Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel

Al‐Hamed, Mohamed H.; Kurdi, Wesam; Alsahan, Nada; Alabdullah, Zainab; Abudraz, Rania; Tulbah, Maha; Alnemer, Maha; Khan, Rubina; Al-Jurayb, Haya; Alahmed, Ahmed S.; Tahir, Asma; Khalil, Dania S.; Edwards, Noel; Abdulaziz, Basma Al; BinHumaid, Faisal S.; Majid, Salma; Faquih, Tariq; El‐Kalioby, Mohamed; Abouelhoda, Mohamed; Al-Tassan, Nada A.; Monies, Dorota; Meyer, Brian F.; Sayer, John A.; Albaqumi, Mamdouh

doi:10.1136/jmedgenet-2015-103469

Cited by 32 publications

(31 citation statements)

References 43 publications

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“…We believe that this new variant identified in this family is likely to cause the hydrops fetalis in two of the fetuses. Other examples in our cohort include compound heterozygous mutations in CC2D2A that were associated with Meckel syndrome 6 (MIM# 612284; Al‐Hamed et al, ), mutations in RAPSN that resulted in fetal akinesia deformation sequence (MIM# 208150; Cox et al, ), mutations in PIEZO1 that led to generalized lymphatic dysplasia with nonimmune fetal hydrops (MIM# 616843; Fotiou et al, ), and CEP290 mutations that were related to Meckel syndrome 4 (MIM# 611134; Frank et al, ). The phenotypes of fetuses in these cases with pathogenic or likely pathogenic variants were consistent with the results obtained from previous studies.…”

Section: Discussionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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Whole-exome sequencing (WES) is widely used to detect genetic mutations that cause Mendelian diseases, and has been successfully applied in combination with preimplantation genetic diagnosis (PGD) to avoid the transmission of genetic defects.We investigated 40 nonconsanguineous families with unexplained, recurrent fetal malformations (two or more malformed fetuses) from May 2016 to December 2018.Using Trio-WES, we identified 32 disease-associated variants in 40 families (80% positive rate), which were subsequently verified. Known Mendelian diseases were identified in 12 families (30%), highly suspected Mendelian diseases in 12 families (30%), variants with uncertain significance in 8 families (20%), and no noticeable variants for 8 families (20%). Further analysis showed variants in 22 genes may cause fetal malformations. Four gene variants were detected in fetuses for the first time, which expanded the spectrum of the disease phenotype. Two novel candidate genes may be related to fetal malformations. Of 26 couples receiving PGD on diseaseassociated genes, 3 healthy newborns were delivered, and 4 couples are undergoing pregnancies. We reported the fetal data and developed an optimized genetic testing strategy. Our finding strongly suggests the presence of single gene Mendelian disorders in 60% of those families, and PGD services for couples to have healthy babies.

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Section: Discussionmentioning

confidence: 99%

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

et al. 2019

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“…To date, more than 25 different genes have been found to be associated with NPHP (Table ) . Mutations in the NPHP1 gene are the most common, being reported in approximately 20% of cases.…”

Section: Genotype–phenotype Correlation Of Nphpmentioning

confidence: 99%

Nephronophthisis: A review of genotype–phenotype correlation

Luo

Tao

2018

Nephrology

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Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end‐stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%–20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. This review provides an update of the recent advances in the clinical features and related gene mutations of nephronophthisis, and novel approaches for therapy in nephronophthisis patients may be needed.

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“…2 with the variant in CEP290 gene is more prevalent in consanguineous families. 25 Our present case is the first report of CEP290 associated MKS4 in Chinese population.…”

Section: Polycystic Kidney Tissues Of Foetus Have Been Suffering Frommentioning

confidence: 53%

“…Centrosomal protein CEP290 is playing a key role in both early and late steps in cilia formation 2. Interestingly, MKS4with the variant in CEP290 gene is more prevalent in consanguineous families 25. 1 It helps in recruiting RAB8A to the primary cilia and also targets the satellite proteins of centriole and transfer it to centrosome.…”

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confidence: 99%

Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome

Zhang

Chen

Han

et al. 2019

J Cellular Molecular Medi

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Meckel syndrome (MKS) is a pre-or perinatal multisystemic ciliopathic lethal disorder with an autosomal recessive mode of inheritance. Meckel syndrome is usually manifested with meningo-occipital encephalocele, polycystic kidney dysplasia, postaxial polydactyly and hepatobiliary ductal plate malformation. Germline variants in CEP290 cause MKS4. In this study, we investigated a 35-years-old Chinese female who was 17+1 weeks pregnant. She had a history of adverse pregnancy of having foetus with multiple malformations. We performed ultrasonography and identified the foetus with occipital meningoencephalocele and enlarged cystic dysplastic kidneys. So, she decided to terminate her pregnancy and further genetic molecular analysis was performed. We identified the aborted foetus without postaxial polydactyly. Histological examination of foetal kidney showed cysts in kidney and thinning of the renal cortex with glomerular atrophy. Whole exome sequencing identified a novel homozygous variant (c.2144T>G; p.L715 * ) in exon 21 of the CEP290 in the foetus. Sanger sequencing confirmed that both the parents of the foetus were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters of the foetus as well as in the 100 healthy individuals. Western blot analysis showed that this variant leads to the formation of truncated CEP290 protein with the molecular weight of 84 KD compared with the wild-type CEP290 protein of 290 KD. Hence, it is a loss-of-function variant.We also found that the mutant cilium appears longer in length than the wild-type cilium. Our present study reported the first variant of CEP290 associated with MKS4 in Chinese population.

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Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel

Cited by 32 publications

References 43 publications

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Trio‐whole‐exome sequencing and preimplantation genetic diagnosis for unexplained recurrent fetal malformations

Nephronophthisis: A review of genotype–phenotype correlation

Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome

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