Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders

Devi, Akella Radha Rama; Naushad, Shaik Mohammad; Lingappa, Lokesh

doi:10.1016/j.pediatrneurol.2020.01.012

Cited by 60 publications

(46 citation statements)

References 35 publications

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“…One extreme example is the p.Arg621Gln variant, which has been observed as a homozygote in two non-syndromic and one mildly syndromic IRD cases in this study and recently reported in one subject with JBTS with no retinal degeneration. 35 These observations indicate that other genetic factors may play a role in the INPP5E disease manifestation.…”

Section: Resultsmentioning

confidence: 90%

“…Homozygous p.(Arg621Gln) and p.(Arg621Trp) changes were found in five patients, three non-syndromic LCA patients (this study and 31 ), one mildly syndromic LCA case (LL135, this study), and one JBTS case without apparent retinal involvement. 35 The p.(Arg621Gln) change has also been associated with non-syndromic IRD cases and with JBTS without retinal involvement in a compound heterozygous scenario. 29,33 Unfortunately, at present the paucity of genotyped INPP5E patients makes it impossible to explain the phenotypic discrepancies in patients carrying the p.(Arg621Gln) variant.…”

Section: Discussionmentioning

confidence: 99%

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Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

Sangermano

Deitch

Peter

et al. 2020

Preprint

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Purpose: Pathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity. Methods: Targeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation. Results: Fourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers. Conclusions: The study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

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Section: Resultsmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

Sangermano

Deitch

Peter

et al. 2020

Preprint

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“…Previous studies have explained genotype–phenotype correlation in terms of location, as well as the type(s) of the alterations in a particular domain and the resulting phenotype. Interestingly, in the literature, we found that the patients affected with JBTS harbour at least one missense variation in CC2D2A either in a compound heterozygous or homozygous fashion, whereas truncating mutations were mostly associated with MSK 22–24 . Moreover, the truncating mutations in the C‐terminal of the protein were present in JBTS patients, suggesting that at least some partially functional protein might be produced 22,25 .…”

Section: Discussionmentioning

confidence: 90%

Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family

Khan

Latif

Saif

et al. 2020

The Journal of Gene Medicine

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BackgroundJoubert syndrome (JBTS) is a heterogenous disorder characterized by intellectual disability, developmental delays, molar tooth sign in brain imaging, hypotonia, ocular motor apraxia and overlapping features of ciliopathies. There are 36 clinical subtypes of JBTS, with an equal number of genes known so far for this phenotype.MethodsWhole exome sequencing (WES) and Sanger sequencing were performed for the molecular diagnosis of a Pakhtun family affected with Joubert syndrome type 9 (JBTS9).ResultsA novel homozygous missense variant (c.4417C>G; Pro1473Ala) in exon 34 was identified in coiled‐coil and C2 domains‐containing the protein 2A (CC2D2A; NM_001080522) gene. The variant co‐segregated in autosomal recessive fashion within the family and was not found in 200 ethnically matched unaffected individuals. In silico analyses supported the pathogenic effect of the altered CC2D2A protein.ConclusionsTo the best of our knowledge, this is the first report of CC2D2A alteration co‐segragating with a JBTS9 phenotype in a Pakhtun family from Pakistan. Our findings broaden the pathogenic spectrum of JBTS9, adding a novel variant to CC2D2A variation pool. WES analysis is a successful molecular diagnostic tool for rare genetic disorders, especially in those populations where the marriage of cousins is more frequent. Efficient and accurate genetic testing and counselling of the affected families are helpful for patient management and for reducing the disease burden in future generations.

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“…There are 35 causative, ciliopathy-related genes that have been identified so far. The inheritance is autosomal recessive [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Total Intravenous Anesthesia in Joubert Syndrome Patient for Otorhinolaryngology Surgery: A Case Report and Mini Review of the Literature

et al. 2020

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Patient: Male, 13-year-old Final Diagnosis: Joubert syndrome Symptoms: Apnea Medication:— Clinical Procedure: Total intravenous anesthesia (TIVA) Specialty: Anesthesiology Objective: Congenital defects/diseases Background: Joubert syndrome is a rare autosomal recessive disorder first described in 1969, with an estimated prevalence of 1 in 100 000. Joubert syndrome is characterized by partial or complete agenesis of the cerebellar vermis – the structure that connects both parts of the cerebellum. This results in the main clinical symptoms, such as muscular hypotonia, ataxia, mental retardation, abnormal eye movements, and a central apnea breathing pattern. Joubert syndrome can combine neurological signs with variable multi-organ involvement, mainly of the retina, kidneys, liver, and musculoskeletal system. Case Report: A 13-year-old boy presenting with recurrent otitis media, fever, respiratory infections, and tonsillar hyperplasia needed surgery. At the otorhinolaryngology outpatient clinic, the indication for surgical paracentesis, adenoidectomy, and tonsillectomy under general anesthesia (first in his life) was set. We performed a total intravenous anesthesia (TIVA) using propofol (described as safe) and remifentanil (organ-independent metabolism) without any side-effects. For postoperative pain therapy we used metamizole instead of paracetamol in order to avoid liver injury. Conclusions: Due to the possible facial dysmorphism we recommend a critical evaluation of the airway to assess a potential difficult airway preoperatively. Our case underlines that TIVA, with the medications used in this case, is safe. We refrained from premedication in order not to trigger central apnea. For safety reasons, all preparatory procedures were carried out in the recovery room under monitor surveillance and with audio-visual distraction for the patient in order to reduce the stress level. For postoperative pain therapy, we recommend the use of metamizole.

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Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders

Cited by 60 publications

References 35 publications

Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

Early onset non-syndromic retinal degeneration due to variants in INPP5E: phenotypic expansion of the ciliary gene previously associated with Joubert syndrome

Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family

Total Intravenous Anesthesia in Joubert Syndrome Patient for Otorhinolaryngology Surgery: A Case Report and Mini Review of the Literature

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