syndrome (CS). Cases of CS present an association of ARM, hemisacrum and presacral mass. A gene responsible for CS has recently been mapped in 7q36. Among the genes localized in this critical region, sonic hedgehog (SHH) was thought to represent a candidate gene for CS as well as for ARM with different levels of sacral hypodevelopment according to its role in the differentiation of midline mesoderm. By linkage analysis we confirmed the critical region in one large family with recurrence of CS. In addition. the screening of SHH in 7 CS and in 15 sporadic ARM patients with sacral hypodevelopment allowed us to exclude its role in the pathogenesis of these disorders.