[Show abstract][Hide abstract] ABSTRACT: The aim of this work was to study the genotype distribution of Sicilian patients with biallelic GJB2 mutations; to correlate genotype classes and/or specific mutations of GJB2 gene (35delG-non-35delG) with audiologic profiles. A total of 10 different mutations and 11 different genotypes were evidenced in 73 SNHL subjects; 35delG (90.36 % of cases) and IVS1+1 (13.69 %) were the most common mutations found in the cohort with a significant difference in the distribution between North and South Sicily. Audiological evaluation revealed a severe (16/73) to profound (47/73) hearing loss (HL) in 86.13 % of cases without significant difference between the degree of HL and the province of origin of the subjects (P = 0.727). The homozygous truncating (T/T) genotype was the most widespread (89.04 % of cases), with a severe-to-profound hearing impairment in 90.36 % of T/T class with respect to truncating/non-truncating (T/NT) and non-truncating/non-truncating (NT/NT) genotypes (P = 0.012). From the comparison of homozygous 35delG and 35delG/non-35delG genotypes, a more profound HL in the homozygous 35delG than in compound heterozygous 35delG/non-35delG (p < 0.0001) resulted. This study confirms that 35delG is the most common mutation in the Mediterranean area with a heterogeneous distribution of the genotypes between North and South Sicily; probands homozygotes for 35delG or presenting a T/T genotype are more apt to have a severe-to-profound HL.
Archives of Oto-Rhino-Laryngology 03/2014; 272(8). DOI:10.1007/s00405-014-2970-1 · 1.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The main purpose of this study was to describe a novel missense mutation (p.D179H) found in a Western Sicily family and to examine the genetic and audiologic profiles of all family members by performing a GJB2 and GJB6 mutations analysis and a complete audiologic assessment. The proband was a 3-month-old infant with a congenital profound sensorineural hearing loss; direct sequencing of the GJB2 revealed the presence of a c.35delG mutation in the heterozygous state and a heterozygous G>C transition at nucleotide 535 in trans; this novel mutation, called p.D179H, resulted in an aspartic acid to histidine change at codon 179. It was also evidenced in the heterozygous state in two members of this family, both with normal hearing. No GJB6 mutations were evidenced in all subjects studied. Considering the genotypic and phenotypic analysis of all family members, we suggest, differently from the p.D179 N mutation previously reported, a recessive mode of inheritance. Functional studies on p.D179H have to be performed to confirm our hypothesis.
Archives of Oto-Rhino-Laryngology 06/2013; 271(6). DOI:10.1007/s00405-013-2613-y · 1.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several mutations in CYP21 locus cause 21-hydroxylase deficiency (21-OHD). The most common mutations are widespread among different geographic areas and their frequencies have been also reported to differ among certain populations.
To obtain a large view on the frequencies of the most common mutations in the CYP21 locus, in Sicily, in the Mediterranean and other major geographic areas worldwide.
Three hundred and eight unrelated CYP21A2 alleles leading 21-OHD in Sicily were genetically typed and compared with other series previously reported in Sicily and in surrounding regions. An analysis of the frequencies of the different geographic areas was also carried out. CYP21A2 typing was carried out using PCR-restriction fragment length polymorphism (RFLP), for the detection of the CYP21A2 deletion, while sequencing analysis was performed to evaluate all the missense/non-sense mutations.
Our study revealed that p.V281L (44.4%), I2splice (21.6%) and p.P30L (11.2%) were very frequent alleles, del8bp (0.4%) was found very rarely in Sicily and a novel mutation leading to non-classical phenotype, p.L198F, was also discovered in this population. Allele frequencies were found to be significantly different from previously observed frequencies in Sicily. In addition, here we present the most significant frequency modifications among different geographic areas worldwide.
As the distribution of the disease CYP21A2 alleles is heterogeneous around the world, the knowledge of the relative distributions allows a better management of 21-OHD for fetuses and newborns in different geographic areas.
[Show abstract][Hide abstract] ABSTRACT: The complex problem of the relationship between genetic mutations and congenital cardiac malforma- tions, especially regarding the etiopathogenesis, has inspired several recent studies in order to understand about the causes and the mechanisms of these disorders.
In these studies, MTHFR gene (C677T), which encodes for the methylenetetrahydrofolate reductase enzy- me, seems to be mainly involved. Methylenetetrahydrofolate reductase enzyme deficiency, due to homo- zygosity in MTHFR gene (677TT), impairs the metabolic cycle of the folic acid, which is essential to the development of the embryo and health of the fetus. Furthermore, MTHFR C677TT mutation can also re- sult in hyperhomocysteinemia. Elevated levels of homocysteine have been associated with placental disea- se, preeclampsia and recurrent pregnancy loss. The true association with the complex congenital heart di- seases is still unknown. Mutations correlated with this disorder are rare and the uncommon events are dif- ficult to investigate. On this topic, the Sicilian population represents a privileged observatory. Indeed, in our region, MTHFR 677TT is prevalent in 20% of the population and that might be optimally suited to as- sociation research studies on possible causative effects of this genetic factor. In our study, we enrolled 300 women from January 2005 to June 2010 with high risks of fetal loss due to complex congenital heart di- seases and pregnancy complications. On this cohort, we have investigated on the relationship between MTHFR 677TT polymorphism/mutation and the cardiac malformations. As result, MTHFR 677TT has been found pre- sent in 90% of the patient suggesting that despite the high prevalence in Sicily this genetic condition might be invol- ved in the pathological mechanisms leading cardiac defects during the embryogenesis.
[Show abstract][Hide abstract] ABSTRACT: When normal development and growth of the calvarial sutures is disrupted, craniosynostosis (premature calvarial suture fusion) may result. Classical craniosynostosis syndromes are autosomal dominant traits and include Apert, Pfeiffer, Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In these conditions, there is premature fusion of skull bones leading to an abnormal head shape, ocular hypertelorism with proptosis, and midface hypoplasia. It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3 cause craniosynostosis. We report on a child with a clinically diagnosed Pfeiffer syndrome that shows the missense point mutation Q289P in exon 8 of the FGFR2 gene. This is a mutation not previously described in the Pfeiffer syndrome but reported in the Crouzon, Jackson-Weiss, and Saethre-Chotzen syndromes. In this paper, we propose the concept that these disorders may represent one genetic condition with phenotypic variability.
European Journal of Pediatrics 03/2009; 168(9):1135-9. DOI:10.1007/s00431-008-0884-x · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinically apparent jaundice is unusual in patients with beta-thalassemia major. Co-inheritance of Gilbert syndrome has been reported to cause hyperbilirubinemia in these subjects. Crigler-Najjar syndrome is another rare disorder of bilirubin metabolism caused by mutation in the gene coding the enzyme UGT1A1. We report a patient of beta-thalassemia major who presented with persistent jaundice due to co-inherited Crigler-Najjar syndrome type 2 secondary to a novel mutation in UGT1A1 gene [homozygous base substitution at position 362 (GGT>AGT) in exon 3].
[Show abstract][Hide abstract] ABSTRACT: Point mutations and deletions of SRY gene have been described in several cases of XY gonadal dysgenesis. To date, most of these mutations affect the HMG domain of SRY which plays a central role in DNA binding activity of SRY. We report on a non-mosaic XY sex-reversed newborn girl (completely female external genitalia). The direct sequencing of SRY showed a new nonsense mutation in a codon of SRY gene flanking the 3' end of the HMG domain: a thymine is replaced by a guanine at position +387 in codon 129, resulting in the replacement of the amino acid tyrosine (TAT) by a stop codon (TAG). The new mutation of this patient provides further evidence to support the functional importance of the putative DNA binding activity of the HMG-box domain.
American Journal of Medical Genetics Part A 08/2004; 128A(1):46-7. DOI:10.1002/ajmg.a.30075 · 2.16 Impact Factor