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1.
Am J Obstet Gynecol ; 223(6): B38-B41, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33168220

Assuntos
Síndrome de Dandy-Walker/diagnóstico por imagem , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Coartação Aórtica/diagnóstico por imagem , Coartação Aórtica/genética , Vermis Cerebelar/anormalidades , Vermis Cerebelar/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Aberrações Cromossômicas , Transtornos da Motilidade Ciliar/diagnóstico por imagem , Transtornos da Motilidade Ciliar/genética , Fossa Craniana Posterior/anormalidades , Fossa Craniana Posterior/diagnóstico por imagem , Anormalidades Craniofaciais/complicações , Anormalidades Craniofaciais/diagnóstico por imagem , Síndrome de Dandy-Walker/complicações , Síndrome de Dandy-Walker/genética , Dura-Máter/anormalidades , Dura-Máter/diagnóstico por imagem , Encefalocele/diagnóstico por imagem , Encefalocele/genética , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/genética , Feminino , Quarto Ventrículo/anormalidades , Quarto Ventrículo/diagnóstico por imagem , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/genética , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/diagnóstico por imagem , Doenças Renais Policísticas/genética , Gravidez , Prognóstico , Retina/anormalidades , Retina/diagnóstico por imagem , Retinite Pigmentosa/diagnóstico por imagem , Retinite Pigmentosa/genética , Seios Transversos/anormalidades , Seios Transversos/diagnóstico por imagem , Síndrome da Trissomía do Cromossomo 18/diagnóstico por imagem , Síndrome da Trissomía do Cromossomo 18/genética , Ultrassonografia Pré-Natal , Síndrome de Walker-Warburg/diagnóstico por imagem , Síndrome de Walker-Warburg/genética
2.
BMC Med Genet ; 21(1): 192, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004012

RESUMO

BACKGROUND: Joubert syndrome (OMIM 213300) is an autosomal recessive disorder with gene heterogeneity. Causal genes and their variants have been identified by sequencing or other technologies for Joubert syndrome subtypes. CASE PRESENTATION: A two-year-old boy was diagnosed with Joubert syndrome by global development delay and molar tooth sign of mid-brain. Whole exome sequencing was performed to detect the causative gene variants in this individual, and the candidate pathogenic variants were verified by Sanger sequencing. We identified two pathogenic variants (NM_006346.2: c.1147delC and c.1054A > G) of PIBF1 in this Joubert syndrome individual, which is consistent with the mode of autosomal recessive inheritance. CONCLUSION: In this study, we identified two novel pathogenic variants in PIBF1 in a Joubert syndrome individual using whole exome sequencing, thereby expanding the PIBF1 pathogenic variant spectrum of Joubert syndrome.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença/genética , Doenças Renais Císticas/genética , Mutação , Proteínas da Gravidez/genética , Retina/anormalidades , Fatores Supressores Imunológicos/genética , Sequenciamento Completo do Exoma/métodos , Anormalidades Múltiplas/diagnóstico , Pré-Escolar , Anormalidades do Olho/diagnóstico , Genes Recessivos , Humanos , Doenças Renais Císticas/diagnóstico , Masculino
6.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
7.
Am J Hum Genet ; 106(5): 623-631, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32275884

RESUMO

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype.


Assuntos
Alelos , Encéfalo/anormalidades , Proteínas de Drosophila/genética , Anormalidades do Olho/genética , Cardiopatias Congênitas/genética , Mutação com Perda de Função/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/metabolismo , Pré-Escolar , Dendritos/metabolismo , Dendritos/patologia , Drosophila melanogaster , Anormalidades do Olho/mortalidade , Feminino , Fibroblastos , Genes Recessivos , Cardiopatias Congênitas/mortalidade , Humanos , Lactente , Recém-Nascido , Judeus/genética , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/deficiência , Convulsões/metabolismo , Síndrome , beta Carioferinas/metabolismo
8.
Hum Genet ; 139(10): 1209-1231, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32274568

RESUMO

Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients' features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene.


Assuntos
Complemento C3/genética , Matriz Extracelular/metabolismo , Anormalidades do Olho/genética , Glaucoma/genética , Mutação com Perda de Função , Inibidor da Tripsina Pancreática de Kazal/genética , alfa-Macroglobulinas/genética , Adulto , Animais , Câmara Anterior/metabolismo , Câmara Anterior/patologia , Câmara Anterior/cirurgia , Sistemas CRISPR-Cas , Estudos de Casos e Controles , Complemento C3/deficiência , Embrião não Mamífero , Matriz Extracelular/patologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/patologia , Anormalidades do Olho/cirurgia , Feminino , Edição de Genes , Expressão Gênica , Genes Recessivos , Glaucoma/metabolismo , Glaucoma/patologia , Glaucoma/cirurgia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Malha Trabecular/metabolismo , Malha Trabecular/patologia , Malha Trabecular/cirurgia , Trabeculectomia , Inibidor da Tripsina Pancreática de Kazal/deficiência , Peixe-Zebra , alfa-Macroglobulinas/deficiência
9.
PLoS Genet ; 16(4): e1008583, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32236127

RESUMO

The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of MYRF are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.


Assuntos
Olho/anatomia & histologia , Olho/metabolismo , Proteínas de Membrana/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Animais , Eletrorretinografia , Anormalidades do Olho/genética , Feminino , Deleção de Genes , Mutação com Perda de Função , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Tamanho do Órgão/genética , Ligação Proteica , Transporte Proteico , Epitélio Pigmentado da Retina/anormalidades , Epitélio Pigmentado da Retina/metabolismo , Retinaldeído/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 509-513, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335874

RESUMO

OBJECTIVE: To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia. METHODS: Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy. RESULTS: The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis. CONCLUSION: The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.


Assuntos
Anormalidades Múltiplas , Proteínas Adaptadoras de Transporte Vesicular , Cerebelo/anormalidades , Anormalidades do Olho , Testes Genéticos , Doenças Renais Císticas , Proteínas de Membrana , Diagnóstico Pré-Natal , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Variação Genética , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Mutação , Gravidez
12.
BMC Med Genet ; 21(1): 18, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000717

RESUMO

BACKGROUND: Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION: We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION: This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Predisposição Genética para Doença , Doenças Renais Císticas/genética , Proteínas de Membrana/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Cerebelo/fisiopatologia , Criança , Éxons/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Feminino , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Mutação/genética , Linhagem , Isoformas de Proteínas/genética , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia , Vietnã , Sequenciamento Completo do Exoma
13.
J Hum Genet ; 65(5): 487-491, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32015378

RESUMO

Microphthalmia, anophthalmia, and anterior segment dysgenesis are severe ocular developmental defects. There is a wide genetic heterogeneity leading to these ocular malformations. By using whole genome, exome and targeted sequencing in patients with ocular developmental anomalies, six biallelic pathogenic variants (including five novel variants) were identified in the PXDN gene in four families with microphthalmia and anterior segment dysgenesis. Only 11 different mutations (11 families) have been described in this gene to date. The phenotype of these patients is variable in severity, ranging from cataract and developmental glaucoma to complex microphthalmia. Interestingly, two unrelated patients of our series presented with an ocular phenotype including aniridia and microspherophakia. However, despite various phenotypic presentations and types of mutations, no genotype-phenotype correlation could be made. Thus, this work improves our knowledge of the recessive phenotype associated with biallelic variants in this gene and highlights the importance of screening PXDN in patients with anterior segment dysgenesis with or without microphthalmia.


Assuntos
Alelos , Anormalidades do Olho/genética , Microftalmia/genética , Mutação , Peroxidases/genética , Anormalidades do Olho/patologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Microftalmia/patologia
14.
Ophthalmology ; 127(6): 758-766, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32085876

RESUMO

PURPOSE: Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. DESIGN: Retrospective, multicenter case series. PARTICIPANTS: A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. PURPOSE: Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. METHODS: Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. MAIN OUTCOME MEASURES: Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. RESULTS: We identified rare (allele frequency < 4×10-5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. CONCLUSIONS: Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment.


Assuntos
Segmento Anterior do Olho/anormalidades , Complemento C3/genética , Anormalidades do Olho/genética , Glaucoma de Ângulo Aberto/genética , Polimorfismo de Nucleotídeo Único , Inibidor da Tripsina Pancreática de Kazal/genética , alfa-Macroglobulinas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Exoma/genética , Feminino , Frequência do Gene , Humanos , Hidroftalmia/genética , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , RNA/genética , Estudos Retrospectivos , Análise de Sequência de DNA , Adulto Jovem
15.
Eur J Med Genet ; 63(5): 103844, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31953238

RESUMO

This report describes siblings with Stromme syndrome, a rare genetic condition that primarily presents with a triad of intestinal atresia, cranial and ocular malformations, and other organ systems could be involved. This clinical triad was initially named after the first person to describe it in 1993. Here, we report a family with two siblings who presented with unusual intestinal atresia and ocular and CNS abnormalities. The first patient is a 6-year-old-boy with apple peel duodeno-jejunal atresia, unilateral microphthalmia and microcephaly. The second patient, a younger brother, presented with intestinal atresia, corneal opacity and alobar holoprosencephaly and passed away at the age of 3 months. Exome sequencing showed a novel homozygous variant in the CENPF gene, NM_016343.3: c.1195-2 A > G that was detected in both of the affected siblings. This is a report and literature review of CENPF-related ciliopathy, which may result in Stromme syndrome. As this is the fourth report linking the CENPF gene variant with Stromme syndrome and first reported case presented with holoprosencephaly, it will expand the current knowledge on the genotype and the phenotype of Stromme syndrome.


Assuntos
Proteínas Cromossômicas não Histona/genética , Anormalidades do Olho/genética , Atresia Intestinal/genética , Microcefalia/genética , Proteínas dos Microfilamentos/genética , Fenótipo , Criança , Anormalidades do Olho/patologia , Homozigoto , Humanos , Lactente , Atresia Intestinal/patologia , Masculino , Microcefalia/patologia , Mutação , Linhagem
16.
Neurology ; 94(8): e797-e801, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31969461

RESUMO

OBJECTIVE: To estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort. METHODS: We enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available. RESULTS: We identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41-0.53), 0.41 (95% CI 0.32-0.49), and 0.53 (95% CI 0.45-0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49-1.97), 1.62 (95% CI 1.31-1.99), and 1.80 (95% CI 1.49-2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r 2 = 0.79; p < 0.001). CONCLUSIONS: We estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients' genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.


Assuntos
Anormalidades Múltiplas/epidemiologia , Cerebelo/anormalidades , Anormalidades do Olho/epidemiologia , Doenças Renais Císticas/epidemiologia , Retina/anormalidades , Anormalidades Múltiplas/genética , Adolescente , Adulto , Fatores Etários , Idade de Início , Criança , Pré-Escolar , Bases de Dados Genéticas , Anormalidades do Olho/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Itália/epidemiologia , Doenças Renais Císticas/genética , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais , Adulto Jovem
17.
BMC Med Genet ; 21(1): 16, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969119

RESUMO

BACKGROUND: Autosomal recessive bestrophinopathy (ARB) is a retinal degenerative disorder caused by BEST1 mutations with autosomal recessive inheritance. We aim to map a comprehensive genomic and metabolomic profile of a consanguineous Chinese family with ARB. METHODS: Ophthalmic examinations were performed on the affected patients with ARB. The proband was screened for potential causative mutations in a panel with 256 known retinal disease genes by using target capture sequencing. The related mutation was further validated and segregated in the family members by Sanger sequencing. In silico prediction tools were used for pathogenicity assessment. A UHPLC-MS/MS metabolomic analysis was performed to explore the disease-associated metabolic feature. RESULTS: The affected patients from this family were characterized by low vision, the presence of subretinal fluid, macular edema, and hyperopia with coincidental angle closure. DNA sequencing identified a novel missense mutation in the BEST1 gene c.646G > A (p.Val216Ile) of the proband. Sanger sequencing further confirmed the mutation. The missense mutation was co-segregation across the pedigree and predicted to be deleterious by SIFT (0.017). The blood metabolic profiles were highly similar among all family members probably because of the same lifestyle, habitat and genomic background. However, ARB patients presented a significant deregulation of metabolites, such as citric acid, L-Threonic acid, and eicosapentaenoic acid. CONCLUSIONS: We identified a novel disease-associated variant in the BEST1 gene as well as a disease-specific metabolic feature in familial ARB. Our findings helped improve the understanding of ARB mechanisms.


Assuntos
Bestrofinas/genética , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Doenças Retinianas/genética , Distrofias Retinianas/genética , Canais de Cloreto/genética , Eletrorretinografia , Anormalidades do Olho/fisiopatologia , Oftalmopatias Hereditárias/fisiopatologia , Feminino , Humanos , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Fenótipo , Retina/diagnóstico por imagem , Retina/patologia , Doenças Retinianas/fisiopatologia , Distrofias Retinianas/diagnóstico por imagem , Distrofias Retinianas/fisiopatologia , Análise de Sequência de DNA
19.
Exp Eye Res ; 190: 107893, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31836490

RESUMO

Childhood glaucoma is an important cause of blindness world-wide. Eleven genes are currently known to cause inherited forms of glaucoma with onset before age 20. While all the early-onset glaucoma genes cause severe disease, considerable phenotypic variability is observed among mutations carriers. In particular, FOXC1 genetic variants are associated with a broad range of phenotypes including multiple forms of glaucoma and also systemic abnormalities, especially hearing loss. FOXC1 is a member of the forkhead family of transcription factors and is involved in neural crest development necessary for formation of anterior eye structures and also pharyngeal arches that form the middle ear bones. In this study we review the clinical phenotypes reported for known FOXC1 mutations and show that mutations in patients with reported ocular anterior segment abnormalities and hearing loss primarily disrupt the critically important forkhead domain. These results suggest that optimal care for patients affected with anterior segment dysgenesis should include screening for FOXC1 mutations and also testing for hearing loss.


Assuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Fatores de Transcrição Forkhead/genética , Perda Auditiva Neurossensorial/genética , Hidroftalmia/genética , Mutação , Criança , Glaucoma/genética , Humanos , Fenótipo
20.
Proc Natl Acad Sci U S A ; 117(2): 1113-1118, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31879347

RESUMO

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Anormalidades do Olho/genética , Genes Modificadores , Doenças Renais Císticas/genética , Retina/anormalidades , Animais , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Predisposição Genética para Doença/genética , Nefropatias , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
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