TSC2/PKD1 contiguous gene syndrome, with emphasis on a case with an atypical mild polycystic kidney phenotype and a novel genetic variant

Reyna-Fabián, Miriam E.; Alcántara-Ortigoza, Miguel Ángel; Hernández‐Martínez, Nancy Leticia; Berúmen, Jaime; Jiménez-García, Raquel; Gómez-Garza, Gilberto; Ángel, Ariadna González-del

doi:10.1016/j.nefroe.2019.03.012

Cited by 3 publications

(6 citation statements)

References 27 publications

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“…In such patients, PKD is frequently associated with TSC2/PKD1 contiguous gene syndrome. [10] The central nervous system is almost invariably involved, with up to 85% of patients presenting with epilepsy, and at least half of the patients have intellectual disabilities or other neuropsychiatric disorders, including autism spectrum disorder. [11] In this study, the patient was characterized by classical multisystematic symptoms, including severe AMLs, pulmonary LAM, multiple calcified subependymal nodules, liver hamartomas, skin impairment, and osteosclerosis, indicating a more severe grade of illness.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel heterozygous TSC2 splicing variant in a patient with Tuberous sclerosis complex

Liu

Yan

2022

Medicine

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Rationale: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by facial angiofibromas, epilepsy, intellectual disability, and the development of hamartomas in several organs, including the heart, kidneys, brain, and lungs. Mutations in either TSC1 or TSC2 result in dysregulated mTOR activation, leading to the occurrence of TSC. Patient concerns: A 44-year-old man was hospitalized for acute lumbago and hematuria. Diagnosis: The patient presented with facial angiofibromas, epilepsy, fibrous plaques, periungual fibroma, renal angiomyolipomas (AML), pulmonary lymphangioleiomyomatosis (LAM), liver hamartomas, and osteosclerosis. A diagnosis of TSC was made based on clinical manifestations. Interventions: Next-generation sequencing (NGS) was performed to screen for potential variants, which were verified using Sanger sequencing. The final variant was analyzed using a minigene assay. Outcomes: A potentially pathogenic novel TSC2 variant (NM_000548.4, c.336_336 + 15delGGTAAGGCCCAGGGCG) was identified using NGS and confirmed using Sanger sequencing. The in vitro minigene assay showed that the variant c.336_336 + 15delGGTAAGGCCCAGGGCG caused erroneous integration of a 74 bp sequence into intron 4. This novel variant was not found in his unaffected parents or 100 unrelated healthy controls. Lessons: We identified a novel heterozygous TSC2 variant, c.336_336 + 15delGGTAAGGCCCAGGGCG, in a patient with classical TSC and demonstrated that this variant leads to aberrant splicing using a minigene assay. Our results extend the understanding of the mutational spectrum of TSC2 .

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Section: Discussionmentioning

confidence: 99%

Identification of a novel heterozygous TSC2 splicing variant in a patient with Tuberous sclerosis complex

Liu

Yan

2022

Medicine

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“…AMLs that are sporadic and less than 2 cm are of little clinical relevance and are not associated with decline in renal function ( 56 ). When AMLs are numerous and actively growing, the risk of renal dysfunction is increased, especially in approximately 3% of TSC patients with a contiguous gene syndrome affecting the TSC2 and PKD1 genes ( 57 ). Recommendation on treatment and monitoring of different sized AML by Dickinson et al is illustrated in Table 4 ( 19 ).…”

Section: Pathophysiologymentioning

confidence: 99%

Renal Manifestations of Tuberous Sclerosis Complex

Nair

Chakraborty

Mahajan

et al. 2020

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Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors, and seizures. TSC can manifest in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts, and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.

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“…Our findings demonstrated the utility of NGS for improving the molecular diagnosis of TSC and PKDTS in a timely and cost-effective manner. Previously, both multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array-CGH) were shown to be useful not only for the diagnosis of PKDTS but also for elucidation of its molecular mechanism 14 , 15 . However, it is also known that a prompt diagnosis of PKDTS can be complicated by the phenotypic heterogeneity of PKD and the absence of a clear phenotype-genotype correlation 15 .…”

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confidence: 99%

“…Previously, both multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (array-CGH) were shown to be useful not only for the diagnosis of PKDTS but also for elucidation of its molecular mechanism 14 , 15 . However, it is also known that a prompt diagnosis of PKDTS can be complicated by the phenotypic heterogeneity of PKD and the absence of a clear phenotype-genotype correlation 15 . Under conditions where there is no strong clinical suspicion of PKDTS, NGS-based technology can be used to simultaneously evaluate multiple genetic alterations causing TSC.…”

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confidence: 99%

“…Sampson et al reported that among 27 unrelated patients with TSC and renal cystic disease, cystic disease was more severe, with early renal insufficiency, in 17 patients with PKDTS showing constitutional deletions 7 . Patients with PKDTS should therefore be diagnosed as early as possible to predict the increased risk of ADPKD-related complications, including cystic kidney disease as well as early end-stage renal disease 6 , 7 , 15 . In addition, most patients with TSC also develop neurological and neuropsychiatric disorders, with up to 90% developing epilepsy and up to 50% developing autism, suggesting that treating infants with TSC and epilepsy early with antiepileptic medications or surgery may result in better neurological outcomes 16 .…”

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confidence: 99%

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Molecular diagnosis of an infant with TSC2/PKD1 contiguous gene syndrome

et al. 2020

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A 1-month-old Japanese infant with cardiac rhabdomyoma was diagnosed with TSC2/PKD1 contiguous gene syndrome by targeted panel sequencing with subsequent quantitative polymerase chain reaction that revealed gross monoallelic deletion, including parts of two genes: exons 19-42 of TSC2 and exons 2-46 of PKD1. Early molecular diagnosis can help to detect bilateral renal cyst formation and multidisciplinary follow-up of this multisystem disease.

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TSC2/PKD1 contiguous gene syndrome, with emphasis on a case with an atypical mild polycystic kidney phenotype and a novel genetic variant

Cited by 3 publications

References 27 publications

Identification of a novel heterozygous TSC2 splicing variant in a patient with Tuberous sclerosis complex

Identification of a novel heterozygous TSC2 splicing variant in a patient with Tuberous sclerosis complex

Renal Manifestations of Tuberous Sclerosis Complex

Molecular diagnosis of an infant with TSC2/PKD1 contiguous gene syndrome

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