Center of Human Genetics

Head

Marina Noris

marina.noris@marionegri.it

The Center of Human Genetics is engaged in multidisciplinary research projects to identify the genetic causes of various rare diseases and characterise their consequences at the molecular and cellular levels. The centre’s goals are to broaden our understanding of pathogenetic mechanisms, improve diagnosis and identify targeted therapies.

Studies carried out in recent years by the Center’s researchers have identified numerous genes whose anomalies cause rare diseases, such as Atypical Haemolytic-Uremic Syndrome (aHUS), Thrombotic Thrombocytopenic Purpura (TTP), Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN), C3 Glomerulopathy (C3G), Glomerulopathy with Fibronectin Deposits, and Steroid-Resistant Nephrotic Syndrome (SRNS).

Important advances have been achieved in the field of some rare diseases caused by abnormal activation of the complement system, a part of the immune system that is critical in defending against infections but which, due to complex genetic changes, attacks body tissues, causing functional deterioration. A thorough evaluation of the genetic and biochemical factors underlying the disease is essential to guide each patient toward personalised therapy with the drug that acts at the precise point in the complement cascade where the patient’s specific abnormality is located.

The Center includes a Diagnostic Laboratory specialised in cytogenetics and medical genetics, accredited by the Region of Lombardy, which was granted the status of Ultra specialised Laboratory for Medical Genetics - Molecular Genetics in 2023, and carries out diagnostic activities within the Italian National Health Service (SSN) for some rare diseases:

- Haemolytic-Uremic Syndrome (HUS)

- Thrombotic Thrombocytopenic Purpura (TTP)

- Membranoproliferative glomerulonephritis (MPGN)

- C3 glomerulopathy (C3G)

- Autosomal Dominant Polycystic Kidney Disease (ADPKD)

- Steroid-Resistant Nephrotic Syndrome (SRNS)

- Alport Syndrome

- Anderson-Fabry Disease

- Autosomal dominant tubulointerstitial kidney disease (ADTKD)

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Aims/Objectives

• Identifying new genetic causes of rare diseases

• Formulating molecular diagnoses for patients with undiagnosed rare diseases

• Characterising the functional consequences, in vitro and in vivo, of newly identified genetic abnormalities

• Stratifying patients with C3G or IC-MPGN into homogeneous groups according to pathogenesis, using genetic, biochemical, clinical, histologic, and novel biomarker data (identified using proteomics and metabolomics) to tailor therapies and optimise recruitment into studies with different drugs that are under development

• Studying, in families, the determinants that influence the risk of developing aHUS in individuals carrying mutations

• Assessing correlations between genotype and phenotype in aHUS

• Performing biochemical and genetic diagnostic investigations in patients with certain rare diseases

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METHODOLOGICAL APPROACHES

• Sequencing single genes, panels of genes, up to the whole exome with Next-generation sequencing (NGS)

• Searching for complex genomic deletions, duplications, and rearrangements with Single molecule real-time sequencing and Multiplex ligation-dependent probe amplification

• Transcriptome and RNA-Seq analysis with NGS

• Bioinformatics analysis of NGS results, annotation and variant selection, statistical analysis

• Obtaining recombinant wild-type and mutant proteins and their purification from plasma for in vitro functional studies

• Protein-protein interaction studies

• Assays of ADAMTS13 protease and its inhibitors

• ELISA assays in serum/plasma of complement system factors and their activation products and anti-CFH antibodies

• Evaluation of C3 convertase activity

• Assay and characterisation of nephritic factor C3 and nephritic factor C5

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Current projects