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1.
Nat Genet ; 51(10): 1438-1441, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570889

RESUMO

Hypopigmentation along Blaschko's lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Our findings pave the way toward elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease.

3.
Cell Mol Life Sci ; 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31218450

RESUMO

The sperm acrosome is a lysosome-related organelle that develops using membrane trafficking from the Golgi apparatus as well as the endolysosomal compartment. How vesicular trafficking is regulated in spermatids to form the acrosome remains to be elucidated. VPS13B, a RAB6-interactor, was recently shown involved in endomembrane trafficking. Here, we report the generation of the first Vps13b-knockout mouse model and show that male mutant mice are infertile due to oligoasthenoteratozoospermia. This phenotype was explained by a failure of Vps13b deficient spermatids to form an acrosome. In wild-type spermatids, immunostaining of Vps13b and Rab6 revealed that they transiently locate to the acrosomal inner membrane. Spermatids lacking Vps13b did not present with the Golgi structure that characterizes wild-type spermatids and showed abnormal targeting of PNA- and Rab6-positive Golgi-derived vesicles to Eea1- and Lamp2-positive structures. Altogether, our results uncover a function of Vps13b in the regulation of the vesicular transport between Golgi apparatus, acrosome, and endolysosome.

5.
Am J Hum Genet ; 104(3): 542-552, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827498

RESUMO

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

6.
Mol Genet Metab Rep ; 12: 103-109, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28725569

RESUMO

Adult onset urea cycle disorders (UCD) may present with psychiatric symptoms, occasionally as the initial presentation. We aimed to describe the characteristics of patients presenting with a psychiatric adult-onset of UCDs, to discuss which signs could suggest this diagnosis in such a situation, and to determine which tests should be conducted. A survey of psychiatric symptoms occurring in teenagers or adults with UCD was conducted in 2010 among clinicians involved in the French society for the study of inborn errors of metabolism (SFEIM). Fourteen patients from 14 to 57 years old were reported. Agitation was reported in 10 cases, perseveration in 5, delirium in 4, and disinhibition in 3 cases. Three patients had pre-existing psychiatric symptoms. All patients had neurological symptoms associated with psychiatric symptoms, such as ataxia or dysmetria, psychomotor slowing, seizures, or hallucinations. Fluctuations of consciousness and coma were reported in 9 cases. Digestive symptoms were reported in 7 cases. 9 patients had a personal history suggestive of UCD. The differential diagnoses most frequently considered were exogenous intoxication, non-convulsive status epilepticus, and meningoencephalitis. Hyperammonemia (180-600 µmol/L) was found in all patients. The outcome was severe: mechanical ventilation was required in 10 patients, 5 patients died, and only 4 patients survived without sequelae. Adult onset UCDs can present with predominant psychiatric symptoms, associated with neurological involvement. These patients, as well as patients presenting with a suspicion of intoxication, must have UCD considered and ammonia measured without delay.

7.
Eur J Hum Genet ; 24(7): 992-1000, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26626311

RESUMO

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.


Assuntos
Substituição de Aminoácidos , Artrite/genética , Doenças do Colágeno/genética , Colágeno Tipo II/genética , Doenças do Tecido Conjuntivo/genética , Perda Auditiva Neurossensorial/genética , Osteocondrodisplasias/genética , Fenótipo , Descolamento Retiniano/genética , Artrite/patologia , Doenças do Colágeno/patologia , Colágeno Tipo II/química , Doenças do Tecido Conjuntivo/patologia , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Osteocondrodisplasias/patologia , Linhagem , Domínios Proteicos , Descolamento Retiniano/patologia
8.
Eur J Hum Genet ; 24(2): 228-36, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26014430

RESUMO

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.


Assuntos
Testes Genéticos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Feminino , Fator de Transcrição GATA4/genética , Variação Genética , Cardiopatias Congênitas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação , Linhagem , Fatores de Transcrição/genética
9.
Orphanet J Rare Dis ; 10: 135, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26471370

RESUMO

BACKGROUND: Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients. METHODS: Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected. RESULTS: Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes. CONCLUSIONS: HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.


Assuntos
Proteínas de Ciclo Celular/genética , Contratura/genética , Doenças Musculares/genética , Fibrose Pulmonar/genética , Esclerose/genética , Anormalidades da Pele/genética , Dermatopatias Genéticas/genética , Tendões/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Contratura/complicações , Contratura/diagnóstico , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doenças Musculares/complicações , Doenças Musculares/diagnóstico , Mutação/genética , Fibrose Pulmonar/complicações , Fibrose Pulmonar/diagnóstico , Esclerose/complicações , Esclerose/diagnóstico , Anormalidades da Pele/complicações , Anormalidades da Pele/diagnóstico , Dermatopatias Genéticas/complicações , Dermatopatias Genéticas/diagnóstico
10.
Eur J Hum Genet ; 23(7): 957-62, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25315659

RESUMO

SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor gene involved in the tumorigenesis of a spectrum of solid cancers. Heterozygous SASH1 variants are known to cause autosomal-dominant dyschromatosis. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous Moroccan family with two affected siblings presenting an unclassified phenotype associating an abnormal pigmentation pattern (hypo- and hyperpigmented macules of the trunk and face and areas of reticular hypo- and hyperpigmentation of the extremities), alopecia, palmoplantar keratoderma, ungueal dystrophy and recurrent spinocellular carcinoma. We identified a homozygous variant in SASH1 (c.1849G>A; p.Glu617Lys) in both affected individuals. Wound-healing assay showed that the patient's fibroblasts were better able than control fibroblasts to migrate. Following the identification of SASH1 heterozygous variants in dyschromatosis, we used reverse phenotyping to show that autosomal-recessive variants of this gene could be responsible for an overlapping but more complex phenotype that affected skin appendages. SASH1 should be added to the list of genes responsible for autosomal-dominant and -recessive genodermatosis, with no phenotype in heterozygous patients in the recessive form, and to the list of genes responsible for a predisposition to skin cancer.


Assuntos
Predisposição Genética para Doença/genética , Ceratodermia Palmar e Plantar/genética , Mutação de Sentido Incorreto , Transtornos da Pigmentação/genética , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Consanguinidade , Análise Mutacional de DNA/métodos , Exoma/genética , Saúde da Família , Feminino , Fibroblastos/metabolismo , Genes Recessivos , Homozigoto , Humanos , Masculino , Linhagem , Análise de Sequência de DNA , Irmãos , Pele/metabolismo , Pele/patologia
11.
Orphanet J Rare Dis ; 9: 207, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25497157

RESUMO

PMM2-CDG (formerly known as CDG Ia) a deficiency in phosphomannomutase, is the most frequent congenital disorder of glycosylation. The phenotype encompasses a wide range of neurological and non-neurological manifestations comprising cerebellar atrophy and intellectual deficiency. The phenotype of the disorder is well characterized in children but the long term course of the disease is unknown and the phenotype of late onset forms has not been comprehensively described. We thus retrospectively collected the clinical, biological and radiological data of 29 French PMM2-CDG patients aged 15 years or more with a proven molecular diagnosis (16 females and 13 males). In addition, thirteen of these patients were reexamined at the time of the study to obtain detailed information. 27 of the 29 patients had a typical PMM2-CDG phenotype, with infantile hypotonia, strabismus, developmental delay followed by intellectual deficiency, epilepsy, retinitis pigmentosa and/or visceral manifestations. The main health problems for these patients as teenagers and in adulthood were primary ovarian insufficiency, growth retardation, coagulation anomalies and thrombotic events, skeletal deformities and osteopenia/osteoporosis, retinitis pigmentosa, as well as peripheral neuropathy. Three patients had never walked and three lost their ability to walk. The two remaining patients had a late-onset phenotype unreported to date. All patients (n = 29) had stable cerebellar atrophy. Our findings are in line with those of previous adult PMM2-CDG cohorts and points to the need for a multidisciplinary approach to the follow up of PMM2-CDG patients to prevent late complications. Additionally, our findings add weight to the view that PMM2-CDG may be diagnosed in teenage/adult patients with cerebellar atrophy, even in the absence of intellectual deficiency or non-neurological involvement.


Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Fenótipo , Fosfotransferases (Fosfomutases)/deficiência , Adolescente , Adulto , Idade de Início , Estudos de Coortes , Defeitos Congênitos da Glicosilação/epidemiologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fosfotransferases (Fosfomutases)/genética , Estudos Retrospectivos , Adulto Jovem
12.
Am J Med Genet A ; 164A(6): 1537-44, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24668847

RESUMO

The 15q13.3 heterozygous microdeletion is a fairly common microdeletion syndrome with marked clinical variability and incomplete penetrance. The average size of the deletion, which comprises six genes including CHRNA7, is 1.5 Mb. CHRNA7 has been identified as the gene responsible for the neurological phenotype in this microdeletion syndrome. Only seven patients with a homozygous microdeletion that includes at least CHRNA7, and is inherited from both parents have been described in the literature. The aim of this study was to further describe the distinctive eye manifestations from the analysis in the three French patients diagnosed with the classical 1.5 Mb homozygous microdeletion. Patients' ages ranged from 30 months to 9 years, and included one sib pair. They all displayed a remarkably severe identifiable clinical phenotype that included congenital blindness and convulsive encephalopathy with inconstant abnormal movements. The ophthalmological examination revealed a lack of eye tracking, optic nerve pallor, an immature response with increased latencies with no response to the checkerboard stimulations at the visual evoked potential examination, and a distinctive retina dystrophy with a negative electroretinogram in which the "b" wave was smaller than the "a" wave after a dark adapted pupil and bright flash in all patients. Clear genotype-phenotype correlations emerged, showing that this eye phenotype was secondary to homozygous deletion of TRPM1, the gene responsible for autosomal recessive congenital stationary night blindness. The main differential diagnosis is ceroid lipofuscinosis.


Assuntos
Cegueira/genética , Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Lipofuscinoses Ceroides Neuronais/genética , Convulsões/genética , Canais de Cátion TRPM/genética , Receptor Nicotínico de Acetilcolina alfa7/genética , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 15/genética , Eletrorretinografia , Olho/patologia , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Feminino , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Deficiência Intelectual/patologia , Masculino , Miopia/genética , Lipofuscinoses Ceroides Neuronais/patologia , Cegueira Noturna/genética , Nervo Óptico/anormalidades , Distrofias Retinianas/genética , Convulsões/patologia
13.
Am J Hum Genet ; 93(6): 1100-7, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24268661

RESUMO

Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.


Assuntos
Proteínas de Ciclo Celular/genética , Contratura/fisiopatologia , Doenças Musculares/complicações , Mutação , Fibrose Pulmonar/complicações , Síndrome de Rothmund-Thomson/complicações , Síndrome de Rothmund-Thomson/genética , Tendões/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Síndrome de Rothmund-Thomson/diagnóstico , Adulto Jovem
14.
Nat Genet ; 44(4): 456-60, S1-3, 2012 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-22406640

RESUMO

Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins that recruit substrates for Cullin3-based ubiquitin ligase complexes. KLHL3 is coexpressed with NCC and downregulates NCC expression at the cell surface. Our study establishes a role for KLHL3 as a new member of the complex signaling pathway regulating ion homeostasis in the distal nephron and indirectly blood pressure.


Assuntos
Proteínas de Transporte/genética , Transporte de Íons/genética , Néfrons/metabolismo , Pseudo-Hipoaldosteronismo/genética , Simportadores de Cloreto de Sódio/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Sequência de Bases , Pressão Sanguínea/genética , Criança , Feminino , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Pseudo-Hipoaldosteronismo/metabolismo , Pseudo-Hipoaldosteronismo/fisiopatologia , Análise de Sequência de DNA , Transdução de Sinais , Simportadores de Cloreto de Sódio/genética , Adulto Jovem
15.
Orphanet J Rare Dis ; 6: 21, 2011 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-21569298

RESUMO

BACKGROUND: Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. METHODS: We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). RESULTS: Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. CONCLUSIONS: Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.


Assuntos
Éxons/genética , Síndromes de Usher/diagnóstico , Síndromes de Usher/genética , Sequência de Aminoácidos , Estudos de Casos e Controles , França/epidemiologia , Genoma Humano , Genômica , Genótipo , Humanos , Dados de Sequência Molecular , Mutação , Linhagem , Síndromes de Usher/epidemiologia
16.
Eur J Hum Genet ; 13(11): 1186-91, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16094309

RESUMO

Splenomegaly with sea-blue histiocytes, thrombocytopenia and hypertriglyceridemia is a very rare association that has been described in only one report to date. The molecular defect in the two reported patients consists in a deletion of a leucine at position 149 in the receptor-binding region of the apoE molecule. Here, we report on another family in whom the proband and his brother were diagnosed with splenomegaly, thrombocytopenia and hypertriglyceridemia. An apoE p.Leu149del mutation was found in both subjects. A large beta band in the VLDL fraction and elevated VLDL cholesterol-to-plasma triglyceride ratio was observed in the proband only. Their mother, presenting with isolated hypertriglyceridemia, also carried the same p.Leu149del mutation. The coexistence of factors facilitating the development of hypertriglyceridemia and/or low HDL-cholesterol level could explain why the proband and his brother developed a splenomegaly with thrombocytopenia, whereas the mother did not. Moreover, the presence of an apoE2 allele in the proband likely explains the more severe phenotype we observed in this subject. In conclusion, the apoE p.Leu149del mutation results in a very striking phenotype including one or all symptoms among splenomegaly, thrombocytopenia and hypertriglyceridemia, and should be considered as a differential diagnosis of storage disorders in the causes of splenomegaly with sea-blue histiocytes.


Assuntos
Apolipoproteínas E/genética , Deleção de Genes , Síndrome do Histiócito Azul-Marinho/genética , Apolipoproteínas E/sangue , Feminino , Humanos , Hiperlipoproteinemia Tipo IV/genética , Lipídeos/sangue , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Esplenomegalia/genética , Síndrome , Trombocitopenia/genética
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