Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families

Al‐Hamed, Mohamed H.; Alsahan, Nada; Rice, S.J.; Edwards, Noel; Nooreddeen, Eman; Alotaibi, Maha; Kurdi, Wesam; Alnemer, Maha; Altaleb, Naderah; Ali, Wafa Bel Haj; Al‐Numair, Nouf S.; Almejaish, Najd; Sayer, John A.; Imtiaz, Faiqa

doi:10.1007/s00467-019-04267-x

Cited by 25 publications

(22 citation statements)

References 37 publications

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“…Family 21 presented a rare type of biallelic ADPKD of the compound heterozygous PKD1 gene. The combined effects of the two PKD1 alleles resulted in a severe foetal‐onset PKD resembling the autosomal recessive ciliopathy syndromes, which was consistent with Al‐Hamed and colleagues' 43 ‘two‐hit’ theory. Biallelic traits were not detected in Family 15 and Family 19, where both parents were phenotypic PKD patients.…”

Section: Discussionsupporting

confidence: 81%

Comprehensive strategy improves the genetic diagnosis of different polycystic kidney diseases

Zhang²,

Qiu

et al. 2021

J Cellular Molecular Medi

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Polycystic kidney disease (PKD) is known to occur in three main forms, namely autosomal dominant PKD (ADPKD), autosomal recessive PKD (ARPKD) and syndromic PKD (SPKD), based on the clinical manifestations and genetic causes, which are diagnosable from the embryo stage to the later stages of life. Selection of the genetic test for the individuals with diagnostic imaging reports of cystic kidneys without a family history of the disease continues to be a challenge in clinical practice. With the objective of maintaining a limit on the time and medical cost of the procedure, a practical strategy for genotyping and targeted validation to resolve cystogene variations was developed in our clinical laboratory, which combined the techniques of whole‐exome sequencing (WES), Long‐range PCR (LR‐PCR), Sanger sequencing and multiplex ligation–dependent probe amplification (MLPA) to work in a stepwise approach. In this context, twenty‐six families with renal polycystic disorders were enrolled in the present study. Thirty‐two variants involving four ciliary genes (PKD1, PKHD1, TMEM67 and TMEM107) were identified and verified in 23 families (88.5%, 23/26), which expanded the variant spectrum by 16 novel variants. Pathogenic variations in five foetuses of six families diagnosed with PKD were identified using prenatal ultrasound imaging. Constitutional biallelic and digenic variations constituted the pathogenic patterns in these foetuses. The preliminary clinical data highlighted that the WES + LR PCR‐based workflow followed in the present study is efficient in detecting divergent variations in PKD. The biallelic and digenic mutations were revealed as the main pathogenic patterns in the foetuses with PKD.

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Section: Discussionsupporting

confidence: 81%

Comprehensive strategy improves the genetic diagnosis of different polycystic kidney diseases

Zhang²,

Qiu

et al. 2021

J Cellular Molecular Medi

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“…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…”

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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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“…Widespread usage of next-generation sequencing strategies allowing analyses of multiple genes at once provide more information about PKD. It is reported that biallelic mutations in PKD1, a well-known ADPKD gene, result in more severe and early-onset PKD [Vujic et al, 2010;Al-Hamed et al, 2019]. In the present study, 2 fetuses in the same family were diagnosed as PKD at antenatal period, and we were able to perform WES in one of them.The DNAJB11 gene c.740+1G>A variant, which was the only variant related to PKD previously, was detected in a homozygous state, and the parents are heterozygous carriers of the mutation.…”

Section: Discussionmentioning

confidence: 61%

Biallelic Mutations in DNAJB11are Associated with Prenatal Polycystic Kidney Disease in a Turkish Family

et al. 2021

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Polycystic kidney disease (PKD) is a life-threatening condition resulting in end-stage renal disease. Two major forms of PKD are defined according to the inheritance pattern. Autosomal dominant PKD (ADPKD) is characterized by renal cysts, where nearly half of the patients suffers from renal failure in the 7th decade of life. Autosomal recessive PKD (ARPKD) is a rarer and more severe form presenting in childhood. Whole-exome sequencing (WES) analyses was performed to investigate molecular causes of the disease in the fetus. In this study, we present 2 fetuses prenatally diagnosed with PKD in a consanguineous family. WES analysis of the second fetus revealed a homozygous variant (c.740+1G>A) in DNAJB11 which is related to ADPKD. This study reveals that DNAJB11 biallelic mutations may cause an antenatal severe form of ARPKD and contributes to understanding the DNAJB11-related ADPKD phenotype. The possibility of ARPKD due to biallelic mutations in ADPKD genes should be considered in genetic counseling.

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Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families

Cited by 25 publications

References 37 publications

Comprehensive strategy improves the genetic diagnosis of different polycystic kidney diseases

Comprehensive strategy improves the genetic diagnosis of different polycystic kidney diseases

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

Biallelic Mutations in <b><i>DNAJB11</i></b>are Associated with Prenatal Polycystic Kidney Disease in a Turkish Family

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