Optical Measurements of Sweat for in Vivo Quantification of CFTR Function in Individual Sweat Glands

Optical measurement of CFTR-dependent sweat secretion stimulated by a beta-adrenergic cocktail (C-phase) vs. CFTR-independent sweat secretion induced by methacholine (M-phase) can discriminate cystic fibrosis (CF) patientts from controls and healthy carriers by the ratio of sweat rate in the C-phase vs. the M-phase (C/M ratio). However, image analysis is experimentally demanding and time-consuming. Here, sweat droplet number (SDN) in the C-phase, corresponding to the number of sweat-secreting glands, was a statistically significant predictor for detecting the effects of CFTR-targeted therapy. We show that in 44 non-CF subjects and 110 CF patients, SDN in the C-phase provides a linear readout of CFTR function that is more sensitive than that using the C/M ratio. In CF patients, increased SDN in the C-phase during treatment with (LUMA/IVA) was associated with a trend toward improved lung function (FEV1). Our method is suitable for multicenter monitoring of the effects of CFTR modulators

Impact of MIF Gene Promoter Polymorphism on F508del Cystic Fibrosis Patients

Macrophage migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine sustaining the acute response to gram-negative bacteria and a regulatory role for MIF in Cystic Fibrosis has been suggested by the presence of a functional, polymorphic, four-nucleotide repeat in this gene's promoter at position -794, with the 5-repeat allele displaying lower promoter activity. We aimed at assessing the association of this polymorphism with disease severity in a group of Cystic Fibrosis patients homozygous for F508del CFTR gene mutation. Genotype frequencies were determined in 189 Cystic Fibrosis and 134 control subjects; key clinical features of patients were recorded and compared among homozygous 5-allele patients and the other MIF genotypes. Patients homozygous for the 5-repeat allele of MIF promoter displayed a slower rate of lung function decline (p\u200a=\u200a0.027) at multivariate survival analysis. Multiple regression analysis on age-normalized respiratory volume showed no association of the homozygous 5-repeat genotype with lung function under stable conditions and no correlation with P.aeruginosa chronic colonization. Therefore, only the Homozygous 5-repeat genotype at MIF -794 is associated with milder disease in F508del Cystic Fibrosis patients

E, Danesino C, Pasquali F, Nicolis E, Cesaro S, Perobelli S. The Italian SDS registry (RI-SDS): evolution form 1999.Proceedings of 8th International Congress on Shwachman-Diamond Syndrome, page 44. Verona 17-20 April 2016

Survival Analysis of italian registry of SDS patient

Long-term survival probability in Shwachman-Diamond syndrome in italian patients.

Description of long-term survival of italian patients with SD

Normative growth charts for Shwachman-Diamond syndrome from Italian cohort of 0-8 years old

Objectives Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder. Its predominant manifestations include exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive and susceptibility to short stature. Average birth weight is at the 25th percentile; by the first birthday, >50% of patients drop below the third percentile for height and weight. The study aims at estimating the growth charts for patients affected by SDS in order to give a reference tool helpful for medical care and growth surveillance through the first 8 years of patient's life. Setting and participants This retrospective observational study includes 106 patients (64 M) with available information from birth to 8 years, selected among the 122 patients included in the Italian National Registry of SDS and born between 1975 and 2016. Gender, birth date and auxological parameters at repeated assessment times were collected. The General Additive Model for Location Scale and Shape method was applied to build the growth charts. A set of different distributions was used, and the more appropriate were selected in accordance with the smallest Akaike information criterion. Results A total of 408 measurements was collected and analysed. The median number of observations per patient amounted to 3, range 1-11. In accordance with the methods described, specific SDS growth charts were built for weight, height and body mass index (BMI), separately for boys and girls. The 50th and 3rd percentiles of weight and height of the healthy population (WHO standard references) respectively correspond to the 97th and 50th percentiles of the SDS population (SDS specific growth charts), while the difference is less evident for the BMI. Conclusions Specific SDS growth charts obtained through our analysis enable a more appropriate classification of patients based on auxological parameters, representing a useful reference tool for evaluating their growth during childhood

The pathogenic variant c.258+533_459+403del in SBDS gene is the commonest rare variant in Italy and shows a founder effect

Shwachman-Diamond syndrome is a rare autosomal recessive disorder (SDS; OMIM #260400) mainly characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal defects. The first causative gene is SBDS, identified in 2003, and patients clinically affected by SDS carry mainly SBDS mutations, and most of them are represented by common pathogenic variants derived from genetic conversion events between SBDS and its pseudogene, SBDSP1. The Italian Registry of SDS collected the index cases who received a clinical SDS diagnosis with the demonstration of SBDS biallelic mutations; one of these is always represented by the [c.258+2T>C], while the second one includes either the [c.183_184delinsTA>CT] or [c.183_184delinsTA>CT+c.258+2T>C] or [c.258+2T>C] in, respectively, 59, 12.5 and 10.83% of cases entered until May 2022. In the 17,67% the SBDS genotype is completed by fourteen different types of rare, private, pathogenic variants and all these alleles were observed once among Italian cases, except for [c.187G>T] and [c.258+533_459+403del] alleles, which were observed in two and four unrelated families, respectively. The first one is present in two families, both originating from Northern Tuscany, while for the second allele, the deletion, three families originate from Sicily and one from Lazio. The presence of the deletion in four families (corresponding to 3.31% of index cases), pushed us to investigate if it could be due to a founder effect, with the same mutation originating from a single ancestral event in all cases. Genotyping the region surrounding the SBDS locus, we defined a common haplotype in the families coming from Sicily, while a completely different one resulted in the family originated from Lazio. This result, identifying the most likely ancestral haplotype associated with the deletion of exon 3, suggested a potential founder effect that might be localized in the provinces of Palermo and Messina, in the middle of the North of Sicily. Our result finds a prompt application in routine molecular diagnostics: to know that a causative mutation is a founder mutation it could improve the diagnosis and the genetic counselling in a genetic disease. In addition, providing evidence that in Italy the deletion [c.258+533_459+403del] originated independently twice in two different geographical place (Sicily and Lazio), this study suggests that this deletion could be quite frequent among "rare" SDS mutations and thus with high priority for testing