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PloS One 2019Mutations in EFTUD2 are responsible for the autosomal dominant syndrome named MFDM (mandibulofacial dysostosis with microcephaly). However, it is not clear how reduced...
Mutations in EFTUD2 are responsible for the autosomal dominant syndrome named MFDM (mandibulofacial dysostosis with microcephaly). However, it is not clear how reduced levels of EFTUD2 cause abnormalities associated with this syndrome. To determine if the mouse can serve as a model for uncovering the etiology of abnormalities found in MFDM patients, we used in situ hybridization to characterize expression of Eftud2 during mouse development, and used CRISPR/Cas9 to generate a mutant mouse line with deletion of exon 2 of the mouse gene. We found that Eftud2 was expressed throughout embryonic development, though its expression was enriched in the developing head and craniofacial regions. Additionally, Eftud2 heterozygous mutant embryos had reduced EFTUD2 mRNA and protein levels. Moreover, Eftud2 heterozygous embryos were born at the expected Mendelian frequency, and were viable and fertile despite being developmentally delayed. In contrast, Eftud2 homozygous mutant embryos were not found post-implantation but were present at the expected Mendelian frequency at embryonic day (E) 3.5. Furthermore, only wild-type and heterozygous E3.5 embryos survived ex vivo culture. Our data indicate that Eftud2 expression is enriched in the precusor of structures affected in MFDM patients and show that heterozygous mice carrying deletion of exon 2 do not model MFDM. In addition, we uncovered a requirement for normal levels of Eftud2 for survival of pre-implantation zygotes.
Topics: Abnormalities, Multiple; Animals; Embryo Implantation; Female; Humans; Loss of Function Mutation; Male; Mandibulofacial Dysostosis; Mice; Mice, Inbred C57BL; Microcephaly; Mutation; Peptide Elongation Factors; Phenotype; Pregnancy; Ribonucleoprotein, U5 Small Nuclear; Sequence Deletion
PubMed: 31276534
DOI: 10.1371/journal.pone.0219280 -
Journal of Medical Genetics Dec 2015In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog...
BACKGROUND
In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings.
METHODS
In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients.
RESULTS
We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune-Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function.
CONCLUSIONS
Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis.
Topics: Abnormalities, Multiple; Animals; Base Sequence; Cell Cycle Proteins; Cells, Cultured; Cerebellum; Chickens; Child; Child, Preschool; Cilia; DNA Mutational Analysis; Ellis-Van Creveld Syndrome; Eye Abnormalities; Female; Fibroblasts; Frameshift Mutation; Gene Expression; Humans; Kidney Diseases, Cystic; Male; Pedigree; Primary Cell Culture; Retina
PubMed: 26386044
DOI: 10.1136/jmedgenet-2015-103316 -
Cold Spring Harbor Molecular Case... Dec 2022Biallelic pathogenic variants in are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized...
Biallelic pathogenic variants in are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cytoplasmic Dyneins; Exome Sequencing; Mutation; Polydactyly; Ribs; RNA, Messenger; Short Rib-Polydactyly Syndrome
PubMed: 36442996
DOI: 10.1101/mcs.a006254 -
Human Mutation Oct 2015We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo...
GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.
We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.
Topics: Abnormalities, Multiple; Adolescent; Child; Craniofacial Abnormalities; Databases, Genetic; Genetic Predisposition to Disease; Heterogeneous-Nuclear Ribonucleoprotein K; Humans; Information Dissemination; Intellectual Disability; Male; Muscular Atrophy; Phenotype; Polymorphism, Single Nucleotide; Ribonucleoproteins; Software; Web Browser
PubMed: 26173930
DOI: 10.1002/humu.22837 -
Case Reports in Pulmonology 2015Short-rib polydactyly syndrome is an autosomal recessively inherited lethal skeletal dysplasia. The syndrome is characterized by marked narrow fetal thorax, short...
Short-rib polydactyly syndrome is an autosomal recessively inherited lethal skeletal dysplasia. The syndrome is characterized by marked narrow fetal thorax, short extremities, micromelia, cleft palate/lip, polydactyly, cardiac and renal abnormalities, and genital malformations. In cases with pulmonary hypoplasia, persistent pulmonary hypertension of the newborn can develop. In this paper, we present a term newborn with persistent pulmonary hypertension of the newborn, which has developed secondary to short-rib polydactyly syndrome and was resistant to therapy with inhaled nitric oxide and oral sildenafil.
PubMed: 26078906
DOI: 10.1155/2015/274639 -
The Journal of Clinical Investigation Mar 2017Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30%...
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.
Topics: Aldehyde-Lyases; Animals; Cell Line; Cell Movement; Drosophila Proteins; Drosophila melanogaster; Female; Humans; Ichthyosis, Lamellar; Male; Mesangial Cells; Mice; Mice, Knockout; Mutation; Nephrotic Syndrome; Protein Transport; Rats
PubMed: 28165339
DOI: 10.1172/JCI89626 -
Clinical Genetics Aug 2017The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically...
The short-rib polydactyly syndromes (SRPS) are autosomal recessively inherited, genetically heterogeneous skeletal ciliopathies. SRPS phenotypes were historically categorized as types I-IV, with type I first delineated by Saldino and Noonan in 1972. Characteristic findings among all forms of SRP include short horizontal ribs, short limbs and polydactyly. The SRP type I phenotype is characterized by a very small thorax, extreme micromelia, very short, poorly mineralized long bones, and multiple organ system anomalies. To date, the molecular basis of this most severe type of SRP, also known as Saldino-Noonan syndrome, has not been determined. We identified three SRP cases that fit the original phenotypic description of SRP type I. In all three cases, exome sequence analysis revealed compound heterozygosity for mutations in DYNC2H1, which encodes the main component of the retrograde IFT A motor, cytoplasmic dynein 2 heavy chain 1. Thus SRP type I, II, III and asphyxiating thoracic dystrophy (ATD), which also result from DYNC2H1 mutations. Herein we describe the phenotypic features, radiographic findings, and molecular basis of SRP type I.
Topics: Cytoplasmic Dyneins; Ellis-Van Creveld Syndrome; Female; Fetus; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Infant, Newborn; Mutation; Phenotype; Pregnancy; Radiography; Short Rib-Polydactyly Syndrome; Exome Sequencing
PubMed: 27925158
DOI: 10.1111/cge.12947 -
Human Molecular Genetics Sep 2016The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened...
The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.
Topics: Abnormalities, Multiple; Cilia; Exome; Female; Hedgehog Proteins; Humans; Infant; MAP Kinase Signaling System; Pedigree; Pregnancy; Protein Serine-Threonine Kinases; Sequence Analysis, DNA; Short Rib-Polydactyly Syndrome; Signal Transduction; Skeleton
PubMed: 27466187
DOI: 10.1093/hmg/ddw240 -
Tremor and Other Hyperkinetic Movements... 2019Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging.
BACKGROUND
Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging.
CASE REPORT
We report a patient with Tourette syndrome (TS), who presented with abrupt tic increase and mild generalized headache 9 years after DBS implantation. On the suspicion of a hardware defect, a fracture of the DBS electrode and extension lead was ruled out by radiography and standard implantable pulse generator readouts. Further investigation revealed position-dependent modifiable therapeutic impedances, suggesting an impaired contact of the extension lead/adaptor. After replacement normal impedances were recorded, and the patient fully recovered.
DISCUSSION
In DBS dysfunction with inconspicuous hardware check, position-dependent defects might be suspected.
Topics: Adult; Deep Brain Stimulation; Electrodes, Implanted; Humans; Male; Postoperative Complications; Tourette Syndrome
PubMed: 31709126
DOI: 10.7916/tohm.v0.713 -
Molecular Genetics & Genomic Medicine Jan 2020This study reports the genetic features of four Caucasian males from the Saguenay-Lac-St-Jean region affected by partial agenesis of the corpus callosum (ACC) with...
BACKGROUND
This study reports the genetic features of four Caucasian males from the Saguenay-Lac-St-Jean region affected by partial agenesis of the corpus callosum (ACC) with hypotonia, epilepsy, developmental delay, microcephaly, hypoplasia, and autistic behavior.
METHODS
We performed whole exome sequencing (WES) to identify new genes involved in this pathological phenotype. The regions of interest were subsequently sequenced for family members.
RESULTS
Single-nucleotide variations (SNVs) and insertions or deletions were detected in genes potentially implicated in brain defects observed in these patients. One patient did not have mutations in genes related to ACC, but carried a de novo pathogenic mutation in Mucolipin-1 (MCOLN1) and was diagnosed with mucolipidosis type IV. Among the other probands, missense SNVs were observed in DCLK2 (Doublecortin Like Kinase 2), HERC2 (HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 2), and KCNH3 (Potassium channel, voltage-gated, subfamily H, member 3). One patient also carried a non-frameshift insertion in CACNA1A (Cav2.1(P/Q-type) calcium channels).
CONCLUSION
Although no common genetic defect was observed in this study, we provide evidence for new avenues of investigation for ACC, such as molecular pathways involving HERC2, CACNA1A, KCNH3, and more importantly DCLK2. We also allowed to diagnose an individual with mucolipidosis type IV.
Topics: Adolescent; Adult; Agenesis of Corpus Callosum; Calcium Channels; Developmental Disabilities; Doublecortin-Like Kinases; Epilepsy; Ether-A-Go-Go Potassium Channels; Exome; Humans; Male; Microcephaly; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Syndrome; Transient Receptor Potential Channels; Ubiquitin-Protein Ligases
PubMed: 31578829
DOI: 10.1002/mgg3.992