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Journal of Pediatric Genetics is an English multidisciplinary peer-reviewed international journal publishing articles on all aspects of genetics in childhood and of the genetics of experimental models. These topics include clinical genetics, molecular genetics, biochemical genetics, formal genetics, neuropsychiatric genetics, behavioral genetics, community genetics, cytogenetics, hereditary or syndromic cancer genetics, genetic mapping, reproductive genetics, fetal pathology and prenatal diagnosis, multiple congenital anomaly syndromes, and molecular embryology of birth defects.
Journal of Pediatric Genetics provides an in-depth update on new subjects, and current comprehensive coverage of the latest techniques in the diagnosis of childhood genetics.
Journal of Pediatric Genetics encourages submissions from all authors throughout the world.
The following articles will be considered for publication: editorials, original and review articles, short report, rapid communications, case reports, letters to the editor, and book reviews. The aim of the journal is to share and disseminate knowledge between all disciplines that work in the field of pediatric genetics.
Abstract: Ciliary chondrodysplasias represent a heterogenous group of rare, nearly exclusively autosomal recessively inherited developmental conditions. While the skeletal phenotype, mainly affecting limbs, ribs and sometimes the craniofacial skeleton, is predominant, extraskeletal disease affecting the kidneys, liver, heart, eyes and other organs and tissues is observed inconsistently. Significant lethality, resulting from cardiorespiratory failure due to thoracic constriction as well as from renal and hepatic insufficiency or primary cardiac failure due to congenital heart disease, is observed with these conditions. The underlying genetic defects as well as developmental biology and cell biology work undertaken using animal model systems, suggest that these rare…conditions result from ciliary malfunction. The skeletal phenotype is believed to result from imbalances in the hedgehog signaling pathway that normally occurs in functional cilia in chondrocytes. Although phenotypes have been historically distinguished based on clinical features into short-rib polydactyly syndrome, Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, Sensenbrenner syndrome (cranioectodermal dysplasia), oral-facial-digital syndrome and Ellis-van Creveld syndrome, recent research suggests that there is significant genetic as well as phenotypic overlap between the conditions. This review discusses ciliary chondrodysplasias from phenotypic hallmarks to clinical management and summarizes progress in identification of the underlying molecular mechanisms as well as potential future therapeutic perspectives.
Keywords: Cilia, chondrodysplasia, Jeune syndrome, short-rib polydactyly syndrome, Sensenbrenner syndrome
Abstract: Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review, we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS…variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone, and act as structural components of the so-called “ciliary gate” to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of transition zone function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cyclic adenosine monophosphate (cAMP). However, challenges remain in the interpretation of the pathogenic potential of genetic variants of unknown significance, and in the elucidation of the molecular mechanisms of phenotypic variability in JBTS and MKS. The further genetic and functional characterization of these conditions is essential to prioritize patients for new targeted therapies.
Keywords: Joubert syndrome, Meckel-Gruber syndrome, primary cilium, transition zone
Abstract: Obesity is an increasing global health problem. Although it is mainly thought to be due to the changing obesogenic environment, the genetic contribution has been estimated between 40–70%. A number of genes have been identified that cause obesity in animals as well as in humans. Rare highly penetrant monogenic forms of obesity can cause both syndromal and non-syndromal forms of obesity. Bardet-Biedl syndrome and Alström syndrome are well known monogenic obesity syndromes caused by primary cilia defects. The pathogenesis of the obesity phenotype in these disorders is however not fully understood. Disturbance of the appetite regulation system, abnormalities in body…composition and decreased energy expenditure have been suggested to cause obesity in these ciliopathies. There are currently 19 known genes associated with Bardet-Biedl syndrome and one Alström syndrome gene. Although ciliopathy genes have been described primarily in these syndromal obesity disorders, non-syndromal obesity may also result from disturbed cilia function. There are multiple genes associated with both obesity and ciliary function. Here we provide an overview of the current knowledge of the clinical, pathophysiological and genetic aspects of obesity in patients with ciliary defects.
Abstract: Autosomal recessive polycystic kidney disease (ARPKD) is a severe, typically early onset form of renal cystic disease. The care of ARPKD patients has traditionally been the purview of pediatric nephrologists for management of systemic hypertension and progressive renal insufficiency. However, the disease has multisystem manifestations and a comprehensive care strategy frequently requires a multidisciplinary team. In severely affected infants, the diagnosis often is first suspected by obstetricians when enlarged, echogenic kidneys and oligohydramnios are detected on prenatal ultrasounds. Neonatologists are central to the care of these infants, who may have respiratory compromise due to pulmonary hypoplasia and massively enlarged kidneys.…Among neonatal survivors, a subset of ARPKD patients has clinically significant congenital hepatic fibrosis, which can lead to portal hypertension, requiring close monitoring by pediatric hepatologists. Surgical consultation may be sought to access pre-emptive nephrectomy to relieve mass effect, placement of dialysis access, surgical shunting procedures, and kidney and/or liver transplantation. Recent data suggest that children with ARPKD may be at risk of neurocognitive dysfunction, and may require neuropsychological referral. In addition to these morbidities, families of patients with ARPKD face decisions regarding genetic testing of affected children, testing of asymptomatic siblings, or consideration of preimplantation genetic diagnosis for future pregnancies. These issues require the input of genetic counselors, geneticists, and reproductive endocrinologists. As a result, the management of ARPKD requires the involvement of multiple subspecialists, as well as the general pediatrician, in a complex care network. In this review, we discuss the genetics of this disorder and provide an overview of the associated pathobiology; outline the spectrum of clinical manifestations of ARPKD and the management of organ-specific complications; discuss other disorders that involve genes encoding cilia-associated proteins that can clinically mimic ARPKD; review the animal models available for preclinical studies; and finally, consider future directions for potential targeted therapies.
Abstract: Nephronophthisis (NPHP) is a childhood cystic kidney disease, which almost invariably leads to end-stage renal disease in those affected. Recognition and diagnosis requires clinical suspicion, biochemical evaluation, renal imaging and historically, renal biopsy. Modern molecular genetics now allows a diagnosis to be made in a significant proportion of cases. Mutations in NPHP1 account for 20% of cases, but the disease is genetically heterogeneous with at least 20 different genes associated with NPHP. Recent developments in the fields of genetics and proteomics have led to increased understanding of the underlying pathogenetic defects. Almost all NPHP genes encode proteins, which localize to…the primary cilia, basal body and centrosome. NPHP is a therefore considered to be a ciliopathy, and can be part of a broad spectrum of clinical disease that includes extra-renal manifestations including retinal degeneration, cerebellar ataxia, liver fibrosis and situs inversus. In this review, we discuss the historical descriptions of NPHP in the context of more recent developments in our understanding of this disease.
Abstract: Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder affecting motile cilia. This can lead to neonatal respiratory distress, early onset upper and lower airway infections, laterality abnormalities and sub- or infertility. Although disease progression shows large individual variability, all adult patients eventually develop extensive bronchiectasis. As in cystic fibrosis, early diagnosis and frequent follow-up with microbiological control is the best therapeutic strategy, as other treatment options are lacking. PCD is underdiagnosed and diagnosed late due to clinical unawareness, limited availability of diagnostic tests and difficult interpretation of test results. Diagnosis is currently based on a combination of assessment…of ciliary motion and ultrastructure by high-speed video microscopy and electron microscopy, respectively. As nasal nitric oxide is low in almost all PCD patients, these measurements can be used for screening. Although there are 26 PCD genes known so far, the genetic basis of the disease has not been unraveled in an estimated 30–40% of patients. However, the rapid discovery of novel PCD genes in recent years is expected to enable accurate genetic characterization of most patients in the near future. Large-scale use of next-generation sequencing and the availability of large ciliary proteomic and transcriptomic databases accelerate the identification of novel PCD genes, especially those that play a key role in cytoplasmic assembly of ciliary ultrastructural components. These genetic advances are revolutionizing the process of obtaining a molecular diagnosis for PCD as we speak and may ultimately lead to an increased understanding of ciliogenesis and function, providing novel handles for therapeutic interventions in PCD patients.
Abstract: The primary cilium is a highly conserved cell organelle that is closely connected to processes involved in cell patterning and replication. Amongst their many functions, cilia act as “signal towers” through which cell-cell signaling cascades pass. Dysfunction of cilia or the myriad processes that are connected with cilium function can lead to disease. Due to the sheer number of cellular processes that at some point involve the primary cilium, the effects of misregulation are highly heterogeneous between different cell populations. However, because of the importance of primary cilia in the development, growth, patterning and orientation of cells and tissues, a…common thread has emerged in which defective cilia can lead to disorganization, which can contribute to the growth of neoplasms, including cancer and pre-cancerous phenotypes. Because cilia are so vital for signaling during cell replication and the cell fate decisions that are important in childhood growth, symptoms often arise early in life. Here we review recent work connecting misregulation of the primary cilium with tumor formation in a variety of tissues in the developing body, with a particular focus on the syndromes in which classic tumor genes are mutated, including von Hippel-Lindau disease (OMIM 193300), adenomatous polyposis coli (OMIM 175100), tuberous sclerosis (OMIM 191100) and Birt-Hogg-Dubé syndrome (OMIM 135150). Timely diagnosis of these syndromes is essential for entry into appropriate screening protocols, which have been shown to effectively prolong life expectancy in these cohorts of patients.
Keywords: Cilia, von Hippel-Lindau disease, cyst, renal cell carcinoma, medulloblastoma