Spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) including renal parenchymal malformations during fetal life and the implementation of prenatal exome sequencing (WES)

Maier, Jutta; Fangmann, Laura; Reinhardt, Charlotte; Weichert, Alexander; Henrich, Wolfgang; Biskup, Saskia; Gabriel, Heinz-Peter

doi:10.1007/s00404-023-07165-8

Cited by 5 publications

(3 citation statements)

References 59 publications

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“…3f). The representative cases with these types of complex SVs disrupting renal (and urinary) tract disorder- 32 and NN disorder-related genes 33 such as KMT2A , AFF2 , and FMR1 , are shown in Figs. 3e-f.…”

Section: Resultsmentioning

confidence: 99%

Deciphering the role of germline complex de novo structural variations in rare disorders

Jung,

Yang,

Walker

et al. 2024

Preprint

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De novo structural variants (dnSVs) have emerged as crucial genetic factors in the context of rare disorders. However, these variations often go undiagnosed in routine genetic screening practices. To shed light on their significance in rare disease, we conducted a comprehensive analysis of the largest cohort of parent-offspring whole-genome sequencing data from the UK 100,000 Genomes Project. Our study encompassed a vast cohort of 12,568 families, including 13,702 offspring affected by rare genetic diseases. We identified a total of 1,872 dnSVs, revealing that approximately 12% of the probands harboured at least one dnSV, of which 9% were identified as likely pathogenic in affected probands (151/1696). Advanced parents' age was found to be associated with an increased chance of having dnSVs in probands. We discovered 148 clustered breakpoints resulting from a single event. 60% of these complex dnSVs were classified into 9 major SV types, and could be observed in multiple individuals, while the remaining 40% were private events and had not been previously reported. We found 12% of pathogenic dnSVs are complex SVs, emphasising the critical importance of thoroughly examining and considering complex dnSVs in the context of rare disorders. Furthermore, we discovered an enrichment of maternal dnSVs at subtelometric, early-replicating regions of chromosome 16, suggesting possible sex-specific mechanisms in generation of dnSVs. This study sheds light on the extent of diversity of dnSVs in the germline and their contribution to rare genetic disorders.

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Section: Resultsmentioning

confidence: 99%

Deciphering the role of germline complex de novo structural variations in rare disorders

Jung,

Yang,

Walker

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…2F). The representative cases with these types of complex SVs disrupting renal and urinary tract disorder- 33 and NN disorder-related genes 34 such as KMT2A, AFF2, FMR1, and SRRM2 are shown in Figs. 2E-G.…”

Section: The Role Of Complex Svs In Rare Disordersmentioning

confidence: 99%

Complex de novo structural variants are an underestimated cause of rare disorders

Rahbari,

Jung,

Yang

et al. 2024

Preprint

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Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conducted a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, as part of the UK 100,000 Genomes Project. We identified 1,872 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n=158; 8.4%) emerged as the third most common type of SV, following simple deletions and duplications. We classified 65% of these complex dnSVs into 11 subtypes, based on the classification established through the analysis of cancer whole genomes. 1.4% of probands with neurodevelopmental disorders harbour at least one complex dnSV, a rate two times higher than previously reported. Intriguingly, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or exome-seq methods were found to be complex dnSVs. This study highlights the importance of complex dnSVs in rare disorders and demonstrates the necessity of careful genomic analysis to avoid overlooking these variants.

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“…Clinically, affected individuals develop secondary or adaptive focal segmental glomerulosclerosis (FGSG) manifested by proteinuria and progressive CKD. Congenital anomalies of the kidney and urinary tract (CAKUT) associated with reduced nephron number occur with a frequency of 4-60 in 10,000 live births (1). Preterm births (before 37 weeks gestation) occur at a rate of ~11% worldwide resulting in 15 million premature births annually (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Deletion of NuRD componentMta2in nephron progenitor cells causes developmentally programmed FSGS

Basta,

Robbins,

Stout

et al. 2023

Preprint

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Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi-organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.

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Spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) including renal parenchymal malformations during fetal life and the implementation of prenatal exome sequencing (WES)

Cited by 5 publications

References 59 publications

Deciphering the role of germline complex de novo structural variations in rare disorders

Deciphering the role of germline complex de novo structural variations in rare disorders

Complex de novo structural variants are an underestimated cause of rare disorders

Deletion of NuRD componentMta2in nephron progenitor cells causes developmentally programmed FSGS

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