Genetic newborn screening and digital technologies: A project protocol based on a dual approach to shorten the rare diseases diagnostic path in Europe.

Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems.

Smoking but not homozygosity for CYP1A2 g-163A allelic variant leads to earlier disease onset in patients with sporadic porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) results from decreased activity of hepatic uroporphyrinogen decarboxylase (UROD). Both sporadic and familial forms are characterised by typical cutaneous lesions triggered by genetic/environmental factors. Studies in rodents showed that cytochrome P4501A2 (CYP1A2) plays a central role in the synthesis of a competitive inhibitor of hepatic UROD, but there is little evidence in humans. The impact of smoking and CYP1A2 g-163C > A allelic variant upon first appearance of clinical signs was investigated in 102 patients (80 sporadic-PCT) and 150 healthy donors from Spain. We found an increase in the frequency of CYP1A2 g-163A allele in patients with PCT when compared with controls, although the more inducible A/A genotype had no effect on the onset age. In sporadic-PCT, smoking leads to earlier onset of clinically overt disease in moderate-to-heavy smokers (>or=10 cigarettes/day). In conclusion, this study provides evidence that smoking hastens the onset of cutaneous symptoms in sporadic-PCT patients.

Outcome of twin babies free of Von Hippel-Lindau disease after a double-factor preimplantation genetic diagnosis: monogenetic mutation analysis and comprehensive aneuploidy screening.

OBJECTIVE: To increase the embryo implantation rate, a double-factor preimplantation genetic diagnosis (DF-PGD) was performed, selecting for transfer potentially euploid evolved embryos free of the mutation responsible for Von Hippel-Lindau syndrome (VHL). DESIGN: Case report. SETTINGS: Medical university center and a private IVF center. PATIENT(S): A patient carrier of the R161Q mutation on the VHL gene. INTERVENTION(S): After first polar body (1PB) biopsy, it was analyzed using comparative genomic hybridization (1PB-CGH). On day +3, mutation detection using minisequencing and short tandem repeat analysis was performed in multiple displacement amplification products of a single blastomere per embryo. MAIN OUTCOME MEASURE(S): Transfering embryos free of the disease and originating from euploid oocytes. RESULT(S): Nine of the twelve oocytes obtained were successfully analyzed using 1PB-CGH. One of them was aneuploid (1PB #1: 29XX,+2,+10,+12,+17,+19), and the rest were euploid. All of the oocytes were fertilized and became evolved embryos. Six of the embryos were VHL unaffected and had good quality. Five (83%) of them were potentially euploid. According to cytogenetic results, two of the evolved and healthy embryos were transfered, achieving the birth of healthy twin babies. CONCLUSION(S): The DF-PGD can be a useful tool to increase implantation of transfered embryos in PGD for monogenic diseases.