RESUMO
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.
Assuntos
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
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.
Assuntos
Anormalidades Múltiplas/genética , Osso e Ossos/anormalidades , Encefalopatias/genética , Ciliopatias/genética , Craniossinostoses/genética , Displasia Ectodérmica/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Proteínas/genética , Anormalidades Múltiplas/patologia , Adolescente , Osso e Ossos/patologia , Encefalopatias/complicações , Encefalopatias/patologia , Criança , Ciliopatias/complicações , Ciliopatias/patologia , Craniossinostoses/complicações , Craniossinostoses/patologia , Proteínas do Citoesqueleto , Displasia Ectodérmica/complicações , Displasia Ectodérmica/patologia , Feminino , Proteínas Hedgehog , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , FenótipoRESUMO
Since most short-rib polydactyly phenotypes are due to genes involved with biogenesis and maintenance of the primary cilium, this group of skeletal dysplasias was recently designated as ciliopathies with major skeletal involvement. Beemer-Langer syndrome or short-rib polydactyly type IV, was first described in 1983, and has, thus far, remained without a defined molecular basis. The most recent classification of the skeletal dysplasias referred to this phenotype as an as-yet unproven ciliopathy. IFT122 is a gene that encodes a protein responsible for the retrograde transport along the cilium; it has been associated with this group of skeletal dysplasias. To date, mutations in this gene were only found in Sensenbrenner syndrome. Using a panel of skeletal dysplasias genes, including 11 related to SRP, we identified biallelic mutations in IFT122 ([c.3184G>C];[c.3228dupG;c.3231_3233delCAT]) in a fetus with a typical phenotype of SRP-IV, finally confirmed that this phenotype is a ciliopathy and adding to the list of ciliopathies with major skeletal involvement.
Assuntos
Ciliopatias/genética , Polidactilia/genética , Proteínas/genética , Síndrome de Costela Curta e Polidactilia/genética , Proteínas Adaptadoras de Transdução de Sinal , Alelos , Osso e Ossos/anormalidades , Osso e Ossos/fisiopatologia , Ciliopatias/fisiopatologia , Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Proteínas do Citoesqueleto , Displasia Ectodérmica/genética , Displasia Ectodérmica/fisiopatologia , Feto , Humanos , Recém-Nascido , Mutação , Polidactilia/fisiopatologia , Síndrome de Costela Curta e Polidactilia/fisiopatologiaRESUMO
ã We report on an infant with Opitz trigonocephaly C syndrome (OTCS), who also had manifestations of ciliopathy, including short ribs (non-asphyxiating), trident acetabular roofs, postaxial polydactyly cone-shaped epiphyses, and dysplasia of the renal, hepatic and pancreatic tissues. To investigate the molecular cause, we used an exome sequencing strategy followed by Sanger sequencing. Two rare variants, both predicted to result in loss of functional protein, were identified in the IFT140 gene; a substitution at the splice donor site of exon 24 (c.723 + 1 G > T) and a 17 bp deletion, impacting the first coding exon (c.-11_6del). The variants were confirmed as being biallelic using Sanger sequencing, showing that the splice variant was inherited from the propositus mother and the deletion from the father. To date, Mainzer-Saldino syndrome, Jeune syndrome, and a form of nonsyndromic retinal dystrophy, have been identified as ciliopathies caused by IFT140 mutations. We provide the first description of an OTCS phenotype that appears to result from IFT140 mutations. The presentation of this patient is consistent with previous reports showing that OTCS already exhibited skeleletal and nonskeletal features of a ciliopathy.