Improving diagnosis for rare diseases: the experience of the Italian undiagnosed Rare diseases network

Abstract

Background For a number of persons with rare diseases (RDs) a definite diagnosis remains undiscovered with relevant physical, psychological and social consequences. Undiagnosed RDs (URDs) require other than specialised clinical centres, outstanding molecular investigations, common protocols and dedicated actions at national and international levels; thus, many “Undiagnosed RDs programs” have been gradually developed on the grounds of a well-structured multidisciplinary approach. Methods The Italian Undiagnosed Rare Diseases Network (IURDN) was established in 2016 to improve the level of diagnosis of persons with URD living in Italy. Six Italian Centres of Expertise represented the network. The National Centre for Rare Diseases at the Istituto Superiore di Sanità coordinates the whole project. The software PhenoTips was used to collect the information of the clinical cases. Results One hundred and ten cases were analysed between March 2016 and June 2019. The age of onset of the diseases ranged from prenatal age to 51 years. Conditions were predominantly sporadic; almost all patients had multiple organs involvements. A total of 13/71 family cases were characterized by WES; in some families more than one individual was affected, so leading to 20/71 individuals investigated. Disease causing variants were identified in two cases and were associated to previously undescribed phenotypes. In 5 cases, new candidate genes were identified, although confirmatory tests are pending. In three families, investigations were not completed due to the scarce compliance of members and molecular investigations were temporary suspended. Finally, three cases (one familial) remain still unsolved. Twelve undiagnosed clinical cases were then selected to be shared at International level through PhenomeCentral in accordance to the UDNI statement. Conclusions Our results showed a molecular diagnostic yield of 53,8%; this value is comparable to the diagnostic rates reported in other international studies. Cases collected were also pooled with those collected by UDNI International Network. This represents a unique example of global initiative aimed at sharing and validating knowledge and experience in this field. IURDN is a multidisciplinary and useful initiative linking National and International efforts aimed at making timely and appropriate diagnoses in RD patients who still do not have a confirmed diagnosis even after a long time.

Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

“…We next pooled genetic and clinical de-identified data of patients with severe developmental disorder (DD) enrolled in the Italian Undiagnosed Rare Diseases Network (IURDN) ( n = 110) 30 and the Deciphering Developmental Disorders study ( n = 13 462) 47 and identified 3 individuals harbouring the de novo variants c.1652G>A (p.G551E) (Fam. IV.1) and c.2219G>A (p.R740Q) (Fam.…”

“…II-XIV: Details on sequencing, alignment, variant calling (inherited and de novo ) and variant annotation have been described previously. 30–36 Presence or absence of the disease-causing variants was confirmed on DNA of the proband and additional members from each family by Sanger sequencing.…”

Biallelic and de novo variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

“…We next pooled genetic and clinical de-identified data of patients with severe developmental disorder (DD) enrolled in the Italian Undiagnosed Rare Diseases Network (IURDN) (n=110) (Salvatore et al, 2020) and the Deciphering Developmental Disorders study (n = 13,462) (Barash et al, 2010) and identified 3 individuals harbouring the de novo variants c.1652G>A (p.G551E) (Fam. IV.1) and c.2219G>A (p.R740Q) (Fam.…”

“…Fam. II-XIV: Details on sequencing, alignment, variant calling (inherited and de novo) and variant annotation have been described previously (Kaplanis et al, 2020;Kinay et al, 2018;Mazzola et al, 2020;McRae et al, 2017;Muona et al, 2015;Niestroj et al, 2020;Salvatore et al, 2020). Presence or absence of the disease-causing variants was confirmed on DNA of the proband and additional members from each family by Sanger sequencing.…”

Developments in pediatrics in 2020: choices in allergy, autoinflammatory disorders, critical care, endocrinology, genetics, infectious diseases, microbiota, neonatology, neurology, nutrition, ortopedics, respiratory tract illnesses and rheumatology

“…Appropriate and timely diagnosis improves patient health status, reducing psychological and social burden of the diseases and allowing proper genetic counselling [ 49 ]. The Italian Undiagnosed Rare Diseases Network [ 50 ] collected information of 110 cases between March 2016 and June 2019. The goal of the network was to make timely and appropriate diagnoses of the most complex disorders.…”