Biallelic loss-of-function variants in <i>CACHD1 </i>cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities

Purpose We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. Methods We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. Results Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. Conclusion Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities

Non-coding RNA and protein effectors of ciliary biology : identification of let-7b as a modulator of ciliogenesis and putative ciliary roles for Ataxin-7 in spinocerebellar ataxia 7

Le cil est une organelle conservée au fil de l’évolution qui se projette de presque toutes les cellules de vertébrés. Des mutations dans les gènes codant pour des protéines impliquées dans la structure ou la fonction des cils peuvent causer différentes anomalies développementales ou dégénératives, qui sont collectivement appelés ciliopathies. Les individus atteints de ciliopathies présentent une importante variabilité inter- et intra-familliale, suggérant la présence de gènes modificateurs de la pénétrance et de l’expression de la maladie. L’utilisation du poisson-zèbre comme organisme modèle permet de 1) valider le rôle du microARN let-7 comme modulateur de la ciliogenèse et ainsi de le considérer comme potentiel gène modificateurs dans les ciliopathies; et 2) d’explorer le rôle putatif de l’Ataxine-7 dans la biologie du cil et une potentielle contribution développementale à la maladie d’ataxie spinocérebelleuse 7 qui est une maladie dégénérative. Une meilleure compréhension de la biologie du cil et des ciliopathies permettrait de mieux diagnostiquer et prendre en charge les patients.Cilia are conserved organelles projecting from almost every vertebrate cell. Mutations in genes coding for proteins involved in cilia structure or function can cause different developmental and degenerative anomalies, which are collectively termed ciliopathies. Ciliopathy patients present an important inter- and intra-familial phenotypic variability, suggesting the presence of modifier genes of the penetrance and expressivity of the disease. Using the zebrafish model organism enables to 1) validate the role of the microRNA let-7 as a modulator of ciliogenesis, and thus consider it as a potential modifier gene of ciliopathies; and 2) explore the putative ciliary role of Ataxin-7 and a potential developmental contribution to spinocerebellar ataxia 7, which is a degenerative disease. A better understanding of cilia biology and ciliopathies would allow better diagnostics and care of patients

ARN non-codants et protéines effecteurs de la biologie du cil : identification du microARN let-7b comme modulateur de la ciliogenèse et rôle ciliaire putatif de l'Ataxine-7 dans l'ataxie spinocérébelleuse 7

Cilia are conserved organelles projecting from almost every vertebrate cell. Mutations in genes coding for proteins involved in cilia structure or function can cause different developmental and degenerative anomalies, which are collectively termed ciliopathies. Ciliopathy patients present an important inter- and intra-familial phenotypic variability, suggesting the presence of modifier genes of the penetrance and expressivity of the disease. Using the zebrafish model organism enables to 1) validate the role of the microRNA let-7 as a modulator of ciliogenesis, and thus consider it as a potential modifier gene of ciliopathies; and 2) explore the putative ciliary role of Ataxin-7 and a potential developmental contribution to spinocerebellar ataxia 7, which is a degenerative disease. A better understanding of cilia biology and ciliopathies would allow better diagnostics and care of patients.Le cil est une organelle conservée au fil de l’évolution qui se projette de presque toutes les cellules de vertébrés. Des mutations dans les gènes codant pour des protéines impliquées dans la structure ou la fonction des cils peuvent causer différentes anomalies développementales ou dégénératives, qui sont collectivement appelés ciliopathies. Les individus atteints de ciliopathies présentent une importante variabilité inter- et intra-familliale, suggérant la présence de gènes modificateurs de la pénétrance et de l’expression de la maladie. L’utilisation du poisson-zèbre comme organisme modèle permet de 1) valider le rôle du microARN let-7 comme modulateur de la ciliogenèse et ainsi de le considérer comme potentiel gène modificateurs dans les ciliopathies; et 2) d’explorer le rôle putatif de l’Ataxine-7 dans la biologie du cil et une potentielle contribution développementale à la maladie d’ataxie spinocérebelleuse 7 qui est une maladie dégénérative. Une meilleure compréhension de la biologie du cil et des ciliopathies permettrait de mieux diagnostiquer et prendre en charge les patients

ARN non-codants et protéines effecteurs de la biologie du cil : identification du microARN let-7b comme modulateur de la ciliogenèse et rôle ciliaire putatif de l'Ataxine-7 dans l'ataxie spinocérébelleuse 7

Cilia are conserved organelles projecting from almost every vertebrate cell. Mutations in genes coding for proteins involved in cilia structure or function can cause different developmental and degenerative anomalies, which are collectively termed ciliopathies. Ciliopathy patients present an important inter- and intra-familial phenotypic variability, suggesting the presence of modifier genes of the penetrance and expressivity of the disease. Using the zebrafish model organism enables to 1) validate the role of the microRNA let-7 as a modulator of ciliogenesis, and thus consider it as a potential modifier gene of ciliopathies; and 2) explore the putative ciliary role of Ataxin-7 and a potential developmental contribution to spinocerebellar ataxia 7, which is a degenerative disease. A better understanding of cilia biology and ciliopathies would allow better diagnostics and care of patients.Le cil est une organelle conservée au fil de l’évolution qui se projette de presque toutes les cellules de vertébrés. Des mutations dans les gènes codant pour des protéines impliquées dans la structure ou la fonction des cils peuvent causer différentes anomalies développementales ou dégénératives, qui sont collectivement appelés ciliopathies. Les individus atteints de ciliopathies présentent une importante variabilité inter- et intra-familliale, suggérant la présence de gènes modificateurs de la pénétrance et de l’expression de la maladie. L’utilisation du poisson-zèbre comme organisme modèle permet de 1) valider le rôle du microARN let-7 comme modulateur de la ciliogenèse et ainsi de le considérer comme potentiel gène modificateurs dans les ciliopathies; et 2) d’explorer le rôle putatif de l’Ataxine-7 dans la biologie du cil et une potentielle contribution développementale à la maladie d’ataxie spinocérebelleuse 7 qui est une maladie dégénérative. Une meilleure compréhension de la biologie du cil et des ciliopathies permettrait de mieux diagnostiquer et prendre en charge les patients

Non-coding RNA and protein effectors of ciliary biology : identification of let-7b as a modulator of ciliogenesis and putative ciliary roles for Ataxin-7 in spinocerebellar ataxia 7

Le cil est une organelle conservée au fil de l’évolution qui se projette de presque toutes les cellules de vertébrés. Des mutations dans les gènes codant pour des protéines impliquées dans la structure ou la fonction des cils peuvent causer différentes anomalies développementales ou dégénératives, qui sont collectivement appelés ciliopathies. Les individus atteints de ciliopathies présentent une importante variabilité inter- et intra-familliale, suggérant la présence de gènes modificateurs de la pénétrance et de l’expression de la maladie. L’utilisation du poisson-zèbre comme organisme modèle permet de 1) valider le rôle du microARN let-7 comme modulateur de la ciliogenèse et ainsi de le considérer comme potentiel gène modificateurs dans les ciliopathies; et 2) d’explorer le rôle putatif de l’Ataxine-7 dans la biologie du cil et une potentielle contribution développementale à la maladie d’ataxie spinocérebelleuse 7 qui est une maladie dégénérative. Une meilleure compréhension de la biologie du cil et des ciliopathies permettrait de mieux diagnostiquer et prendre en charge les patients.Cilia are conserved organelles projecting from almost every vertebrate cell. Mutations in genes coding for proteins involved in cilia structure or function can cause different developmental and degenerative anomalies, which are collectively termed ciliopathies. Ciliopathy patients present an important inter- and intra-familial phenotypic variability, suggesting the presence of modifier genes of the penetrance and expressivity of the disease. Using the zebrafish model organism enables to 1) validate the role of the microRNA let-7 as a modulator of ciliogenesis, and thus consider it as a potential modifier gene of ciliopathies; and 2) explore the putative ciliary role of Ataxin-7 and a potential developmental contribution to spinocerebellar ataxia 7, which is a degenerative disease. A better understanding of cilia biology and ciliopathies would allow better diagnostics and care of patients

The complexity of the cilium: spatiotemporal diversity of an ancient organelle

Cilia are microtubule-based appendages present on almost all vertebrate cell types where they mediate a myriad of cellular processes critical for development and homeostasis. In humans, impaired ciliary function is associated with an ever-expanding repertoire of phenotypically-overlapping yet highly variable genetic disorders, the ciliopathies. Extensive work to elucidate the structure, function, and composition of the cilium is offering hints that the `static' representation of the cilium is a gross oversimplification of a highly dynamic organelle whose functions are choreographed dynamically across cell types, developmental, and homeostatic contexts. Understanding this diversity will require discerning ciliary versus non-ciliary roles for classically-defined `ciliary' proteins; defining ciliary protein-protein interaction networks within and beyond the cilium; and resolving the spatiotemporal diversity of ciliary structure and function. Here, focusing on one evolutionarily conserved ciliary module, the intraflagellar transport system, we explore these ideas and propose potential future studies that will improve our knowledge gaps of the oversimplified cilium and, by extension, inform the reasons that underscore the striking range of clinical pathologies associated with ciliary dysfunction

Loss of zebrafish Ataxin-7, a SAGA subunit responsible for SCA7 retinopathy, causes ocular coloboma and malformation of photoreceptors

Polyglutamine (polyQ) expansion in Ataxin-7 (ATXN7) results in spinocerebellar ataxia type 7 (SCA7) and causes visual impairment. SCA7 photoreceptors progressively lose their outer segments (OSs), a structure essential for their visual function. ATXN7 is a subunit of the transcriptional coactivator Spt-Ada-Gcn5 Acetyltransferase complex, implicated in the development of the visual system in flies. To determine the function of ATXN7 in the vertebrate eye, we have inactivated ATXN7 in zebrafish. While ATXN7 depletion in flies led to gross retinal degeneration, in zebrafish, it primarily results in ocular coloboma, a structural malformation responsible for pediatric visual impairment in humans. ATXN7 inactivation leads to elevated Hedgehog signaling in the forebrain, causing an alteration of proximo-distal patterning of the optic vesicle during early eye development and coloboma. At later developmental stages, malformations of photoreceptors due to incomplete formation of their OSs are observed and correlate with altered expression of crx, a key transcription factor involved in the formation of photoreceptor OS. Therefore, we propose that a primary toxic effect of polyQ expansion is the alteration of ATXN7 function in the daily renewal of OS in SCA7. Together, our data indicate that ATXN7 plays an essential role in vertebrate eye morphogenesis and photoreceptor differentiation, and its loss of function may contribute to the development of human coloboma

Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G&gt;C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T&gt;C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in&nbsp;vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G&gt;A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in&nbsp;vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor

Erratum: Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations (The American Journal of Human Genetics (2017) 101(5) (789–802) (S0002929717303877) (10.1016/j.ajhg.2017.09.018))

(The American Journal of Human Genetics 101, 789–802; November 2, 2017) In the version of this paper originally published, the author's name Anna Materna-Kiryluk was incorrectly hyphenated. It appears correctly here and online. The authors apologize for this error

Betekening door een gerechtsdeurwaarder-lastgever aan de gekozen woonplaats i.c. zijn eigen kantoor: een bizarre driehoeksverhouding

(The American Journal of Human Genetics 101, 789â\u80\u93802; November 2, 2017) In the version of this paper originally published, the author's name Anna Materna-Kiryluk was incorrectly hyphenated. It appears correctly here and online. The authors apologize for this error