Exome Analysis Reveals Novel Missense and Deletion Variants in the CC2D2A Gene as Causative of Joubert Syndrome.

The CC2D2A gene is essential for primary cilia formation, and its disruption has been associated with Joubert Syndrome-9 (JBTS9), a ciliopathy with typical neurodevelopmental features. Here, we describe an Italian pediatric patient with typical features of Joubert Syndrome (JBTS): "Molar Tooth Sign", global developmental delay, nystagmus, mild hypotonia, and oculomotor apraxia. Whole exome sequencing and segregation analysis identified in our infant patient a novel heterozygous germline missense variant c.3626C > T; p.(Pro1209Leu) inherited from the father and a novel 7.16 kb deletion inherited from the mother. To the best of our knowledge, this is the first report showing a novel missense and deletion variant involving exon 30 of the CC2D2A gene.

IL12RB2 Polymorphisms correlate with risk of lung adenocarcinoma.

In a previous study, lack of IL-12 signaling in il12rb2 knock-out mice was found to predispose to lung adenocarcinoma (LAC). We asked whether specific polymorphisms of the human IL12RB2 gene may confer susceptibility to LAC. We studied IL12RB2 single nucleotide polymorphisms (SNPs) spanning from the promoter to the first untranslated exon of the gene. Genotypes of 49 individuals with LAC were compared with those of 93 healthy subjects. Two allele variants were found to be associated with increased susceptibility to LAC. One haplotype (hap), hap18, was more frequent in patients (18%) versus controls (6%) and significantly associated with increased probability of disease occurrence. Furthermore, IL-12 driven STAT4 phosphorylation in T cell blasts from healthy individuals was found to correlate with both single allele variants and haplotypes. In conclusion, genetically determined low signaling activity of IL-12R predisposes to the development of LAC.

Periostin gene variants are associated with disease course and severity in juvenile idiopathic arthritis.

OBJECTIVES: This study aimed to identify polymorphic variants of the Periostin gene associated with disease severity and clinical course in children with juvenile idiopathic arthritis. METHODS: DNA genotyping of 7 single-nucleotide polymorphisms within the periostin gene was performed in 117 patients and their parents and in 102 control samples. Our patients were divided in the following 4 disease categories: 1) persistent oligoarthritis; 2) extended oligoarthritis; 3) polyarthritis; 4) systemic arthritis. Quantitative association analysis was performed in order to test for association between the 7 genetic variants and 18 selected clinical traits. RESULTS: A harmful association was observed between the minor allele of rs17197936 and 2 clinical traits, count of joints with active arthritis and count of joints with pain on motion/tenderness, in patients with extended oligoarthritis. Furthermore, the haplotype represented by the minor allele variants of rs3829364, rs6750 and rs9547951 showed an unfavourable association with the above 2 traits plus the following 3 in the whole patient group: juvenile arthritis damage index articular score, childhood health assessment questionnaire score and disease duration. CONCLUSIONS: These associations suggest that the variants involved can be regarded as genetic factors influencing some phenotypic aspects of juvenile idiopathic arthritis. Genotyping of this gene may represent a useful tool to identify patients who are at greatest risk of experiencing a poorer long-term outcome.

A polymorphism in the 5' UTR of the DEFB1 gene is associated with the lung phenotype in F508del homozygous Italian cystic fibrosis patients.

BACKGROUND: The identification of cystic fibrosis (CF) patients who are at greater risk of lung damage could be clinically valuable. Thus, we attempted to replicate previous findings and verify the possible association between three single nucleotide polymorphisms (SNPs c.-52G>A, c.-44C>G and c.-20G>A) in the 5' untranslated region (5' UTR) of the ß defensin 1 (DEFB1) gene and the CF pulmonary phenotype. METHODS: Genomic DNA from 92 Italian CF patients enrolled in different regional CF centres was extracted from peripheral blood and genotyped for DEFB1 SNPs using TaqMan(®) allele specific probes. In order to avoid genetic confounding causes that can account for CF phenotype variability, all patients were homozygous for the F508del CFTR mutation, and were then classified on the basis of clinical and functional data as mild lung phenotype (Mp, n=50) or severe lung phenotype patients (Sp, n=42). RESULTS: For the c.-20G>A SNP, the frequency of the A allele, as well as the AA genotype, were significantly more frequent in Mp than in Sp patients, and thus this was associated with a protective effect against severe pulmonary disease (OR=0.48 and 0.28, respectively). The effect of the c.-20G>A A allele is consistent with a recessive model, and the protective effect against Sp is exerted only when it is present in homozygosis. For the other two SNPs, no differences were observed as allelic and genotypic frequency in the two subgroups of CF patients. CONCLUSIONS: Our results, although necessary to be confirmed in larger and multiethnic populations, reinforce DEFB1 as a candidate modifier gene of the CF pulmonary phenotype.

Sex chromosome rearrangements leading to partial aneuploidies and mosaicisms: use of QF-PCR for detection and quantification of the involved cell lines.

Chromosome rearrangements can lead to aneuploidies of specific chromosome regions and could be present in the entire individual or limited to some tissues (mosaicism) depending on the developmental stage of the embryo when the rearrangement occurs. We report 6 cases with sex chromosome rearrangements identified by conventional cytogenetics and tested by quantitative fluorescent polymerase chain reaction (QF-PCR). QF-PCR has been largely employed for rapid detection of common aneuploidies in pre-natal and post-natal diagnosis and consists in DNA amplification by polymerase chain reaction (PCR) using fluorescent labelled primers and the analysis of chromosome specific small tandem repeats (STR). We tested 5 sex chromosome specific STR markers in multiplex PCR amplifications together with other chromosome specific STR markers as control amplifications. The PCR products were analysed by capillary electrophoresis. The results from QF-PCR analysis were obtained within one day and confirmed our cytogenetic observations. This study shows that QF-PCR analysis can detect sex chromosome imbalance and also suspect mosaicism or chromosome rearrangement.