Biomedical subjects
Publications and source records attributed to R Mingarelli.
A male patient with brachycephalosyndactyly syndrome associated with ocular and skin anomalies is reported and it is suggested that this patient has a previously undescribed disorder.
A male patient is reported with a 45,X karyotype and Leri-Weill dyschondrosteosis (LWD). FISH analysis with SHOX and SRY gene probes was carried out. One copy of both SHOX and SRY was detected in interphase nuclei, clarifying the origin of LWD and the male phenotype. Molecular results suggested that the 45,X karyotype arose through two independent events. The first occurred at paternal meiosis leading to an unequal crossing over between the short arms of the X and Y chromosomes. As a consequence, the SRY gene was translocated onto Xp, thereby explaining the male phenotype of the patient. The second event probably occurred at maternal meiosis or at the early stages of the zygote resulting in the loss of the maternal X chromosome.
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Cytogenetic investigations and molecular analysis of the Y chromosome by the polymerase chain reaction amplification of sequence-tagged sites (STS-PCR) technique were performed in 126 patients affected by idiopathic oligo-azoospermia following accurate selection of cases. Seventeen patients evidenced an abnormal karyotype. Fourteen patients with a normal karyotype had microdeletions of the Y chromosome within interval 6. In azoospermic patients microdeletions were scattered along different subintervals, while in oligozoospermic patients they were clustered in subinterval 6E. The size of the deletion was not apparently related to the severity of the disease. These results suggest that cytogenetic analysis and the STS-PCR technique can detect a genetic cause of infertility in about one-quarter of patients with idiopathic oligo-azoospermia.
We report a personal experience of first-trimester prenatal diagnosis of Ellis-van Creveld (EvC) syndrome based on typing of microsatellite markers flanking the EvC locus. An heterozygous fetus was diagnosed with a diagnostic accuracy of 96 per cent. The DNA prediction was confirmed by ultrasound at 22 weeks of gestation and by clinical evaluation at birth.
We report on the father-to-son transmission of a progeroid syndrome characterized by facial anomalies, sparse subcutaneous fat, and hand anomalies including syndactyly, camptodactyly, and finger deviation. Mild mental retardation, microcephaly, and congenital heart defect were found only in the son. To our knowledge, this syndrome has not been described previously.
The present genome era is characterized by speedy progress and prompt transfer of results into clinical practice. This creates the need for rapid disclosure of results and renewal of laboratory's protocols. Molecular cytogenetics has provided and increased ability to identify chromosomes, correlate chromosome structure with gene location, find out cryptic aberrations, and detect specific DNA sequences. These advances have allowed the confident discovery of a number of contiguous gene syndromes. The positional cloning and positional candidate strategies have greatly expedited the search process of disease genes, and become relevant methods for genes' discovery. Understanding the molecular basis of diseases has shown an unpredicted wide genetic heterogeneity, which has splitted single disorders into many clinically similar conditions, and added complexity to the nosology of human diseases. The opposite process, allelism, where clinical diversity results from allelic mutations, has lumped together many distinct disorders, by showing that different clinical entities are not necessarily due to mutations in different genes. Dynamic mutations have provided the molecular understanding of interindividual and intrafamilial variability including anticipation, in a number of diseases. The discovery of distinct correlations between the molecular pattern and disease severity is providing a unique opportunity for using molecular results to assess the clinical outcome. Diagnostic, presymptomatic and predictive molecular testing are becoming widely used and provide enormous opportunities for improving the lot of our patients.
A newborn girl is described with an association of spondylo-acrodysplasia, mild short limbed dwarfism without significant metaphyseal changes, joint dislocations, and severe immune system dysfunction. This association is distinct from other known immuno-osseous dysplasias, including Schimke dysplasia, ADA deficiency with osseous changes, and Omenn phenotype with short limbed dwarfism.
Y chromosome molecular analysis was performed using the STS-PCR technique in 50 patients with oligozoospermia. Microdeletions of interval 6 of the Y chromosome were detected in seven patients, in six of whom subinterval E was affected. All patients retained the RBM1 and DAZ genes, while in one deletion involved the SPGY gene. The size of the deletion was not apparently related to the severity of the disease. These results suggest the presence of an oligozoospermia critical region on the Y chromosome within subinterval E of interval 6.
Two patients are reported who presented with 4q deletion and r(4), respectively. Cytogenetic and FISH analysis defined the breakpoints respectively at bands 4q33-->q35 proximal to the telomere, and 4pter and 4q35.2 qter. Moreover in both cases rearranged chromosomes maintained telomeric sequences. The first patient showed some clinical features of deletion 4q and a pointed 5th finger, a characteristic finding in deletion 4q31-->qter. The second patient had mild dysmorphism associated with growth retardation.
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Autosomal dominant polycystic kidney disease (ADPKD) is a relatively common genetic disorder, and its prenatal diagnosis has been reported with increasing frequency. Nevertheless, no data are available on the significance of prenatal ultrasound (US) patterns in predicting postnatal renal function and outcome. We report on one case of ADPKD diagnosed prenatally by US, and on two cases diagnosed immediately after birth, with different prenatal US and renal outcomes. Data on prenatal US findings and postnatal renal evolution are scanty and largely incomplete. Apparently, none of the prenatal findings are consistently different in cases with and without normal postnatal renal function and blood pressure. More complete information on prenatal US findings and postnatal renal evolution is urgently needed.
To detect in children with tetralogy of Fallot (ToF) the prevalence of associated cardiac anomalies in syndromic and isolated cases, the additional cardiac defects of 150 consecutive patients with ToF (102 isolated and 48 syndromic cases) were evaluated by review of echocardiographic, angiocardiographic, and surgical reports. Syndromic patients were classified into groups with branchial arch defects, Down syndrome, and other genetic conditions. ToF is significantly associated with additional cardiac malformations in patients with branchial arch (11 of 21, p <0.01) and Down (10 of 20, p <0.0001) syndromes. The subarterial ventricular septal defect with deficiency of the infundibular septum (4 of 21, p <0.01) and the right aortic arch (6 of 21, p <0.05) were prevalent in patients with branchial arch syndromes, whereas atrioventricular canal (10 of 20, p <0.0001) was associated with ToF in patients with Down syndrome. Peculiar anatomic cardiac patterns are present in children with ToF and may alert the cardiologist to look at additional cardiac anomalies. Moreover, the presence of some associated cardiac anomalies may suggest careful clinical evaluation for genetic syndromes.
Seven formalin-fixed, paraffin-embedded heart specimens set up at autopsy performed from 3 to 18 years before analysis of newborns in which DiGeorge syndrome (DGS) was suspected were evaluated by fluorescence in situ hybridization (FISH) using a DGS region-specific probe and a control probe on nuclei released from thick sections. The diagnosis was confirmed in four of the six specimens, which provided valuable results, and in none of the controls. This study supports the feasibility and usefulness of FISH genotyping of archival autoptic material, which improves and assists the counselling procedures.
Neurofibromatosis type 1 (NF1) of von Recklinghausen is a common autosomal dominant disorder, characterized by peripheral neurofibromas, café-au-lait spots and Lisch nodules of the iris. The high mutation rate at the NF1 locus results in a wide range of molecular abnormalities. We have scanned 14 different exons from the first part of the NF1 gene using the RNA-single strand conformation polymorphism (RNA-SSCP) method in a series of 40 NF1 patients. Three novel mutations, two nonsense and one missense, and two polymorphisms have been detected in familial cases. Genotype-phenotype correlations have been investigated, but no particular association has been detected. After this screening, the majority of NF1 chromosomes has not yet been characterized, confirming the difficulty in detecting the defect underlying NF1 in most families, even following extensive DNA analysis.
Three patients carrying an isodicentric (idic) Y chromosome associated with a mosaic 45,X cell line were studied using molecular techniques. Genotype-phenotype correlations suggested an effect of the 45,X cell line on sexual differentiation. A relationship was established between instability of the idic(Y) chromosome and localization of the breakpoint on Yq, and between azoospermia and deletion of interval 6 on Yq.