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KIAA0586 variants have been associated with a wide range of ciliopathies, mainly Joubert syndrome (JS, OMIM #616490) and short-rib thoracic dysplasia syndrome (SRTD, OMIM #616546). However, the hypothesis that this gene is involved with hydrolethalus syndrome (HSL, OMIM #614120) and orofaciodigital syndrome IV (OMIM #258860) has already been raised. Ciliopathies' clinical features are often overlapped despite differing in phenotype severity. Besides KIAA0586, HYLS1 and KIF7 are also known for being causative of ciliopathies, indicating that all three genes may have similar or converging genomic pathways. Overall, the genotypic and phenotypic spectrum of ciliopathies becomes wider and conflicting while more and more new variants are added to this group of disorders' molecular pot. In this case report we discuss the first Brazilian individual clinically diagnosed with hydrolethalus syndrome and molecular findings that demonstrate the role of KIAA0586 as a causative gene of a group of genetic disorders. Also, recent reports on individuals with intronic and exonic variants combined leading to ciliopathies support our patient's molecular diagnosis. At the same time, we discuss variable expressivity and overlapping features in ciliopathies.
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Anormalidades Múltiplas , Cerebelo , Anormalidades do Olho , Doenças Renais Císticas , Fenótipo , Retina , Humanos , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Anormalidades Múltiplas/genética , Retina/anormalidades , Retina/patologia , Retina/metabolismo , Cerebelo/anormalidades , Cerebelo/patologia , Ciliopatias/genética , Masculino , Mutação , Feminino , Proteínas de Ciclo CelularRESUMO
Introduction: Primary ciliary dyskinesia (PCD) is a rare genetic disorder that can result in significant morbidity and mortality if left untreated. Clinical manifestations of PCD include recurrent respiratory infections, laterality defects, and infertility, all of which arise from impaired or absent ciliary motility. Diagnostic approaches for PCD may include high-speed video microscopy, measurement of nasal nitric oxide levels, and genetic testing; however, no single definitive diagnostic test exists. The present study aims to highlight the lack of standardized diagnostic and treatment guidelines for PCD in Latin America (Central and South America, and the Caribbean). To this effect, we compared North American and European recommendations for the diagnosis and management of PCD and found that certain diagnostic tools and treatment options mentioned in these guidelines are not readily accessible in many Latin American countries. Methods & Results: This review gathers disease information in North America, Europe, and Latin America organizing guideline results into tables for clarity and potential interventions. Management information for Latin America is inferred from case reports, as most findings are from North American recommendations and studies on PubMed, Google Scholar, and Scopus. Treatment and management information is based on North American and European standards.Among 5,774 publications reviewed, only 15 articles met the inclusion criteria (focused on PCD management, peer-reviewed, and located in America). No clinical guideline for PCD in Latin America was found, but recommendations on respiratory management from Colombia and Chile were discovered. The lack of guidelines in Latin America may originate from limited resources and research on the disease in those countries. Discussion: PCD lacks documentation, research, and recommendations regarding its prevalence in Latin America, likely due to unfavorable economic conditions. This disadvantage results in limited access to diagnostic tests available in North America and Europe. The PICADAR score, discussed in this review, can be used in low-income nations as a screening tool for the disorder.
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BACKGROUND: Ellis-van Creveld syndrome (EvCS) is an autosomal recessive ciliopathy with a disproportionate short stature, polydactyly, dystrophic nails, oral defects, and cardiac anomalies. It is caused by pathogenic variants in the EVC or EVC2 genes. To obtain further insight into the genetics of EvCS, we identified the genetic defect for the EVC2 gene in two Mexican patients. METHODS: Two Mexican families were enrolled in this study. Exome sequencing was applied in the probands to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in the parents. Finally, a prediction of the three-dimensional structure of the mutant proteins was made. RESULTS: One patient has a compound heterozygous EVC2 mutation: a novel heterozygous variant c.519_519 + 1delinsT inherited from her mother, and a heterozygous variant c.2161delC (p.L721fs) inherited from her father. The second patient has a previously reported compound heterozygous EVC2 mutation: nonsense mutation c.645G > A (p.W215*) in exon 5 inherited from her mother, and c.273dup (p.K92fs) in exon 2 inherited from her father. In both cases, the diagnostic was Ellis-van Creveld syndrome. Three-dimensional modeling of the EVC2 protein showed that truncated proteins are produced in both patients due to the generation of premature stop codons. CONCLUSION: The identified novel heterozygous EVC2 variants, c.2161delC and c.519_519 + 1delinsT, were responsible for the Ellis-van Creveld syndrome in one of the Mexican patients. In the second Mexican patient, we identified a compound heterozygous variant, c.645G > A and c.273dup, responsible for EvCS. The findings in this study extend the EVC2 mutation spectrum and may provide new insights into the EVC2 causation and diagnosis with implications for genetic counseling and clinical management.
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Síndrome de Ellis-Van Creveld , Proteínas de Membrana , Humanos , Feminino , Proteínas de Membrana/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/diagnóstico , Linhagem , Mutação , Códon sem SentidoRESUMO
The identification of new proteins that regulate the function of one of the main cellular phosphatases, protein phosphatase 1 (PP1), is essential to find possible pharmacological targets to alter phosphatase function in various cellular processes, including the initiation and development of multiple diseases. IIIG9 is a regulatory subunit of PP1 initially identified in highly polarized ciliated cells. In addition to its ciliary location in ependymal cells, we recently showed that IIIG9 has extraciliary functions that regulate the integrity of adherens junctions. In this review, we perform a detailed analysis of the expression, localization, and function of IIIG9 in adult and developing normal brains. In addition, we provide a 3D model of IIIG9 protein structure for the first time, verifying that the classic structural and conformational characteristics of the PP1 regulatory subunits are maintained. Our review is especially focused on finding evidence linking IIIG9 dysfunction with the course of some pathologies, such as ciliopathies, drug dependence, diseases based on neurological development, and the development of specific high-malignancy and -frequency brain tumors in the pediatric population. Finally, we propose that IIIG9 is a relevant regulator of PP1 function in physiological and pathological processes in the CNS.
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Neoplasias , Proteína Fosfatase 1 , Criança , Humanos , Encéfalo/metabolismo , Proteína Fosfatase 1/metabolismo , Proteínas/metabolismoRESUMO
La nefronoptisis es una enfermedad renal quística, de herencia autosómica recesiva, causada por mutaciones en genes que codifican proteínas involucradas en la función de cilios primarios, lo que resulta en enfermedad renal y manifestaciones extrarrenales como degeneración retiniana y fibrosis hepática. Según la edad de desarrollo de enfermedad renal crónica terminal, se describen tres formas clínicas de presentación: infantil, juvenil y adolescente. El diagnóstico se realiza por una prueba genética positiva o una biopsia de riñón que demuestre cambios tubulointersticiales crónicos con un engrosamiento de las membranas basales tubulares. No existe hasta la actualidad una terapia curativa, por lo que el trasplante renal oportuno es determinante en cuanto al pronóstico. Se presenta un paciente de 13 meses de edad con poliuria de 3 meses de evolución, insuficiencia renal, anemia y elevación de transaminasas. Con hallazgos histológicos compatibles en la biopsia renal, se arribó al diagnóstico de nefronoptisis infantil, con afectación hepática
Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis. According to the age of development of end-stage chronic kidney disease, three clinical forms of presentation are described: infantile, juvenile and adolescent. Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes. At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis.We present a 13-month old male patient with polyuria, kidney failure, anemia and elevated aminotransferases over three months. With compatible histological kidney biopsy, the diagnosis of infantile nephronophthisis with liver involvement was reached.
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Humanos , Masculino , Lactente , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Nefropatias , Falência Renal Crônica/genética , Proteínas , Testes GenéticosRESUMO
Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis. According to the age of development of end-stage chronic kidney disease, three clinical forms of presentation are described: infantile, juvenile and adolescent. Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes. At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis. Nefronoptisis: reporte de un caso pediátrico Nephronophthisis: a pediatric case report We present a 13-month old male patient with polyuria, kidney failure, anemia and elevated aminotransferases over three months. With compatible histological kidney biopsy, the diagnosis of infantile nephronophthisis with liver involvement was reached.
La nefronoptisis es una enfermedad renal quística, de herencia autosómica recesiva, causada por mutaciones en genes que codifican proteínas involucradas en la función de cilios primarios, lo que resulta en enfermedad renal y manifestaciones extrarrenales como degeneración retiniana y fibrosis hepática. Según la edad de desarrollo de enfermedad renal crónica terminal, se describen tres formas clínicas de presentación: infantil, juvenil y adolescente. El diagnóstico se realiza por una prueba genética positiva o una biopsia de riñón que demuestre cambios tubulointersticiales crónicos con un engrosamiento de las membranas basales tubulares. No existe hasta la actualidad una terapia curativa, por lo que el trasplante renal oportuno es determinante en cuanto al pronóstico. Se presenta un paciente de 13 meses de edad con poliuria de 3 meses de evolución, insuficiencia renal, anemia y elevación de transaminasas. Con hallazgos histológicos compatibles en la biopsia renal, se arribó al diagnóstico de nefronoptisis infantil, con afectación hepática.
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Doenças Renais Císticas , Nefropatias , Falência Renal Crônica , Adolescente , Criança , Feminino , Testes Genéticos , Humanos , Lactente , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Falência Renal Crônica/genética , Masculino , ProteínasRESUMO
Oro-facial-digital syndrome is a group of rare heterogeneous hereditary disorders characterized by abnormalities of the oral cavity, face and digits, along with varying degrees of mental retardation. Currently, Oro-facial-digital syndrome has been classified into 14 types and two additional unclassified variants have been proposed. Amongst the various variants described, Oro-facial-digital syndrome type I is the most common. We report an interesting subclinical sporadic case of Oro-facial-digital syndrome type I in a 21-year-old female patient. Interestingly, our patient presented with a few novel hitherto unreported clinical findings like midline pits in the philtrum area and a hamartomatous proliferation of tissue in the anterior maxillary alveolar gingival region. This case report highlights the importance of prudent histopathological-clinical correlation, which can direct the flow of clinical investigations leading to the detection and diagnosis of unsuspected conditions as learned in this case. We would also like to emphasize that comprehensive examination of new born for structural abnormalities of the orofacial region is crucial to early diagnosis of syndromes and subsequent referral for further evaluation and management.
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Oro-facial-digital syndrome is a group of rare heterogeneous hereditary disorders characterized by abnormalities of the oral cavity, face and digits, along with varying degrees of mental retardation. Currently, Oro-facial-digital syndrome has been classified into 14 types and two additional unclassified variants have been proposed. Amongst the various variants described, Oro-facial-digital syndrome type I is the most common. We report an interesting subclinical sporadic case of Oro-facial-digital syndrome type I in a 21-year-old female patient. Interestingly, our patient presented with a few novel hitherto unreported clinical findings like midline pits in the philtrum area and a hamartomatous proliferation of tissue in the anterior maxillary alveolar gingival region. This case report highlights the importance of prudent histopathological-clinical correlation, which can direct the flow of clinical investigations leading to the detection and diagnosis of unsuspected conditions as learned in this case. We would also like to emphasize that comprehensive examination of new born for structural abnormalities of the orofacial region is crucial to early diagnosis of syndromes and subsequent referral for further evaluation and management.
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Humanos , Feminino , Adulto , Neoplasias Palatinas , Hamartoma , Fissura Palatina , Diagnóstico Precoce , CiliopatiasRESUMO
Background Microcephaly and chorioretinopathy (MCCRP) is a rare neuro-ophthalmologic disorder that causes microcephaly and chorioretinopathy. In a recessive inheritance pattern, there are three types: MCCRP1; MCCRP2 and MCCRP3. MCCRP3 results from pathogenic variants in the tubulin-gamma complex-associated protein 4 (TUBGCP4) gene.Materials and Methods This is a case report of a patient with a molecular diagnosis defined by mutations in the TUBGCP4 gene. Segregation analyses were carried out.Results The molecular investigation found two heterozygous variants c.1380 G > A (p.Trp460*) a novel nonsense variant, and c.1746 G > T (p Leu582=) a synonymous variant in TUBGCP4. The clinical phenotype was characterized by microcephaly, microphthalmia, chorioretinopathy, a punched-out retinal appearance, dysmorphic facial features, decreased visual acuity, and learning difficulties. The clinical features were similar to those described previously in children with MCCRP3. The proband also had additional features including centripetal obesity, stretch marks, acanthosis nigricans, scoliosis, and hypercholesterolemia. These other features could be part of a ciliopathy syndrome.Conclusions MCCRP2 caused by pathogenic variants in PLK4 is well established as a ciliopathy disease. The role of TUBGCP4 is not well established in the cilium physiology. MCCRP3 may be part of the ciliopathy spectrum.
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Doenças da Coroide/patologia , Microcefalia/patologia , Proteínas Associadas aos Microtúbulos/genética , Mutação , Doenças Retinianas/patologia , Criança , Doenças da Coroide/genética , Feminino , Humanos , Microcefalia/genética , Fenótipo , Doenças Retinianas/genéticaRESUMO
We describe a patient severely affected with multiple congenital anomalies, including brain malformations and skeletal dysplasia suggestive of cranioectodermal dysplasia (CED) ciliopathy, who unusually carries several homozygosity tracts involving homozygous missense mutations in SPAG17 (exon 8; c.1069G > C; p.Asp357His) and WDR35 (exon 13; c.1415G > A; p.Arg472Gln) as revealed by homozygosity mapping and next generation sequencing. SPAG17 is essential for the function and structure of motile cilia, while WDR35 belongs to the same intraflagellar transport (IFT) gene family whose protein products are part of functional IFT A and B complexes. Formerly, SPAG17 was related - through polymorphic variants - to an influence on individuals' height; more recently, Spag17-/- mice models were reported to present skeletal and bone defects, reduced mucociliary clearance, respiratory distress, and cerebral ventricular enlargement. Homozygous or compound heterozygous mutations in WDR35 have mainly been related to CED2 or short-rib thoracic dysplasia 7, with only three cases showing some brain anomalies. Given that our patient presents these clinical features and the close functional relationship between SPAG17 and WDR35, it is feasible that the combined effects from both mutations contribute to his phenotype. To our knowledge, this patient is the first to harbor a likely pathogenic homozygous mutation in both genes at the same time. Thus, the resulting complex phenotype of this patient illustrates the heterogeneity associated with ciliopathies and further expands the clinical and mutational spectrum of these diseases. Finally, we highlight the combined use of high-throughput tools to diagnose and support the proper handling of this and other patients.