Retinal degeneration due to photoreceptor ciliary-related proteins dysfunction accounts for more than 25% of all inherited retinal dystrophies. The cilium, being an evolutionarily conserved and ...ubiquitous organelle implied in many cellular functions, can be investigated by way of many models from invertebrate models to nonhuman primates, all these models have massively contributed to the pathogenesis understanding of human ciliopathies. Taking the Bardet-Biedl syndrome (BBS) as an emblematic example as well as other related syndromic ciliopathies, the contribution of a wide range of models has enabled to characterize the role of the BBS proteins in the archetypical cilium but also at the level of the connecting cilium of the photoreceptors. There are more than 24 BBS genes encoding for proteins that form different complexes such as the BBSome and the chaperone proteins complex. But how they lead to retinal degeneration remains a matter of debate with the possible accumulation of proteins in the inner segment and/or accumulation of unwanted proteins in the outer segment that cannot return in the inner segment machinery. Many BBS proteins (but not the chaperonins for instance) can be modeled in primitive organisms such as
,
,
, and
These models have enabled clarifying the role of a subset of BBS proteins in the primary cilium as well as their relations with other modules such as the intraflagellar transport (IFT) module, the nephronophthisis (NPHP) module, or the Meckel-Gruber syndrome (MKS)/Joubert syndrome (JBTS) module mostly involved with the transition zone of the primary cilia. Assessing the role of the primary cilia structure of the connecting cilium of the photoreceptor cells has been very much studied by way of zebrafish modeling (
) as well as by a plethora of mouse models. More recently, large animal models have been described for three BBS genes and one nonhuman primate model in rhesus macaque for
In completion to animal models, human cell models can now be used notably thanks to gene editing and the use of induced pluripotent stem cells (iPSCs). All these models are not only important for pathogenesis understanding but also very useful for studying therapeutic avenues, their pros and cons, especially for gene replacement therapy as well as pharmacological triggers.
Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and ...hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those,
is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia. This study reports on a European
patient with a severe BBS phenotype. Genetic analysis was performed using multiple next-generation sequencing (NGS) tests (targeted exome, TES and whole exome, WES), and biallelic pathogenic variants could only be identified using whole-genome sequencing (WGS), including a previously missed large deletion of the first exons. Despite the absence of family samples, the biallelic status of the variants was confirmed. The BBS5 protein's impact was confirmed on the patient's cells (presence/absence and size of the cilium) and ciliary function (Sonic Hedgehog pathway). This study highlights the importance of WGS and the challenge of reliable structural variant detection in patients' genetic explorations as well as functional tests to assess a variant's pathogenicity.
Background
Whether spinocerebellar ataxia 27B (SCA27B) may present as a cerebellar multiple system atrophy (MSA-C) mimic remains undetermined.
Objectives
To assess the prevalence of
FGF14
(GAA)
≥250
...expansions in patients with MSA-C, to compare SCA27B and MSA-C clinical presentation and natural history.
Methods
FGF14
expansion screening combined with longitudinal deep-phenotyping in a prospective cohort of 195 patients with sporadic late-onset cerebellar ataxia.
Results
After a mean disease duration of 6.4 years, 111 patients were not meeting criteria for MSA-C while 24 and 60 patients had a final diagnosis of possible and probable MSA-C, respectively. 16 patients carried an
FGF14
(GAA)
≥250
expansion in the group not meeting MSA-C criteria (14.4%), 3 patients in the possible MSA-C group (12.5%), but none among probable MSA-C cases. SCA27B patients were evolving more slowly than probable MSA-C patients.
Conclusions
FGF14
(GAA)
≥250
expansion may account for MSA look-alike cases and should be screened among slow progressors.
Bardet-Biedl syndrome (BBS; MIM 209900) is a rare ciliopathy characterized by retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. ...Mutations in 22 BBS genes have been identified to cause the disease. We report a family with typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, cognitive impairment, and atrioventricular septal defect) mutated in
. IFT27 is part of the Intraflagellar transport (IFT), a bidirectional mechanism allowing the protein motility within the cilia. Using whole exome sequencing, two compound heterozygous mutations were found in the proband (NM_006860.4:c.104A > G;349+1G > T, p.Tyr35Cys;?) consistent with the expected autosomal recessive inheritance mode. These two mutations have already been reported but independently in other families and lacking either familial segregation or functional validation. This is the third report of
mutations in BBS patients confirming
as a BBS gene (
). Mutations in IFT genes (
and
) confirm the IFT-pathway as a pathomechanism for BBS.
Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high‐genetic heterogeneity. Among the many genes involved, either in isolated or ...syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole‐exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients’ fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrate a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.
In this study, we report the confirmation of IQCE as a gene whose defects cause isolated postaxial polydactyly. Whole‐exome sequencing has been applied to three families and revealed biallelic pathogenic variations in IQCE. Further functional analysis using the patient's cells (skin fibroblast) revealed no effect on the formation of the cilia but a mislocalization of the EVC2 and a defective hedgehog signaling. Zebrafish experiments demonstrated a full spectrum of phenotypes associated with defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects.
Bardet‐Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the ...molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid‐specific SINE‐R/VNTR/Alu type F (SVA‐F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD‐SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient‐derived cell lines confirmed that the BBS1 SVA‐F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
Alors que le groupe des gènes associés aux dyskinésies paroxystiques kinésigéniques (PKD) est en expansion, la cause moléculaire reste insaisissable dans plus de 50 % des cas.
Identifier les causes ...génétiques manquantes de PKD.
Caractérisation phénotypique, séquençage de l’exome et test d’association entre variants rares dans KNCK10 et PKD ont été réalisés à partir d’une cohorte de 53 cas de PKD.
Nous avons identifié 4 variants causaux dans KCNJ10, gène déjà associé au syndrome EAST. Un variant homozygote p. (Ile209Thr) a été trouvé chez deux frères d’une même famille de PKD autosomique récessive. Des variants hétérozygotes p. (Cys294Tyr) et p. (Thr178Ile) ont été trouvés chez 6 patients issus de deux familles de PKD autosomiques dominantes. Le variant hétérozygote p. (Arg180His) a été identifié chez un cas sporadique de PKD (Fig. 1–3).
En comparaison à GnomADv2.1.1, notre cohorte de patients PKD était significativement enrichie en variants faux-sens rares hétérozygotes (odds ratio=21,6, p=9,7×10^-8) et homozygotes (odds ratio=2047, p=1,65×10^-6) dans KCNJ10.
Nous avons démontré que les variants faux-sens rares monoalléliques et bialléliques dans KCNJ10 sont associés aux PKD.
Une expansion hétérozygote GAA dans le gène FGF14 a été liée à une ataxie cérébelleuse autosomique dominante (SCA27B-MIM:620174). Il reste à déterminer si elle représente une cause fréquente d’ataxie ...cérébelleuse sporadique d’apparition tardive (SLOCA).
Estimer la prévalence, caractériser le spectre phénotypique, identifier les caractéristiques discriminantes et modéliser la progression longitudinale de SCA27B dans une cohorte prospective de patients SLOCA.
Dépistage des expansions GAA dans FGF14 combiné à un phénotypage profond longitudinal dans une cohorte prospective de 118 patients SLOCA (apparition>40 ans, pas d’antécédents familiaux d’ataxie cérébelleuse) sans diagnostic définitif.
La prévalence de SCA27B était de 12,7 % (15/118). Un âge d’apparition plus élevé, un score fonctionnel de dégénérescence spinocérébelleuse plus élevé, la présence de vertiges, de diplopie, de nystagmus, l’absence d’hypotension orthostatique et une neuropathie sensorimotrice étaient significativement associés à SCA27B. La progression de l’ataxie était ≈0,4 points par an sur l’échelle d’évaluation de l’ataxie (SARA) (Fig. 1).
La progression de SCA27B semble être lente, conduisant à des échantillons de taille élevée pour détecter des différences significatives dans essais interventionnels prolongés en groupes parallèles. Cela souligne la nécessité d’identifier des critères d’évaluation de substitution pour faciliter la démonstration de l’effet du traitement à court terme, incluant la neuroimagerie ou des biomarqueurs dérivés du sang.
L’expansion GAA dans FGF14 est une cause majeure de SLOCA. Nos données d’histoire naturelle préparent de futurs essais cliniques sur SCA27B.
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