Generation of induced pluripotent stem cell (iPSC) lines from a Joubert syndrome patient with compound heterozygous mutations in C5orf42 gene.

We have generated new disease-specific induced pluripotent stem cell (iPSC) lines from skin fibroblasts obtained from a female patient with Joubert syndrome (JS) caused by compound heterozygous mutations in C5orf42 gene. The generated iPSCs offer an unprecedented opportunity to obtain iPSC-derived neurons to investigate the pathogenesis of JS in vitro and to develop therapeutic strategies

Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome

Background Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases.Methods While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in similar to 550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of similar to 600 JS probands from the USA.Results All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant (TMEM216 c.218G>T) was significantly enriched in American compared with European patients with JS, while MKS1 c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes. Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from a MKS1 c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from a KIAA0586 c.428delG healthy homozygote.Conclusion This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants

Genotype-phenotype correlates in Joubert syndrome: A review

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

Marked intrafamilial variability of clinical and neuroimaging manifestations in NFIB-related developmental disorder

: NFIB belongs to the nuclear factor I (NFI) family of transcription factors that, by activating or repressing gene expression during embryogenesis, has a relevant role in the development of several organs including the brain. Heterozygous pathogenic variants of NFIB have recently been associated with developmental delay and mild-to-moderate intellectual disability, macrocephaly, nonspecific facial dysmorphisms, and corpus callosum dysgenesis. We identified a heterozygous missense variant in the NFIB gene in a 15-year-old boy with neurodevelopmental disorder and brain malformations, who inherited the variant from his substantially healthy mother presenting only minor physical and neuroanatomical defects

A novel IRF2BPL truncating variant is associated with endolysosomal storage

De novo mutations in the IRF2BPL gene have been identified to date in 18 patients presenting with neuromotor regression, epilepsy and variable neurological signs. Here, we report a female child carrying a novel heterozygous truncating variant in IRF2BPL. Following normal development for two and half years, she developed a progressive neurological condition with psychomotor regression, dystonic tetraparesis with hyperkinetic movements, but no overt epilepsy. Skin biopsy revealed enlarged lysosomes containing granular and tubular material, suggestive of a lysosomal storage disorder. This case expands the IRF2BPL phenotypic spectrum, for the first time providing evidence of endolysosomal storage

Spontaneous rupture of a simple renal cyst: clinical management

Spontaneous rupture of a simple renal cyst: clinical management Spontaneous renal bleeding mainly occurs in patients with polycystic kidney diseases or cancer. Indeed, despite the high prevalence of simple cysts, their spontaneous atraumatic rupture is a rare event. Underlying mechanisms may involve the increase of intracystic pressure and/or the development of a haemorrhage into the cyst. Management of this condition includes surgery, interventional radiology or conservative strategies. Here, we report a case of spontaneous rupture of a simple renal cyst, successfully managed with conservative treatment

Human trisomy 21 fibroblasts rescue methotrexate toxic effect after treatment with 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate

Trisomy 21 causes Down syndrome (DS), the most common human genetic disorder and the leading genetic cause of intellectual disability. The alteration of one-carbon metabolism was described as the possible metabolic cause of the intellectual disability development in subjects with DS. One of the biochemical pathways involved in the one-carbon group transfer is the folate cycle. The cytotoxic drug methotrexate (MTX) is a folic acid (FA) analogue which inhibits the activity of dihydrofolate reductase enzyme involved in the one-carbon metabolic cycle. Trisomy 21 cells are more sensitive to the MTX effect than euploid cells, and in 1986 J\ue9r\uf4me Lejeune and Coll. demonstrated that MTX was twice as toxic in trisomy 21 lymphocytes than in control cells. In the present work, the rescue effect on MTX toxicity mediated by FA and some of its derivatives, tetrahydrofolate (THF), 5-formyl-THF, and 5-methyl-THF, in both normal and trisomy 21 skin fibroblast cells, was evaluated. A statistically significant rescue effect was obtained by 5-formyl-THF, 5-methyl-THF, and their combination, administered together with MTX. In conclusion, trisomy 21 fibroblast cell lines showed a good response to the rescue effects of 5-formyl-THF and 5-methyl-THF on the MTX toxicity almost as normal cell lines

The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued

Abstract Background The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti–Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient. Results Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI. Conclusions Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA