Copy number variants analysis in a cohort of isolated and syndromic developmental delay/intellectual disability reveals novel genomic disorders, position effects and candidate disease genes.

BACKGROUND: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). AIMS: Identification of genomic disorders in DD/ID. MATERIALS AND METHODS: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. RESULTS: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. DISCUSSION AND CONCLUSION: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.

MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Eyebrow anomalies as a diagnostic sign of genomic disorders.

Microdeletions and microduplications in the human genome, termed genomic disorders, contribute to a high proportion of human multisystemic neurodevelopmental diseases and are detected by array-based comparative genomic hybridization (aCGH). In general, most genomic disorders are associated with craniofacial and skeletal features and behavioural abnormalities, in addition to learning disability and developmental delay (LD/DD). Specifically, recognition of a characteristic 'facial gestalt' has been the key to distinguish one genomic disorder from the other. Here, we report our experience concerning the relevance of abnormal eyebrow pattern as a diagnostic indicator of specific genomic disorders.

A novel H208D TP63 mutation in a familial case of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome without clefting.

Ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) syndrome is an autosomal dominant form of ectodermal dysplasia associated with limb anomalies and orofacial clefting. The TP63 gene has been shown to be the cause of the disease, and some tentative genotype-phenotype correlations have been reported. We describe a familial case of EEC syndrome, diagnosed in two siblings affected by severe ectrodactyly and mild ectodermal dysplasia, without clefting. Moreover, one of the siblings had a history of delayed developmental milestones in the first years of life. Family history revealed mild hand malformations in the father and grandfather, who were not available for clinical evaluation. The TP63 gene molecular study showed in both siblings a heterozygous H208D mutation, which has not been previously reported to our knowledge, suggesting that this molecular lesion is associated with EEC syndrome without orofacial clefting.

[Morbidity and mortality in patients undergoing dialysis. Comparison of hemodialysis and peritoneal dialysis. Our experience]. / Morbilità e mortalità in pazienti in dialisi. Confronto fra emodialisi e dialisi peritoneale. Nostra esperienza.

BACKGROUND: We have compared the hemodialysis and peritoneal dialysis populations of our Center for morbidity and mortality, in a retrospective study of six years of activity. METHODS: We enrolled 125 patients (104 patients/year/million inhabitants), who had been in chronic dialysis from 1992 to 1997: 90 (22-90 years old) initiated in hemodialysis and 35 (27-82 years old) in peritoneal dialysis. RESULTS: We have evaluated survival and morbility, as hospitalization/patient/year in both groups. Mortality did not prove significantly different in the two groups. The global average of hospitalization was 8 days/patient/year for hemodialysis and 6 for peritoneal dialysis. CONCLUSIONS: In spite of the short time of observation and the exiguity of numbers, our experience shows that the two methods are equivalent.

[Prevalence of anti-HCV antibody positivity and seroconversion incidence in hemodialysis patients]. / Prevalenza di positività per anticorpi antiHCV e incidenza di sieroconversione in pazienti in emodialisi.

BACKGROUND AND AIMS: The prevalence of positivity to anti-HCV antibodies and the incidence of seroconversion in a group of patients undergoing replacement hemodialytic treatment was evaluated using a retrospective analysis. The study was carried out in a hemodialysis centre with no areas and/or equipment dedicated to patients positive to anti-HCV antibodies. The aim was to check whether the rigid application of universal aseptic precautions, which are always adopted by the centre, are sufficient to prevent contagion by hepatitis C virus in patients undergoing dialysis. METHODS: The study was carried out in patients receiving dialysis in the Centre (74 patients at the start of the observation period) for two years (7/95-7/97). Anti-HCV antibodies were assayed every two months using a third generation ELISA tests and positive results were confirmed by RIBA III test. At the start of the observation period, 10/74 patients showed positive levels of anti-HCV antibodies (13.5%). RESULTS: During the period in question none of the patients with negative levels of anti-HCV antibodies at the start of the study became positive. Of the patients undergoing dialysis after 1/7/95, four were already positive for anti-HCV antibodies and none of the others became positive. CONCLUSIONS: The experience confirms that the application of universal aspeptic precautions may be sufficient to prevent the spread of hepatitis C virus in dialysis centres.

[Vascular access for hemodialysis under difficult conditions. Our experience]. / Accessi vascolari per emodialisi in condizioni difficili. Nostra esperienza.

Having examined the causes that lead, on the one hand, to an increased number of vascular accesses in difficult conditions and, on the other, to their reduction and having examined their personal series of vascular accesses for hemodialysis studied between 4 December 1974 to 30 September 1996, and lastly having outlined the correct protocol for the preparation of these accesses, the authors focus on vascular accesses created in difficult conditions, namely the exhaustion of the natural venous and/or arterial bed below the proximal third of the upper limb. In particular, they examine the use of definitive jugular catheters, a more recent and therefore non-standardised method, and conclude that, although not regarded as vascular accesses of first choice, they should no longer be regarded as heroic but, after a short period of learning, they are easy to position and maintain.

[Treatment with erythropoietin and iron requirements in dialyzed patients]. / Trattamento con eritropoietina (Epo) e fabbisogno di ferro nel paziente dializzato.

The use of erythropoietin in dialysed patients leads to the gradual depletion of the body's iron reserves. It is important to assay iron blood levels in both patients receiving Epo therapy and those undergoing dialysis without this treatment. The most common method used is to assay ferritinemia, transferrinemia and the transferrin saturation levels. Using a retrospective study it was found that there is no significant difference in the request for iron supplementation in patients receiving Epo treatment compared to a control group not treated with Epo.

[Vascular access for hemodialysis. Our experience in 20 years]. / Accessi vascolari per emodialisi. Nostra esperienza in 20 anni.

A personal series arterio-venous fistulas from the last 20 years is examined. The authors have tried to verify the correctness of their present proctocol which is based on the abolition of those fistulas applied to the anatomic tabac. In fact in some cases they have caused problems of flow, but in other cases they have lasted much longer than any other kind of fistulas.

[Erythropoietin treatment in Piedmont and Valle d'Aosta]. / Il trattamento con eritropoietina in Piemonte e Valle d'Aosta.

The paper reports a study carried out in the Dialysis Centres of Piedmont and the Aosta Valley on the use of erythropoietin in the treatment of anemia in patients undergoing regular dialysis. The efficacy of the drug and collateral and/or undesirable effects were evaluated. It was found that the drug was efficacious in 99.2% of the 342 patients receiving treatment on 30-6-1990, whereas undesirable effects were observed in 14.6% of cases. Data from the Nephrology and Dialysis Service in Asti are also reported.

[Use of calcium carbonate as an intestinal chelator of phosphorus]. / Utilizzo del calcio carbonato (CaCO3) come chelante intestinale del fosforo.

Fourteen patients undergoing periodic dialysis who had been taking AL(OH)3 as an intestinal chelant of phosphorus have been examined. AL(OH)3 was replaced by CaCO3 for a period of 6 months. At the end of the study, statistically significant reductions were evidenced in alkaline phosphatase, basal serum aluminiaemia and its increase after Desferal test, while the bicarbonates (HCO3) were found to be increased. Statistically non-significant increases were observed in calcaemia, PTH, and pH. It is concluded that the replacement of AL(OH)3 with CaCO3 is effective in controlling phosphoraemia, in diminishing serum concentrations and tissue deposits of Al and in improving uraemic acidosis.