Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease

Durkie, Miranda; Chong, Jiehan; Valluru, Manoj K.; Harris, Peter C.; Ong, Albert

doi:10.1038/s41436-020-01026-4

Cited by 37 publications

(53 citation statements)

References 40 publications

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“…It is now clear that many Mendelian conditions can be characterized by complex modes of inheritance. In this context, NGS-based genetic testing has revolutionized the diagnosis of genetic diseases by identification of multi-locus inheritance for several diseases, such as Charcot–Marie–Tooth disease [ 19 ], polycystic kidney disease [ 20 ], and congenital hypogonadotropic hypogonadism [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients

Andolfo

Martone

Rosato

et al. 2021

Genes

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Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). PIEZO1 and SPTA1 were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated hereditary stomatocytosis/xerocytosis and hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated hereditary stomatocytosis and hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance.

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Section: Discussionmentioning

confidence: 99%

Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients

Andolfo

Martone

Rosato

et al. 2021

Genes

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“…Combined autosomal dominant and autosomal recessive inheritance has been reported for ciliopathies. Heterozygous PKD1 variants are the most common cause of adult‐onset autosomal dominant polycystic kidney disease, while biallelic PKD1 variants are associated with early and potentially neonatal‐onset, severe polycystic kidney disease (Al‐Hamed et al, 2019 ; Audrézet et al, 2016 ; Durkie et al, 2021 ). Heterozygous DNAJB11 variants are associated with autosomal dominant polycystic kidney disease, while biallelic variants cause Ivemark II syndrome or renal‐hepatic‐pancreatic dysplasia syndrome (Jordan et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…The axoneme (blue) is composed of microtubule doublets that provides structure to the cilium and also forms the framework for ciliary transport. The nucleus (orange) is an important target of ciliary signaling (EHZ) [Color figure can be viewed at wileyonlinelibrary.com]Hamed et al, 2019;Audrézet et al, 2016;Durkie et al, 2021).Heterozygous DNAJB11 variants are associated with autosomal dominant polycystic kidney disease, while biallelic variants cause Ivemark II syndrome or renal-hepatic-pancreatic dysplasia syndrome(Jordan et al, 2021). We propose that TOPORS has similar properties, with…”

mentioning

confidence: 99%

Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes

Strong

Simone

Krentz³

et al. 2021

American J of Med Genetics Pt A

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Oral-facial-digital syndromes (OFDS) are a heterogeneous and rare group of Mendelian disorders characterized by developmental abnormalities of the oral cavity, face, and digits caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates organ patterning and growth. OFDS is inherited both in an X-linked dominant, X-linked recessive, and autosomal recessive manner. Importantly, though many of the causal genes for OFDS have been identified, up to 40% of OFD syndromes are of unknown genetic basis. Here we describe three children with classical presentations of OFDS including lingual hamartomas, polydactyly, and characteristic facial features found by exome sequencing to harbor variants in causal genes not previously associated with OFDS. We describe a female with hypothalamic hamartoma, urogenital sinus, polysyndactyly, and multiple lingual hamartomas consistent with OFDVI with biallelic pathogenic variants in CEP164, a gene associated with ciliopathy-spectrum disease, but never before with OFDS. We additionally describe two unrelated probands with postaxial polydactyly, multiple lingual hamartomas, and dysmorphic features both found to be homozygous for an identical TOPORS missense variant, c.29 C>A; (p.Pro10Gln). Heterozygous TOPORS pathogenic gene variants are associated with autosomal dominant retinitis pigmentosa, but never before with syndromic ciliopathy. Of note, both probands are of Dominican ancestry, suggesting a possible founder allele.Ciliopathy syndromes are rare Mendelian disorders caused by dysfunction of the primary cilium, a mechanosensory organelle that exists atop most cell types that facilitates proper organ patterning and growth (Berbari et al., 2009;Fry et al., 2014). Oral-facial-digital syndromes (OFDS) represent a heterogenous group of ciliopathies, characterized by the core features of oral cavity malformations, such as tongue hamartomas, cleft palate, lobulated tongue, and hyperplastic frenula, craniofacial dysmorphisms such as down-slanted palpebral

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“…While homozygous PKD1 mutations appear to be incompatible with life [39], biallelic hypomorphic PKD1 mutations can cause severe ARPKD-like forms [40,41], and the combination of a classical and an ultra-low penetrant PKD1 mutation can also cause severe, early ADPKD [42]. Patients with early ADPKD are more likely to have such biallelic transmission than those with classical ADPKD [36,41]. Digenic disease with variants in PKD1 and the newly identified ADPKD gene GANAB has also recently been identified in a child with early ADPKD [43].…”

Section: Extrarenal Disease Manifestations and Distinguishing Phenocomentioning

confidence: 99%

The wind of change in the management of autosomal dominant polycystic kidney disease in childhood

2021

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Significant progress has been made in understanding the genetic basis of autosomal dominant polycystic kidney disease (ADPKD), quantifying disease manifestations in children, exploring very-early onset ADPKD as well as pharmacological delay of disease progression in adults. At least 20% of children with ADPKD have relevant, yet mainly asymptomatic disease manifestations such as hypertension or proteinuria (in line with findings in adults with ADPKD, where hypertension and cardiovascular damage precede decline in kidney function). We propose an algorithm for work-up and management based on current recommendations that integrates the need to screen regularly for hypertension and proteinuria in offspring of affected parents with different options regarding diagnostic testing, which need to be discussed with the family with regard to ethical and practical aspects. Indications and scope of genetic testing are discussed. Pharmacological management includes renin-angiotensin system blockade as first-line therapy for hypertension and proteinuria. The vasopressin receptor antagonist tolvaptan is licensed for delaying disease progression in adults with ADPKD who are likely to experience kidney failure. A clinical trial in children is currently ongoing; however, valid prediction models to identify children likely to suffer kidney failure are lacking. Non-pharmacological interventions in this population also deserve further study.

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Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease

Abstract: This is a repository copy of Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease.

Cited by 37 publications

References 40 publications

Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients

Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients

Expanding the genetic landscape of oral‐facial‐digital syndrome with two novel genes

The wind of change in the management of autosomal dominant polycystic kidney disease in childhood

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