Irish Kidney Gene Project

Over one third of people in Ireland who develop kidney disease will have another family member affected by kidney disease. Genetics plays an important role in the development of kidney disease.

 The Irish Kidney Gene Project was set up in 2014 to explore the links between inheritance and kidney disease. It is collaboration between the Department of Renal Medicine at Beaumont Hospital and Department of Human Genetics at The Royal College of Surgeons.

We have international ties with Duke University,  Boston Children’s Hospital and Harvard Medical School.

We operate a renal genetics clinic twice a month to help diagnose and manage those with hereditary kidney disease. We are happy to see patients and family affected by kidney disease.  If this effects you, please ask your GP or nephrologist to send us a referral.

Key Collaborators:

Professor Peter Conlon, Consultant Nephrologist, Beaumont Hospital/RCSI

Professor Gianpiero Cavalleri, Associate Professor in Human Genetics and Deputy Head of the School of Postgraduate Studies

Dr Katherine Benson, RCSI

Ms Caragh Stapleton, RCSI

Dr Dervla Connaughton, Beaumont Hospital/ Harvard Medical School

Dr Claire Kennedy, Beaumont Hospital

Dr Susan Murray, Beaumont Hospital

Ms Claire Foley, Research Nurse, Beaumont Hospital/ RCSI

Prevalence of Familial Kidney Disease in Ireland

This project involved interviews with 1800 Irish patients with chronic kidney disease at nephrology clinics and dialysis units nationwide. We observed a prevalence of family history of kidney disease amongst 34% of patients (or 27% when polycystic kidney disease cases were excluded). Familial kidney disease was particularly prevalent amongst those patients with Alport syndrome, Congenital Abnormalities of the Kidney and Urinary Tract (CAKUT), tubulointerstitial kidney disease and those with an uncertain aetiology.

This study highlighted the high prevalence of inherited kidney disease among our patients nationwide, and suggested that focused genetic analysis of certain groups was appropriate. This study was the foundation for the following studies all undertaken under the auspices of the IKGP group.

Familial IgA Nephropathy

Fourteen families with familial IgA have been identified and recruited to IKGP. In this cohort, probable autosomal dominant and recessive modes of inheritance were observed. There were 42 affected individuals in the fourteen families (with either biopsy-proven IgA nephropathy or ESRD). A detailed clinical analysis of the patients and families has been accepted for publication by Nephron (Ref NEF-2017-7-14/R2).

Since this description, we have undertaken exome sequencing of ten of these families. In three out of the ten families we have identified candidate mutations. We identified collagen gene (COL4A3 and COL4A5) mutations in two families - one of which was definitely pathogenic and one likely pathogenic according to American College of Medical Genetics (ACMG standards) suggesting the alternate diagnosis of Alport Syndrome in these patients. In another family, we identified a mutation in the LMX1b gene which has previously been associated with Nail-patella syndrome, however further work is required to access the significance of this variant.

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

The IKGP database includes 49 patients from twelve families in Ireland with ADTKD. Of these, 19 patients, from three families, were demonstrated to have a pathogenic frameshift (cytosine insertion) MUC-1 mutation confirming the diagnosis to be ADTKD-MUC1. A further fourteen patients, from three families, are confirmed heterozygotes for a UMOD mutation, confirming ADTKD-UMOD. Each UMOD mutation led to a single amino acid substitution at protein level (tyrosine to cysteine substitution (p.Y274C), cysteine to tyrosine substitution (p.C223Y) and cysteine to tyrosine substitution (p.C106Y) respectively). All three mutations have been described in other families worldwide.  Investigations are pending for the remaining six families.

All in all, although likely under-recognised and under-diagnosed, this disease entity is thought to account for approximately 0.5% of Irish ESRD patients.

We have collaborated with Tony Bleyer in Bowman Grey University in North Carolina and the Broad Institute, Boston to make these observations. Our experience has been presented internationally and manuscript preparation is underway.

Current Research Projects Of The Irish Kidney Project

• The utility of broad range of gene sequencing strategies in diagnosing inherited kidney disease, including whole exome sequencing, MUC1 genotyping, and multiplex ligation-dependent probe amplification (MLPA) assay.
• Identification of novel genes associated with kidney disease.
• A study of the natural history of autosomal dominant interstitial kidney disease (ADTKD).
• Studies of ultra-rare inherited kidney disease by way of international consortium including:         

  • Fanconi anemia-associated nuclease (FAN1)-Related Nephropathy
  • Transient receptor potential canonical type 6 (TRPC6) Nephropathy
  • Inverted Formin 2 (INF2) Nephropathy
  • Intrafamilial variability in progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
  • Impact of hypomorphic variants in Autosomal Dominant Polycystic Kidney Disease on disease phenotype and progression
  • Impact of Polygenic Risk Scores for common risk factors for chronic kidney disease and age of end-stage kidney disease
  • Impact of Polygenic Risk Scores for common risk factors for chronic kidney disease and age of end-stage kidney disease in kidney transplant recipients and donor cause of death.