The utility of broad range of gene sequencing strategies in diagnosing inherited kidney disease, including whole exome sequencing (WES), MUC1 genotyping, and multiplex ligation-dependent probe amplification (MLPA) assay.
Identification of novel genes associated with kidney disease.
The Irish Kidney Gene Project has collaborated with multiple members of ERKnet a European consortium to study rare inherited kidney disease. We have presented findings on our work on rare kidney disease at their annual meeting and contribute to the ERKnet Registry.
The Irish Kidney Gene Project is a member of a European Consortium of researchers studying the natural history and genetics of of autosomal dominant interstitial kidney disease (ADTKD). This involves maintaining a registry of ADTKD patients and biobanking of their samples.
Studies of ultra-rare inherited kidney disease by way of international consortium including:
The Irish Kidney Gene Project--Prevalence of Family History in Patients with Kidney Disease in Ireland. Connaughton DM, Bukhari S, Conlon P, Cassidy E, O'Toole M, Mohamad M, Flanagan J, Butler T, O'Leary A, Wong L, O'Regan J, Moran S, O'Kelly P, Logan V, Griffin B, Griffin M, Lavin P, Little MA, Conlon P.. Nephron. 2015;130(4):293-301. doi: 10.1159/000436983. Epub 2015 Jul 18. PMID: 26202451.
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.
Clinical Heterogeneity in Familial IgA Nephropathy. Fennelly NK, Kennedy C, Jenkinson AC, Connaughton DM, Stapleton C, Dorman AM, Doyle B, Conlon PJ.. Nephron. 2018;139(1):63-69. doi: 10.1159/000486018. Epub 2018 Jan 19. PMID: 29402819.
An Exome Sequencing Study of 10 Families with IgA Nephropathy. Stapleton CP, Kennedy C, Fennelly NK, Murray SL, Connaughton DM, Dorman AM, Doyle B, Cavalleri GL, Conlon PJ.. Nephron. 2020;144(2):72-83. doi: 10.1159/000503564. Epub 2019 Dec 19. PMID: 31865346.
Fourteen families with familial IgA were 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).
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) in Ireland. Cormican S, Connaughton DM, Kennedy C, Murray S, Živná M, Kmoch S, Fennelly NK, O'Kelly P, Benson KA, Conlon ET, Cavalleri G, Foley C, Doyle B, Dorman A, Little MA, Lavin P, Kidd K, Bleyer AJ, Conlon PJ.. Ren Fail. 2019 Nov;41(1):832-841. doi: 10.1080/0886022X.2019.1655452. PMID: 31509055; PMCID: PMC6746258.
This study 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.
Other publications associated with the Irish Kidney Gene Project and our collaborators
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