Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

Brunetti-Pierri, Raffaella; Karali, Marianthi; Testa, Francesco; Cappuccio, Gerarda; Onore, Maria Elena; Romano, Francesca; Rosa, Giuseppe De; Tedeschi, Enrico; Brunetti‐Pierri, Nicola; Banfi, Sandro; Simonelli, Francesca

doi:10.3390/diagnostics11071218

Cited by 5 publications

(4 citation statements)

References 27 publications

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“…Yet, there is still a long way to go in our understanding of this complex disorder and several aspects still remain unexplained, deeply challenging genotype–phenotype correlates. For instance, while usually complete loss of function of RPGRIP1L or MKS1 causes a lethal MKS phenotype, rare biallelic truncating variants in these genes have been reported in living patients with JS (Brancati et al, 2008; Brunetti‐Pierri et al, 2021; Romani et al, 2014a; Romani et al, 2014b). Moreover, both missense and truncating variants affecting the entire length of CPLANE1 have been found in patients with either exclusively neurological JS phenotype or severe/lethal OFD6 phenotypes (Lopez et al, 2014; Romani et al, 2015); similarly, pathogenic variants in CEP290 and TMEM231 have been associated to a large spectrum of ciliopathies even within the same family, without clear genotype–phenotype correlation (Coppieters, Lefever, Leroy, & De Baere, 2010; Maglic et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlates in Joubert syndrome: A review

Gana

Serpieri

Valente

2022

American J of Med Genetics Pt C

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Joubert syndrome (JS) is a genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the “molar tooth sign,” and variable organ involvement. Over 40 causative genes have been identified to date, explaining up to 94% of cases. To date, gene‐phenotype correlates have been delineated only for a handful of genes, directly translating into improved counseling and clinical care. For instance, JS individuals harboring pathogenic variants in TMEM67 have a significantly higher risk of liver fibrosis, while pathogenic variants in NPHP1, RPGRIP1L, and TMEM237 are frequently associated to JS with renal involvement, requiring a closer monitoring of liver parameters, or renal functioning. On the other hand, individuals with causal variants in the CEP290 or AHI1 need a closer surveillance for retinal dystrophy and, in case of CEP290, also for chronic kidney disease. These examples highlight how an accurate description of the range of clinical symptoms associated with defects in each causative gene, including the rare ones, would better address prognosis and help guiding a personalized management. This review proposes to address this issue by assessing the available literature, to confirm known, as well as to propose rare gene‐phenotype correlates in JS.

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Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlates in Joubert syndrome: A review

Gana

Serpieri

Valente

2022

American J of Med Genetics Pt C

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“…To establish whether a genotype could explain the disease, we assessed the concordance with the inheritance mode, available segregation results and, most importantly, the clinical phenotype. A total of 15 cases (out of 2036) were clinically reconsidered and reclassified after genetic testing: 6 cases with a non-RP diagnosis and mutations in ABCA4, CRB1 , NRL , RLBP1, PRPF6 , RPGR were reclassified as RP, whereas 9 RP cases were revised as non-RP (3 cases with mutations in NR2E3 and CHM ) or as syndromic IRD forms (6 cases with mutations in SMARCA4 , AHI1 , CLN3, PCYT1A, MFN2 and MKS1 57 ). Therefore, the integrative management of IRD patients should avail the combined expertise of clinicians and ophthalmic geneticists.…”

Section: Discussionmentioning

confidence: 99%

Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy

Karali

Testa

Iorio

et al. 2022

Sci Rep

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Inherited retinal diseases (IRDs) are the leading cause of vision loss in the working-age population. We performed a retrospective epidemiological study to determine the genetic basis of IRDs in a large Italian cohort (n = 2790) followed at a single referral center. We provided, mainly by next generation sequencing, potentially conclusive molecular diagnosis for 2036 patients (from 1683 unrelated families). We identified a total of 1319 causative sequence variations in 132 genes, including 353 novel variants, and 866 possibly actionable genotypes for therapeutic approaches. ABCA4 was the most frequently mutated gene (n = 535; 26.3% of solved cases), followed by USH2A (n = 228; 11.2%) and RPGR (n = 102; 5.01%). The other 129 genes had a lower contribution to IRD pathogenesis (e.g. CHM 3.5%, RHO 3.5%; MYO7A 3.4%; CRB1 2.7%; RPE65 2%, RP1 1.8%; GUCY2D 1.7%). Seventy-eight genes were mutated in five patients or less. Mitochondrial DNA variants were responsible for 2.1% of cases. Our analysis confirms the complex genetic etiology of IRDs and reveals the high prevalence of ABCA4 and USH2A mutations. This study also uncovers genetic associations with a spectrum of clinical subgroups and highlights a valuable number of cases potentially eligible for clinical trials and, ultimately, for molecular therapies.

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“…[7] Genetic testing is widely used in the diagnosis of JS and has the potential to become a diagnostic gold standard in some atypical cases. [8] Here we report an atypical JS case presenting with gait disturbance and bilateral peroneal neuropathies.…”

Section: This Study Was Supported By National Research Foundation Of ...mentioning

confidence: 91%

“…[7] Genetic testing is widely used in the diagnosis of JS and has the potential to become a diagnostic gold standard in some atypical cases. [8]…”

Section: Introductionmentioning

confidence: 99%

Joubert syndrome presenting bilateral peroneal neuropathies: A case report

Kim,

Jo,

Han

et al. 2024

Medicine

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Rationale: Joubert syndrome (JS) is a rare genetic disorder that presents with various neurological symptoms, primarily involving central nervous system dysfunction. Considering the etiology of JS, peripheral nervous system abnormalities cannot be excluded; however, cases of JS accompanied by peripheral nervous system abnormalities have not yet been reported. Distinct radiological findings on brain magnetic resonance imaging were considered essential for the diagnosis of JS. However, recently, cases of JS with normal or nearly normal brain morphology have been reported. To date, there is no consensus on the most appropriate diagnostic method for JS when imaging-based diagnostic approach is challenging. This report describes the case of an adult patient who exhibited bilateral peroneal neuropathies and was finally diagnosed with JS through genetic testing. Patient concerns and diagnosis: A 27-year-old man visited our outpatient clinic due to a gait disturbance that started at a very young age. The patient exhibited difficulty maintaining balance, especially when walking slowly. Oculomotor apraxia was observed on ophthalmic evaluation. During diagnostic workups, including brain imaging and direct DNA sequencing, no conclusive findings were detected. Only nerve conduction studies revealed profound bilateral peroneal neuropathies. We performed whole genome sequencing to obtain a proper diagnosis and identify the gene mutation responsible for JS. Lessons: This case represents the first instance of peripheral nerve dysfunction in JS. Further research is needed to explore the association between JS and peripheral nervous system abnormalities. Detailed genetic testing may serve as a valuable tool for diagnosing JS when no prominent abnormalities are detected in brain imaging studies.

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Mild Clinical Presentation of Joubert Syndrome in a Male Adult Carrying Biallelic MKS1 Truncating Variants

Cited by 5 publications

References 27 publications

Genotype–phenotype correlates in Joubert syndrome: A review

Genotype–phenotype correlates in Joubert syndrome: A review

Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy

Joubert syndrome presenting bilateral peroneal neuropathies: A case report

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