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Published on: June 23, 2015
Prenatal-Onset Autosomal Dominant Polycystic Kidney Disease: Clinical Spectrum and Genetic Complexity of a
Margarita Sharova1, Marina Shumikchina2, Larisa Prikhodina3
1Research Centre for Medical Genetics, Moscow, Russia.
Insights
Rare prenatal Autosomal Dominant Polycystic Kidney Disease (ADPKD) cases reveal novel PKD1 variants. Prenatal diagnosis doesn't always predict rapid progression, offering new prognostic insights for severe ADPKD.
Area of Science:
- Genetics
- Nephrology
- Developmental Biology
Background:
- Renal cystic dysplasia involves primary cilia dysfunction.
- Autosomal dominant polycystic kidney disease (ADPKD) typically presents in adulthood.
Purpose of the Study:
- Investigate rare prenatal-onset ADPKD cases.
- Understand the genetic basis and clinical implications of early-onset ADPKD.
- Identify novel genetic variants in prenatal ADPKD.
Main Methods:
- Whole-genome sequencing in trios.
- Long-read sequencing for haplotype resolution.
- Variant interpretation using ACMG guidelines, focusing on hypomorphic alleles.
Main Results:
- Identified three novel hypomorphic PKD1 variants.
- Observed biallelic inheritance patterns in four families.
- Prenatal ultrasound findings were severe, but neonatal dialysis was rare; no oligohydramnios or end-stage kidney disease (ESKD) at diagnosis in most cases.
Conclusions:
- Next-generation sequencing (NGS) is crucial for diagnosing ADPKD, especially for hypomorphic variants.
- Prenatal ADPKD detection does not necessarily predict rapid disease progression.
- Findings provide prognostic insights and a framework for interpreting early-onset ADPKD, emphasizing the need for functional studies.
Objective:
Renal cystic dysplasia represents a group of disorders involving primary cilia dysfunction. Autosomal dominant polycystic kidney disease (ADPKD) due to PKD1 pathogenic variants typically presents in adulthood; we investigated rare prenatal-onset cases to better understand their genetic basis and clinical implications.
Method:
We performed whole-genome sequencing in trio and long-read sequencing on seven prenatal ADPKD cases. Variant interpretation followed ACMG guidelines, with special consideration for hypomorphic alleles and long-read sequencing for haplotype resolution in some cases.
Results:
Our study identified three novel hypomorphic PKD1 variants. Four families showed biallelic inheritance patterns, including one with two affected parents. Despite severe prenatal ultrasound findings, only one case required neonatal dialysis, and all cases lacked oligohydramnios. All other patients revealed no ESKD at the age of diagnosis.
Conclusions:
NGS analysis proves essential for diagnosis but requires comprehensive approaches to detect hypomorphic variants and underscores the necessity for comprehensive evaluation of hypomorphic alleles. Our findings demonstrate that prenatal detection does not necessarily predict rapid disease progression, offering new prognostic insights for severe ADPKD presentations that is extremely important for accurate genetic counseling. These results emphasize the need for functional studies of hypomorphic variants while providing a framework for clinical interpretation of early-onset ADPKD cases.
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