RESUMO
BACKGROUND AND AIMS: Joubert Syndrome (JS) is a rare, inherited, ciliopathy defined by cerebellar and brainstem malformations and is variably associated with liver, kidney, and ocular dysfunction. This study characterizes the hepatic findings in JS and identifies factors associated with probable portal hypertension. METHODS: Hundred individuals with JS were prospectively evaluated at the National Institutes of Health Clinical Center. Laboratory tests, imaging, and DNA sequencing were performed. Patients were stratified based on the spleen length/patient height ratio as a marker of splenomegaly, used as a surrogate for probable portal hypertension. RESULTS: Forty-three patients (43%) had liver involvement based on elevated liver enzymes and/or liver hyperechogenicity and/or splenomegaly. None of the patients had macroscopic liver cysts or bile duct dilatation. Based on the spleen length/patient height ratio, 13 patients were stratified into a probable portal hypertension group. We observed significant elevations in alkaline phosphatase (269 vs 169âU/L, Pâ≤â0.001), alanine aminotransferase (92 vs 42âU/L, Pâ=â0.004), aspartate aminotransferase (77 vs 40âU/L, Pâ=â0.002), and gamma-glutamyl transferase (226 vs 51âU/L, Pâ≤â0.001) in the probable portal hypertension group. Platelets were lower in the probable portal hypertension cohort (229 vs 299â×â10 cells/µL, Pâ=â0.008), whereas synthetic function was intact in both groups. Probable portal hypertension was also more prevalent in patients with kidney disease (Pâ=â0.001) and colobomas (Pâ=â0.02), as well as mutations in the TMEM67 gene (Pâ=â0.001). CONCLUSIONS: In JS, probable portal hypertension is associated with abnormal hepatic enzymes, as well as presence of kidney disease, coloboma, and/or mutation in TMEM67. These findings may allow early identification of JS patients who have or are more likely to develop liver disease.
Assuntos
Anormalidades Múltiplas/diagnóstico , Cerebelo/anormalidades , Anormalidades do Olho/diagnóstico , Doenças Renais Císticas/diagnóstico , Hepatopatias/diagnóstico , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Progressão da Doença , Anormalidades do Olho/genética , Anormalidades do Olho/fisiopatologia , Feminino , Humanos , Lactente , Doenças Renais Císticas/genética , Doenças Renais Císticas/fisiopatologia , Hepatopatias/congênito , Hepatopatias/genética , Hepatopatias/fisiopatologia , Modelos Logísticos , Masculino , Estudos Prospectivos , Retina/fisiopatologia , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. RESULTS: Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). CONCLUSIONS: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.
Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Cerebelo/anormalidades , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular , Adolescente , Adulto , Idade de Início , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Criança , Pré-Escolar , Proteínas do Citoesqueleto , Anormalidades do Olho/complicações , Anormalidades do Olho/diagnóstico por imagem , Feminino , Genótipo , Humanos , Lactente , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Falência Renal Crônica/etiologia , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Rim Displásico Multicístico/complicações , Rim Displásico Multicístico/diagnóstico por imagem , Rim Displásico Multicístico/genética , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/diagnóstico por imagem , Rim Policístico Autossômico Recessivo/genética , Estudos Prospectivos , Proteínas/genética , Retina/diagnóstico por imagem , Retina/metabolismo , Ultrassonografia Pré-Natal , Adulto JovemRESUMO
OBJECTIVE: Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult height (AH) in boys with familial male-limited precocious puberty (FMPP). To evaluate the effect of long-term antiandrogen, aromatase inhibitor, and GnRHa on AH, boys with FMPP who were treated were followed to AH. STUDY DESIGN: Twenty-eight boys with FMPP, referred to the National Institutes of Health, were started on antiandrogen and aromatase inhibitor at 4.9 ± 1.5 years of age; GnRHa was added at 6.9 ± 1.5 years of age. Treatment was discontinued at 12.2 ± 0.5 years of age (bone age, 14.4 ± 1.3). AH was assessed at 16.4 ± 1.3 years of age (bone age, 18.5 ± 0.6). RESULTS: AH (mean ± SD) for all treated subjects was 173.6 ± 6.8 cm (-0.4 ± 1.0 SD relative to adult US males). For 25 subjects with pretreatment predicted AH, AH significantly exceeded predicted AH at treatment onset (173.8 ± 6.9 vs 164.9 ± 10.7 cm; P < .001), but fell short of predicted AH at treatment discontinuation (177.3 ± 9.0 cm; P < .001). For 11 subjects with maternal or sporadic inheritance, the mean AH was 3.1 cm (0.4 SD score) below sex-adjusted midparental height (175.4 ± 5.8 vs 178.5 ± 3.1 cm [midparental height]; P = .10). For 16 subjects with affected and untreated fathers, AH was significantly greater than fathers' AH (172.8 ± 7.4 vs 168.8 ± 7.2 cm; P < .05). CONCLUSIONS: Long-term treatment with antiandrogen, aromatase inhibitor, and GnRHa in boys with FMPP results in AH modestly below sex-adjusted midparental height and within the range for adult males in the general population.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Estatura/efeitos dos fármacos , Leuprolida/uso terapêutico , Puberdade Precoce/tratamento farmacológico , Pamoato de Triptorrelina/análogos & derivados , Adulto , Anastrozol , Criança , Pré-Escolar , Esquema de Medicação , Quimioterapia Combinada , Seguimentos , Hormônio Liberador de Gonadotropina/análogos & derivados , Humanos , Masculino , Nitrilas/uso terapêutico , Puberdade Precoce/fisiopatologia , Espironolactona/uso terapêutico , Testolactona/uso terapêutico , Resultado do Tratamento , Triazóis/uso terapêutico , Pamoato de Triptorrelina/uso terapêuticoRESUMO
Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.
Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Anormalidades do Olho/genética , Hormônio do Crescimento/deficiência , Doenças Renais Císticas/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Sequência de Aminoácidos , Animais , Cerebelo/diagnóstico por imagem , Criança , Anormalidades do Olho/diagnóstico por imagem , Feminino , Humanos , Doenças Renais Císticas/diagnóstico por imagem , Masculino , Retina/diagnóstico por imagem , Homologia de Sequência de AminoácidosRESUMO
Joubert syndrome is a ciliopathy characterized by a specific constellation of central nervous system malformations that result in the pathognomonic "molar tooth sign" on imaging. More than 27 genes are associated with Joubert syndrome, but some patients do not have mutations in any of these genes. Celsr1, Celsr2, and Celsr3 are the mammalian orthologues of the drosophila planar cell polarity protein, flamingo; they play important roles in neural development, including axon guidance, neuronal migration, and cilium polarity. Here, we report bi-allelic mutations in CELSR2 in a Joubert patient with cortical heterotopia, microophthalmia, and growth hormone deficiency. © 2017 Wiley Periodicals, Inc.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Caderinas/genética , Cerebelo/anormalidades , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Hormônio do Crescimento Humano/deficiência , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Microftalmia/genética , Mutação , Retina/anormalidades , Alelos , Caderinas/química , Criança , Fácies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imageamento por Ressonância Magnética , Modelos Moleculares , Polimorfismo de Nucleotídeo Único , Conformação ProteicaRESUMO
BACKGROUND: Laminins are heterotrimeric complexes, consisting of α, ß and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions. METHODS: Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells. RESULTS: In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery. CONCLUSION: This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1â 000â 000. TRIAL REGISTRATION NUMBER: NCT00068224.
Assuntos
Doenças Cerebelares/metabolismo , Laminina/genética , Mutação , Miopia/metabolismo , Transtorno Obsessivo-Compulsivo/metabolismo , Adulto , Adesão Celular , Movimento Celular , Doenças Cerebelares/genética , Doenças Cerebelares/fisiopatologia , Criança , Feminino , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Humanos , Masculino , Miopia/genética , Miopia/fisiopatologia , Neurônios/metabolismo , Neurônios/fisiologia , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/fisiopatologia , Linhagem , Distrofias Retinianas/genética , Distrofias Retinianas/metabolismo , Distrofias Retinianas/fisiopatologia , Síndrome , Transtornos de Tique/genética , Transtornos de Tique/metabolismo , Transtornos de Tique/fisiopatologia , Adulto Jovem , Proteína cdc42 de Ligação ao GTPRESUMO
BACKGROUND: In chicken, loss of TALPID3 results in non-functional cilia and short-rib polydactyly syndrome. This phenotype is caused by a frameshift mutation in the chicken ortholog of the human KIAA0586 gene, which encodes a novel coiled-coil domain protein essential for primary ciliogenesis, suggesting that KIAA0586 can be associated with ciliopathy in human beings. METHODS: In our patients with ciliopathy (http://www.clinicaltrials.gov: NCT00068224), we have collected extensive clinical and neuroimaging data from affected individuals, and performed whole exome sequencing on DNA from affected individuals and their parents. We analysed gene expression on fibroblast cell line, and determined the effect of gene mutation on ciliogenesis in cells derived from patients. RESULTS: We identified biallelic mutations in the human TALPID3 ortholog, KIAA0586, in six children with findings of overlapping Jeune and Joubert syndromes. Fibroblasts cultured from one of the patients with Jeune-Joubert syndrome exhibited more severe cilia defects than fibroblasts from patients with only Joubert syndrome; this difference was reflected in KIAA0586 RNA expression levels. Rescue of the cilia defect with full-length wild type KIAA0586 indicated a causal link between cilia formation and KIAA0586 function. CONCLUSIONS: Our results show that biallelic deleterious mutations in KIAA0586 lead to Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Furthermore, our results confirm that KIAA0586/TALPID3 is essential in cilia formation in human beings, expand the KIAA0586 phenotype to include features of Jeune syndrome and provide a pathogenetic connection between Joubert and Jeune syndromes, based on aberrant ciliogenesis.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Síndrome de Ellis-Van Creveld/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Animais , Sequência de Bases , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Galinhas/genética , Criança , Pré-Escolar , Cílios/patologia , Análise Mutacional de DNA , Feminino , Fibroblastos/patologia , Mutação da Fase de Leitura , Expressão Gênica , Humanos , Masculino , Linhagem , Cultura Primária de CélulasRESUMO
BACKGROUND & AIMS: Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS: Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS: Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient's height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS: Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224.
Assuntos
Hipertensão Portal/fisiopatologia , Cirrose Hepática/congênito , Cirrose Hepática/patologia , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Colangiopancreatografia por Ressonância Magnética , Endoscopia Gastrointestinal , Varizes Esofágicas e Gástricas/etiologia , Feminino , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/complicações , Lactente , Transplante de Rim , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/genética , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Mutação , Tamanho do Órgão , Contagem de Plaquetas , Rim Policístico Autossômico Recessivo/complicações , Pressão na Veia Porta , Tempo de Protrombina , Albumina Sérica , Índice de Gravidade de Doença , Esplenomegalia/diagnóstico por imagem , Ultrassonografia Doppler em Cores , Adulto Jovem , gama-Glutamiltransferase/sangueRESUMO
Autosomal recessive polycystic kidney disease (ARPKD), characterized by progressive cystic degeneration of the kidneys and congenital hepatic fibrosis (CHF), is the most common childhood onset ciliopathy, with an estimated frequency of 1 in 20,000 births. It is caused by mutations in PKHD1. The carrier frequency for ARPKD in the general population is estimated at 1 in 70. Given the recessive inheritance pattern, individuals who are heterozygous for PKHD1 mutations are not expected to have clinical findings. We performed ultrasound (USG) evaluations on 110 parents from 64 independent ARPKD families and identified increased medullary echogenicity in 6 (5.5%) and multiple small liver cysts in 10 parents (9%). All ARPKD parents with these abnormal imaging findings were asymptomatic; kidney and liver function tests were unremarkable. Complete sequencing of PKHD1 in the 16 ARPKD parents with abnormal imaging confirmed the mutation transmitted to the proband, but did not reveal any other pathogenic variants. Our data suggest that carrier status for ARPKD is a predisposition to polycystic liver disease and renal involvement associated with increased medullary echogenicity on USG. Whether some of these individuals become symptomatic as they age remains to be determined.
Assuntos
Heterozigoto , Rim/patologia , Fígado/patologia , Rim Policístico Autossômico Recessivo/genética , Receptores de Superfície Celular/genética , Adulto , Idoso , Cistos/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Humanos , Rim/diagnóstico por imagem , Fígado/diagnóstico por imagem , Hepatopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Pais , UltrassonografiaRESUMO
OFD I is an X-linked dominant male-lethal ciliopathy characterized by prominent external features including oral clefts, hamartomas or cysts of the tongue, and digital anomalies. Although these external features are easy to recognize and often lead to diagnosis in early childhood, visceral findings in OFD I, especially the fibrocystic liver and pancreas disease, are under-recognized. In addition, while the occurrence of polycystic kidney disease (PKD) in OFD I is well known, few patients are evaluated and monitored for this complication. We report on two adult females diagnosed with OFD I in infancy, but not evaluated for visceral involvement. In adulthood, they were incidentally found to have severe hypertension and chronic renal insufficiency due to undiagnosed PKD. A pancreatic cystic lesion, also discovered incidentally, was thought to be malignant and led to consideration of major surgery. We present NIH evaluations, including documentation of OFD I mutations, extreme beading of the intrahepatic bile ducts, pancreatic cysts, and tabulate features of reported OFD I cases having hepatic, pancreatic, and renal cystic disease. Liver and pancreas are not routinely evaluated in OFD I patients. Increased awareness and lifelong monitoring of visceral complications, particularly involving the liver, pancreas, and kidney, are essential for timely and accurate treatment.
Assuntos
Fibrose Cística/genética , Cirrose Hepática/genética , Rim Policístico Autossômico Dominante/genética , Proteínas/genética , Anormalidades Múltiplas/genética , Adulto , Fibrose Cística/complicações , Éxons/genética , Feminino , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Deleção de Sequência , Língua/anormalidadesRESUMO
BACKGROUND AND OBJECTIVES: Renal function and imaging findings have not been comprehensively and prospectively characterized in a broad age range of patients with molecularly confirmed autosomal recessive polycystic kidney disease (ARPKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Ninety potential ARPKD patients were examined at the National Institutes of Health Clinical Center. Seventy-three fulfilled clinical diagnostic criteria, had at least one PKHD1 mutation, and were prospectively evaluated using magnetic resonance imaging (MRI), high-resolution ultrasonography (HR-USG), and measures of glomerular and tubular function. RESULTS: Among 31 perinatally symptomatic patients, 25% required renal replacement therapy by age 11 years; among 42 patients who became symptomatic beyond 1 month (nonperinatal), 25% required kidney transplantation by age 32 years. Creatinine clearance (CrCl) for nonperinatal patients (103 +/- 54 ml/min/1.73 m(2)) was greater than for perinatal patients (62 +/- 33) (P = 0.002). Corticomedullary involvement on HR-USG was associated with a significantly worse mean CrCl (61 +/- 32) in comparison with medullary involvement only (131 +/- 46) (P < 0.0001). Among children with enlarged kidneys, volume correlated inversely with function, although with wide variability. Severity of PKHD1 mutations did not determine kidney size or function. In 35% of patients with medullary-only abnormalities, standard ultrasound was normal and the pathology was detectable with HR-USG. CONCLUSIONS: In ARPKD, perinatal presentation and corticomedullary involvement are associated with faster progression of kidney disease. Mild ARPKD is best detected by HR-USG. Considerable variability occurs that is not explained by the type of PKHD1 mutation.
Assuntos
Genes Recessivos , Rim/patologia , Rim/fisiopatologia , Doenças Renais Policísticas/genética , Receptores de Superfície Celular/genética , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Criança , Pré-Escolar , Creatinina/urina , Cistatina C/sangue , Análise Mutacional de DNA , Progressão da Doença , Feminino , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Humanos , Lactente , Estimativa de Kaplan-Meier , Rim/diagnóstico por imagem , Túbulos Renais/patologia , Túbulos Renais/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Tamanho do Órgão , Linhagem , Fenótipo , Doenças Renais Policísticas/patologia , Doenças Renais Policísticas/fisiopatologia , Doenças Renais Policísticas/terapia , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Ultrassonografia , Estados Unidos , Adulto JovemRESUMO
PKHD1, the gene mutated in autosomal recessive polycystic kidney disease (ARPKD)/congenital hepatic fibrosis (CHF), is an exceptionally large and complicated gene that consists of 86 exons and has a number of alternatively spliced transcripts. Its longest open reading frame contains 67 exons that encode a 4074 amino acid protein called fibrocystin or polyductin. The phenotypes caused by PKHD1 mutations are similarly complicated, ranging from perinatally-fatal PKD to CHF presenting in adulthood with mild kidney disease. To date, more than 300 mutations have been described throughout PKHD1. Most reported cohorts include a large proportion of perinatal-onset ARPKD patients; mutation detection rates vary between 42% and 87%. Here we report PKHD1 sequencing results on 78 ARPKD/CHF patients from 68 families. Differing from previous investigations, our study required survival beyond 6 months and included many adults with a CHF-predominant phenotype. We identified 77 PKHD1 variants (41 novel) including 19 truncating, 55 missense, 2 splice, and 1 small in-frame deletion. Using computer-based prediction tools (GVGD, PolyPhen, SNAP), we achieved a mutation detection rate of 79%, ranging from 63% in the CHF-predominant group to 82% in the remaining families. Prediction of the pathogenicity of missense variants will remain challenging until a functional assay is available. In the meantime, use of PKHD1 sequencing data for clinical decisions requires caution, especially when only novel or rare missense variants are identified.