Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic Alleles
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic &...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/6/1230 |
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| author | Enrico Ambrosini Francesca Montanari Carlotta Pia Cristalli Irene Capelli Claudio La Scola Andrea Pasini Claudio Graziano |
| author_facet | Enrico Ambrosini Francesca Montanari Carlotta Pia Cristalli Irene Capelli Claudio La Scola Andrea Pasini Claudio Graziano |
| author_sort | Enrico Ambrosini |
| collection | DOAJ |
| description | Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic <i>PKD1</i> variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including <i>PKHD1</i>, <i>HNF1B</i> and <i>PKD1</i> allowed the identification of biallelic <i>PKD1</i> variants. Furthermore, we review the medical literature in order to report likely <i>PKD1</i> hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare <i>PKD1</i> missense variants, especially if previously unreported, remain challenging. |
| first_indexed | 2024-03-11T02:25:41Z |
| format | Article |
| id | doaj.art-b89346ba17174a098429050e3b7d9874 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T02:25:41Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-b89346ba17174a098429050e3b7d98742023-11-18T10:34:36ZengMDPI AGGenes2073-44252023-06-01146123010.3390/genes14061230Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic AllelesEnrico Ambrosini0Francesca Montanari1Carlotta Pia Cristalli2Irene Capelli3Claudio La Scola4Andrea Pasini5Claudio Graziano6Medical Genetics Unit, University of Parma, 43126 Parma, ItalyMedical Genetics Unit, IRCCS Sant’Orsola University Hospital of Bologna, 40138 Bologna, ItalyMedical Genetics Unit, IRCCS Sant’Orsola University Hospital of Bologna, 40138 Bologna, ItalyNephrology Unit, IRCCS Sant’Orsola University Hospital of Bologna, 40138 Bologna, ItalyPaediatric Nephrology Program, Paediatrics Unit, IRCCS Sant’Orsola University Hospital of Bologna, 40138 Bologna, ItalyPaediatric Nephrology Program, Paediatrics Unit, IRCCS Sant’Orsola University Hospital of Bologna, 40138 Bologna, ItalyMedical Genetics Unit, AUSL Romagna, 47522 Cesena, ItalyAutosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic <i>PKD1</i> variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including <i>PKHD1</i>, <i>HNF1B</i> and <i>PKD1</i> allowed the identification of biallelic <i>PKD1</i> variants. Furthermore, we review the medical literature in order to report likely <i>PKD1</i> hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare <i>PKD1</i> missense variants, especially if previously unreported, remain challenging.https://www.mdpi.com/2073-4425/14/6/1230ADPKDhypomorphic variantsdisease modifiersbiallelic inheritance<i>PKD1</i><i>PKD2</i> |
| spellingShingle | Enrico Ambrosini Francesca Montanari Carlotta Pia Cristalli Irene Capelli Claudio La Scola Andrea Pasini Claudio Graziano Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic Alleles Genes ADPKD hypomorphic variants disease modifiers biallelic inheritance <i>PKD1</i> <i>PKD2</i> |
| title | Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic Alleles |
| title_full | Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic Alleles |
| title_fullStr | Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic Alleles |
| title_full_unstemmed | Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic Alleles |
| title_short | Modifiers of Autosomal Dominant Polycystic Kidney Disease Severity: The Role of <i>PKD1</i> Hypomorphic Alleles |
| title_sort | modifiers of autosomal dominant polycystic kidney disease severity the role of i pkd1 i hypomorphic alleles |
| topic | ADPKD hypomorphic variants disease modifiers biallelic inheritance <i>PKD1</i> <i>PKD2</i> |
| url | https://www.mdpi.com/2073-4425/14/6/1230 |
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