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Genome Biology Nov 2016Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically...
BACKGROUND
Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.
RESULTS
We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their "mutation load" beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population.
CONCLUSIONS
Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.
Topics: Alleles; Cilia; Ciliary Motility Disorders; Ciliopathies; DNA Mutational Analysis; Encephalocele; Genetic Association Studies; Genetic Heterogeneity; Genetic Predisposition to Disease; Humans; Mutation; Phenotype; Polycystic Kidney Diseases; Retina; Retinitis Pigmentosa
PubMed: 27894351
DOI: 10.1186/s13059-016-1099-5 -
Human Genome Variation 2015Mutations in KIF7, the gene that encodes a component of the kinesin complex of anterograde intraflagellar transport in the cilia, have been reported to cause a range of... (Review)
Review
Mutations in KIF7, the gene that encodes a component of the kinesin complex of anterograde intraflagellar transport in the cilia, have been reported to cause a range of phenotypes including hydrolethalis, acrocallosal syndrome and Joubert syndrome. In a cohort of patients with various neurogenetic phenotypes, we identified novel KIF7 mutations in two families that span the known phenotypic spectrum of KIF7-related disorders. Surprisingly, we also identified a novel truncating KIF7 mutation in a third consanguineous family, in which the index presented with intellectual disability but no overt signs of ciliopathy, and his brain magnetic resonance imaging revealed an isolated dysgenesis of corpus callosum. This small cohort contributes novel pathogenic alleles of KIF7 and suggests that KIF7-related phenotypes can include isolated dysgenesis of corpus callosum with intellectual disability, thus expanding the range of phenotypes that warrant sequencing of this gene.
PubMed: 27081521
DOI: 10.1038/hgv.2015.6 -
Orphanet Journal of Rare Diseases Apr 2008The Greig cephalopolysyndactyly syndrome (GCPS) is a pleiotropic, multiple congenital anomaly syndrome. It is rare, but precise estimates of incidence are difficult to... (Review)
Review
The Greig cephalopolysyndactyly syndrome (GCPS) is a pleiotropic, multiple congenital anomaly syndrome. It is rare, but precise estimates of incidence are difficult to determine, as ascertainment is erratic (estimated range 1-9/1,000,000). The primary findings include hypertelorism, macrocephaly with frontal bossing, and polysyndactyly. The polydactyly is most commonly preaxial of the feet and postaxial in the hands, with variable cutaneous syndactyly, but the limb findings vary significantly. Other low frequency findings include central nervous system (CNS) anomalies, hernias, and cognitive impairment. GCPS is caused by loss of function mutations in the GLI3 transcription factor gene and is inherited in an autosomal dominant pattern. The disorder is allelic to the Pallister-Hall syndrome and one form of the acrocallosal syndrome. Clinical diagnosis is challenging because the findings of GCPS are relatively non-specific, and no specific and sensitive clinical have been delineated. For this reason, we have proposed a combined clinical-molecular definition for the syndrome. A presumptive diagnosis of GCPS can be made if the patient has the classic triad of preaxial polydactyly with cutaneous syndactyly of at least one limb, hypertelorism, and macrocephaly. Patients with a phenotype consistent with GCPS (but which may not manifest all three attributes listed above) and a GLI3 mutation may be diagnosed definitively with GCPS. In addition, persons with a GCPS-consistent phenotype who are related to a definitively diagnosed family member in a pattern consistent with autosomal dominant inheritance may be diagnosed definitively as well. Antenatal molecular diagnosis is technically straightforward to perform. Differential diagnoses include preaxial polydactyly type 4, the GCPS contiguous gene syndrome, acrocallosal syndrome, Gorlin syndrome, Carpenter syndrome, and Teebi syndrome. Treatment of the disorder is symptomatic, with plastic or orthopedic surgery indicated for significant limb malformations. The prognosis for typically affected patients is excellent. There may be a slight increase in the incidence of developmental delay or cognitive impairment. Patients with large deletions that include GLI3 may have a worse prognosis. The Article is a work of the United States Government. Title 17 U.S.C 5 105 provides that copyright protection is not available for any work of the United States Government in the United States. The United States hereby grants to anyone a paid-up, nonexclusive, irrevocable worldwide license to reproduce, prepare derivative works, distribute copies to the public and perform publicly and display publicly the work, and also retains the nonexclusive right to do all of the above for or on behalf of the United States.
Topics: Abnormalities, Multiple; Brain; Diagnosis, Differential; Humans; Hypertelorism; Kruppel-Like Transcription Factors; Nerve Tissue Proteins; Prenatal Diagnosis; Prognosis; Rare Diseases; Recurrence; Risk Factors; Syndactyly; Syndrome; Zinc Finger Protein Gli3
PubMed: 18435847
DOI: 10.1186/1750-1172-3-10 -
Pediatric Radiology Sep 2019We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in...
We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation.
Topics: Abnormalities, Multiple; Acrocallosal Syndrome; Acrocephalosyndactylia; Brain; Child, Preschool; Female; Humans; Infant; Magnetic Resonance Imaging; Olfactory Bulb; Tomography, X-Ray Computed
PubMed: 31399769
DOI: 10.1007/s00247-019-04480-8 -
Molecular Syndromology Oct 2015Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the...
Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the hands as well as preaxial polydactyly of the feet, and developmental delay. Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog (SHH) pathway, have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome. We report here on a Tunisian boy who shows the clinical characteristics of ACLS and was found to have a novel homozygous KIF7 nonsense mutation. Further, we summarize the current knowledge about the clinical spectrum associated with KIF7 mutations as well as genetic and/or phenotypic overlap with ciliopathies and other mutations in the SHH pathway.
PubMed: 26648833
DOI: 10.1159/000439414 -
Italian Journal of Pediatrics Sep 2010Corpus callosum agenesis is a relatively common brain malformation. It can be isolated or included in a complex alteration of brain (or sometimes even whole body)... (Review)
Review
Corpus callosum agenesis is a relatively common brain malformation. It can be isolated or included in a complex alteration of brain (or sometimes even whole body) morphology. It has been associated with a number of neuropsychiatric disorders, from subtle neuropsychological deficits to Pervasive Developmental Disorders.Etiology and pathogenetic mechanisms have been better understood in recent years, due to the availability of more adequate animal models and the relevant progresses in developmental neurosciences. These recent findings are reviewed (through a MedLine search including papers published in the last 5 years and most relevant previously published papers) in view of the potential impact on children's global functioning and on the possible rehabilitative treatment, with an emphasis on the possibility to exploit brain plasticity and on the use of the ICF-CY framework.
Topics: Acrocallosal Syndrome; Brain; Chromosome Aberrations; Humans; Interpersonal Relations; Neuronal Plasticity; Social Conformity
PubMed: 20849621
DOI: 10.1186/1824-7288-36-64 -
Journal of Medical Genetics Sep 1992Acrocallosal syndrome is an autosomal recessive form of polysyndactyly associated with mental retardation and agenesis of the corpus callosum. There have been... (Comparative Study)
Comparative Study
Acrocallosal syndrome is an autosomal recessive form of polysyndactyly associated with mental retardation and agenesis of the corpus callosum. There have been suggestions that it is allelic to the Greig cephalopolysyndactyly syndrome. Linkage analysis, using flanking markers, shows this suggestion is unlikely to be correct.
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Alleles; Chromosomes, Human, Pair 7; DNA Mutational Analysis; Fingers; Genetic Markers; Hand Deformities, Congenital; Humans; Intellectual Disability; Lod Score; Pedigree; Phenotype; Syndrome
PubMed: 1404293
DOI: 10.1136/jmg.29.9.635 -
Taiwanese Journal of Obstetrics &... Mar 2008Fetuses with neural tube defects (NTDs) may be associated with syndromes, disorders, and maternal risk factors. This article provides a comprehensive review of... (Review)
Review
Fetuses with neural tube defects (NTDs) may be associated with syndromes, disorders, and maternal risk factors. This article provides a comprehensive review of syndromes, disorders, and maternal risk factors associated with NTDs, such as acrocallosal syndrome, autosomal dominant brachydactyly-clinodactyly syndrome, Manouvrier syndrome, short rib-polydactyly syndrome, Disorganization ( Ds )-like human malformations, isolated hemihyperplasia, X-linked NTDs, meroanencephaly, schisis association, diprosopus, fetal valproate syndrome, DiGeorge syndrome/velocardiofacial syndrome, Waardenburg syndrome, folic acid antagonists, diabetes mellitus, and obesity. NTDs associated with syndromes, disorders, and maternal risk factors are a rare but important cause of NTDs. The recurrence risk and the preventive effect of maternal folic acid intake in NTDs associated with syndromes, disorders, and maternal risk factors may be different from those of non-syndromic multifactorial NTDs. Perinatal identification of NTDs should alert one to the syndromes, disorders, and maternal risk factors associated with NTDs, and prompt a thorough etiologic investigation and genetic counseling.
Topics: Congenital Abnormalities; Diabetes Complications; Female; Folic Acid Antagonists; Genetic Counseling; Humans; Neural Tube Defects; Obesity; Pregnancy; Risk Factors; Syndrome; Ultrasonography, Prenatal
PubMed: 18400576
DOI: 10.1016/S1028-4559(08)60048-0 -
Iranian Journal of Child Neurology 2014The presentation of the typical characteristics of the acrocallosal syndrome (ACLS) are hypoplasia/agenesis of corpus callosum, moderate to severe mental retardation,...
The presentation of the typical characteristics of the acrocallosal syndrome (ACLS) are hypoplasia/agenesis of corpus callosum, moderate to severe mental retardation, characteristic craniofacial abnormalities, distinctive digital malformation, and growth retardation in a neonate. An Indian neonate presented on day 1 of life (youngest in the literature to be reported) with combination of abnormalities consistent with the acrocallosal syndrome and some additional findings. The baby, born to non-consanguineous, healthy parents, presented with macrocephaly, prominent forehead, hypertelorism, polydactyly of the hands and feet, duplication of hallux, hypotonia, recurrent cyanotic episodes, rib anomalies, dextro-positioning of heart, and delayed fall of umbilical cord. As the mode of inheritance of ACLS is autosomal recessive, the risk of recurrence is 25%. Genetic counselling is of prime importance, Polydactyly, and central nervous system malformations can be detected by ultrasonography in the second trimester, but due to variability of presentation, prenatal diagnosis may not always be possible.
PubMed: 24949054
DOI: No ID Found -
Journal of Medical Genetics May 1988First cousins, related through their mothers, showed a pattern of craniofacial, brain, and limb anomalies consistent with the acrocallosal syndrome. Both patients had a...
First cousins, related through their mothers, showed a pattern of craniofacial, brain, and limb anomalies consistent with the acrocallosal syndrome. Both patients had a defect of the corpus callosum, macrocephaly with a protruding forehead and occiput, hypertelorism, non-horizontal palpebral fissures, a small nose, notched ear lobes, and postaxial polydactyly of the hands. The boy, in addition, had hypospadias, cryptorchidism, inguinal hernias, duplication with syndactyly of the phalanges of the big toe, and a bipartite right clavicle. The girl had an arachnoidal cyst, a calvarian defect, and digitalisation of the thumbs. Motor and mental development was retarded in both patients. This observation provides further evidence of probable autosomal recessive inheritance of the acrocallosal syndrome and widens the spectrum of clinical findings and the variability of features in this rare malformation syndrome.
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Facial Bones; Female; Genes, Recessive; Humans; Infant; Limb Deformities, Congenital; Male; Pedigree; Phenotype; Skull; Syndrome
PubMed: 3385741
DOI: 10.1136/jmg.25.5.332