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1.
Am J Med Genet A ; 188(9): 2555-2559, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35775617

RESUMO

Infantile Krabbe disease (OMIM 245200) is a severe, fatal autosomal recessive neurodegenerative disorder that is relatively frequent in two Muslims villages within Jerusalem. After the characterization of the founder mutation, a population carrier screening for Krabbe disease became a component of the Israeli program for the detection and the prevention of birth defects. Between 2010 and 2018, 3366 individuals were tested and among them 247 carriers for Krabbe disease were identified (7.3%). Most of the 21 carrier couples identified that had pregnancies after being informed that they were at risk used preventive measures including termination of pregnancies of affected fetuses. During the study period, eight children affected with Krabbe disease were born in the villages, four to couples not detected though the program. Twenty years after the beginning of the carrier screening program, Krabbe disease remained relatively frequent in the villages. The establishment of a genetic clinic in the villages may allow to improve the carrier screening program while giving individual counseling for the risk to the other genetic diseases existing in the villages.


Assuntos
Leucodistrofia de Células Globoides , Criança , Feminino , Triagem de Portadores Genéticos , Humanos , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/epidemiologia , Leucodistrofia de Células Globoides/genética , Programas de Rastreamento , Gravidez
2.
Reprod Sci ; 29(5): 1408-1413, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-33977503

RESUMO

Fanconi anemia (FA) is a multisystem disease, characterized by the triad of physical abnormalities, bone marrow failure, and increased risk for malignancy. In the past few years, data has accumulated regarding fertility issues in FA patients, mostly due to gonadal dysfunction, which is prevalent in FA patients reaching puberty. It seems that attenuated FA phenotype lacking the classical manifestations often is presented with POI or azoospermia. Searching the literature, we summarized data regarding FA patients presenting as suffering from sub/infertility due to gonadal dysfunction, with or without other FA symptoms. We present a summary of the patients having biallelic pathogenic variants in FA genes FANCA, FANCM, BRCA2, and XRCC2 that presented with gonadal dysfunction with or without other phenotypic features of FA. Some were in mosaic, while some are considered hypomorphic, enabling residual protein function. There are also a few descriptions of POI associated with monoallelic pathogenic variants in FANCA, BRCA2, and FANCL. We conclude that the diagnosis of FA in gonadal dysfunction patients is of utmost importance due to its actionability. Follow-up strategies in FA patients are designed to discover early stages of leukemias and solid tumors and thus save lives. The feasibility of next-generation sequencing (NGS) can now ease this diagnostic procedure. An open question is the justification of performing NGS for all isolated azoospermia/POI patients.


Assuntos
Azoospermia , Anemia de Fanconi , Azoospermia/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Anemia de Fanconi/complicações , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Humanos , Mutação , Fenótipo
3.
Prenat Diagn ; 40(3): 301-310, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31774570

RESUMO

Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay-Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X-linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry-based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.


Assuntos
Triagem de Portadores Genéticos , Testes Genéticos , Internacionalidade , Aborto Induzido/estatística & dados numéricos , Austrália , Chipre , Fibrose Cística/genética , Feminino , Triagem de Portadores Genéticos/métodos , Testes Genéticos/métodos , Hemoglobinopatias/genética , Heterozigoto , Humanos , Israel , Itália , Malásia , Países Baixos , Gravidez , Diagnóstico Pré-Implantação/estatística & dados numéricos , Diagnóstico Pré-Natal/estatística & dados numéricos , Arábia Saudita , Doença de Tay-Sachs/genética , Talassemia/genética , Reino Unido , Estados Unidos
4.
Hum Genet ; 138(10): 1117-1122, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243543

RESUMO

The Israeli population mainly includes Jews, Muslim and Christian Arabs, and Druze. Data on genetic diseases present in the population have been systematically collected and are available online in the Israeli national genetic database. Among the Israeli Arabs in December 31 2018, the database included molecular data on six diseases relatively frequent in the whole population: thalassemia, familial Mediterranean fever (FMF), cystic fibrosis, deafness, phenylketonuria or congenital adrenal hyperplasia as well as data on 632 autosomal recessive diseases among Muslim Israeli Arabs, 52 among the Christian Arabs and 79 among Druze. A single variant was characterized in 590 out of the 771 genes causing disorders in which the molecular basis was known. Many of the variants reported among Arabs in Israel are novels, most being found in one community only. Some variants are ancient and for instance, consistent with the migration history, several variants are found in the Bedouins from the Negev as well as from the Arab peninsula. In the 181 other disorders more than one variant was characterized either in the same gene or in more than one gene. While it is probable that most of these cases represent random events in some cases the reason may be a selective advantage to the heterozygotes.


Assuntos
Árabes/genética , Genes Recessivos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Doenças Genéticas Inatas/diagnóstico , Variação Genética , Heterozigoto , Humanos , Israel/epidemiologia , Programas de Rastreamento , Vigilância da População
5.
Genet Med ; 18(2): 203-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25880436

RESUMO

PURPOSE: The Israeli population genetic screening program for reproductive purposes, launched in January 2013, includes all known, nationally frequent severe diseases (carrier frequency 1:60 and/or disease frequency 1 in 15,000 live births). The carrier screening program is free of charge and offers testing for cystic fibrosis, fragile X syndrome, and spinal muscular atrophy for nearly the entire population, according to disease frequency among the different groups within the population. We report the results of the first year of the program. METHODS: Data on the tests performed over a 12-month period were collected from laboratories nationwide. RESULTS: More than 62,000 individuals were examined. The carrier frequency was within the expected range for most of the diseases. The few exceptions included lower carrier rates for cystic fibrosis among Muslim Arabs (1:236) and Druze (1:1,021) and Niemann-Pick type A among Muslim Arabs in a delineated region of Israel (1:229). CONCLUSION: The national population genetic carrier screening is aimed toward providing couples with knowledge of the existing options for the prevention of serious genetic conditions when it is relevant for them. It is still too early to determine whether this aim has been achieved.


Assuntos
Triagem de Portadores Genéticos , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Programas Nacionais de Saúde , Feminino , Doenças Genéticas Inatas/etnologia , Doenças Genéticas Inatas/genética , Humanos , Israel , Masculino , Programas de Rastreamento
6.
Isr Med Assoc J ; 14(9): 538-42, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23101415

RESUMO

BACKGROUND: Genetic screening tests for cystic fibrosis (CF), fragile X (FRAX) and spinal muscular atrophy (SMA) have been offered to the entire Arab population of Israel in the last few years. Since 2008, screening for CF is provided free of charge, but for FRAX and SMA the screening is privately funded with partial coverage by complementary health insurance programs. OBJECTIVES: To assess the compliance of Arab couples with regard to genetic screening tests, and the factors that affect their decisions. METHODS: We analyzed compliance for genetic screening tests at the Emek Medical Center Genetic Institute, and in outreach clinics in four Arab villages. We enquired about the reasons individuals gave for deciding not to undergo testing. We also assessed the compliance of these individuals for the triple test (a screening test for Down syndrome). RESULTS: Of the 167 individuals included in our study, 24 (14%) decided not to be tested at all. Of the 143 (86%) who decided to be tested, 109 were tested for CF only (65%) and 34 (20%) for SMA and FRAX (as well as CF). The compliance rate for the triple test was 87%. Technical reasons, mainly financial issues, were the most significant factor for not undergoing all three tests. CONCLUSIONS: The compliance of the Arab community for genetic testing for SMA and FRAX is extremely low. We believe that this low utilization of screening is due to economic reasons, especiallywhen a complementary health plan has not been acquired, and largely reflects the perception that these tests are less important since they are privately funded.


Assuntos
Árabes/genética , Fibrose Cística/genética , Síndrome de Down/genética , Síndrome do Cromossomo X Frágil/genética , Testes Genéticos/economia , Testes Genéticos/estatística & dados numéricos , Atrofia Muscular Espinal/genética , Cooperação do Paciente , Adulto , Tomada de Decisões , Feminino , Humanos , Israel , Masculino , Gravidez
7.
Hum Genet ; 128(5): 473-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20852892

RESUMO

The Israeli population mainly includes Jews, Muslim and Christian Arabs, and Druze In the last decade, data on genetic diseases present in the population have been systematically collected and are available online in the Israeli national genetic database ( http://www.goldenhelix.org/server/israeli ). In the non-Jewish population, up to 1 July 2010, the database included molecular data on six diseases relatively frequent in the whole population: thalassemia, familial Mediterranean fever (FMF), cystic fibrosis, deafness, phenylketonuria and congenital adrenal hyperplasia, as well as data on 195 autosomal recessive diseases among Muslim Israeli Arabs, 11 among the Christian Arabs and 31 among Druze. A single mutation was characterized in 149 out of the 238 rare disorders for which the molecular basis was known. In many diseases, mutation had never been observed in any other population and was present in one family only suggesting that it occurred as a de novo event. In other diseases, the mutation was present in more than one community or even in other populations such as Bedouins from the Arab peninsula or Christians from Lebanon. In the 89 other disorders, more than one mutation was characterized either in the same gene or in more than one gene. While it is probable that most of these cases represent random events in some cases such as Bardet Biedl among the Bedouins, the reason may be a selective advantage to the heterozygotes.


Assuntos
Árabes/genética , Genes Recessivos , Doenças Genéticas Inatas/genética , Mutação , Albinismo/genética , Ataxia Telangiectasia/genética , Síndrome de Bardet-Biedl/genética , Cristianismo , Epidermólise Bolhosa/genética , Doenças Genéticas Inatas/epidemiologia , Humanos , Hipoparatireoidismo/genética , Deficiência Intelectual/genética , Islamismo , Israel/epidemiologia , Leucodistrofia de Células Globoides/genética , Leucodistrofia Metacromática/genética , Doença da Urina de Xarope de Bordo/genética , Mucopolissacaridose I/genética , Xantomatose Cerebrotendinosa/genética
8.
Lancet Oncol ; 10(12): 1142, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19959073
10.
Isr Med Assoc J ; 8(9): 601-4, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17058407

RESUMO

BACKGROUND: Open neural tube defects are among the most common severely disabling birth defects. Secondary prevention by early diagnosis during pregnancy and abortion of affected fetuses lead to a marked reduction of NTD incidence at birth. For primary prevention of these defects, in August 2000 the Israel Ministry of Health issued guidelines recommending a daily 0.4 mg folic acid supplement for all women in their childbearing years with special emphasis on the 3 months preceding conception and the first trimester of pregnancy. OBJECTIVES: To compare the epidemiologic characteristics of NTD in Israel before and after the guidelines for folic acid supplementation. METHODS: A national registry of NTD was begun in 1999. Since the Ministry of Health published the recommendation for folic acid supplementation in mid-2000, the years 1999-2000 represent the status prior to the recommendation and the years 2002-2004 the status after. RESULTS: A marked decline in the rate of spina bifida was observed in the last 3 years (from 4.9 to 2.7 per 10,000 live births among Jews and 9.5 to 6.2 among Arabs and Druze). There was no apparent reduction for anencephaly. CONCLUSIONS: Following the Ministry of Health guidelines on folic acid supplementation for women in the reproductive age, a marked reduction in the rates of NTD was observed. In light of this apparent success, continuous efforts should be made to increase the percentage of women taking the supplementation and, especially, to introduce folic acid fortification.


Assuntos
Suplementos Nutricionais/normas , Ácido Fólico/uso terapêutico , Fidelidade a Diretrizes , Defeitos do Tubo Neural/epidemiologia , Vigilância da População , Guias de Prática Clínica como Assunto , Feminino , Ácido Fólico/administração & dosagem , Humanos , Recém-Nascido , Israel/epidemiologia , Defeitos do Tubo Neural/prevenção & controle , Gravidez , Sistema de Registros , Medição de Risco , Fatores de Risco
11.
Hum Mol Genet ; 14(24): 3911-20, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16301218

RESUMO

A four-generation family was studied in which nine children had congenital cerebral palsy (CP), characterized by quadriplegia and mental retardation. All the affected children were born to healthy, related fathers, whereas the children of their healthy female relatives were unaffected. Linkage analysis attributed the condition to chromosome 9p24.3, where a 225 kb deletion was identified. The deletion spans a single gene, ANKRD15 (ankyrin repeat domain 15), which is ubiquitously expressed. In the affected children, the ANKRD15 is not expressed in lymphoblastoid cells, whereas in their healthy fathers, who harbor the same deletion, the expression of ANKRD15 did not deviate from controls. This expression pattern can be interpreted as a maternal imprinted gene that is expressed only from the paternal allele. The expression of ANKRD15 in lymphoblastoid cells from the control group was monoallelic but not imprinted. The monoallelic expression was restricted to the ANKRD15 gene, whereas biallelic expression was found in the DOCK8 gene, which resides at the telomeric side of the deletion. No correlation was found between the expression of the ANKRD15 gene and the pattern of DNA methylation in the CpG islands 5' of the gene. However, differences in methylation pattern were found in the CpG islands flanking the DMRT1 gene, which is located at the 3' side of the ANKRD15 gene. In the affected individuals, as in the control group, the CpG islands were hypo-methylated, whereas in the healthy fathers, the CpG islands were hyper-methylated in cis with the deletion. This unique family demonstrates a phenomenon of a deletion that creates imprinting-like inheritance. The implication of this family to sporadic CP is discussed.


Assuntos
Paralisia Cerebral/genética , Cromossomos Humanos Par 9 , Proteínas Supressoras de Tumor/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Bases , Estudos de Casos e Controles , Deleção Cromossômica , Ilhas de CpG , Proteínas do Citoesqueleto , Metilação de DNA , Feminino , Deleção de Genes , Regulação da Expressão Gênica , Ligação Genética , Impressão Genômica , Humanos , Linfócitos/fisiologia , Masculino , Dados de Sequência Molecular , Pais , Linhagem
12.
Brain ; 128(Pt 1): 42-51, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15548556

RESUMO

We describe a new autosomal recessive myopathy of early onset and very slow progression distinguished by the prominent external ophthalmoplegia in 16 subjects of eight families from a large and highly inbred Arab community. Characteristic clinical features include mild facial and skeletal muscle weakness and atrophy more pronounced proximally in the upper limbs, facial dysmorphism and scoliosis associated with conjugate, non-restrictive ocular motility impairment greatest in the upgaze and without ptosis or aberrant eye movements. Orbital MRI in the patients demonstrated atrophy with fatty replacement of the oculorotatory muscles. The major pathological alteration on skeletal muscle biopsy was a marked type 1 fibre predominance with core-like formations. A genome wide search for regions of homozygosity in the affected members from two informative families identified linkage with chromosome 17p13.1-p12 markers. Maximum two-point logarithm of odds scores were obtained at loci D17S1803 and AFMA070WD1 (Zmax = 3.74 at = 0). Two independent recombination events at D17S1812 and D17S947 further defined a critical region of 12 cM. Several genes map to this interval, including a cluster of sarcomeric myosin heavy chain genes. One of these genes, MYH2, is involved in inclusion body myopathy 3, but no exonic mutations were found by direct sequencing. The molecular basis for this new myopathy remains to be identified.


Assuntos
Cromossomos Humanos Par 17/genética , Doenças Musculares/genética , Oftalmoplegia/genética , Adolescente , Adulto , Criança , Saúde da Família , Feminino , Ligação Genética/genética , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/complicações , Debilidade Muscular/genética , Músculo Esquelético/patologia , Doenças Musculares/complicações , Doenças Musculares/patologia , Oftalmoplegia/complicações , Oftalmoplegia/patologia , Linhagem , Acuidade Visual/fisiologia
13.
Hum Genet ; 114(6): 521-6, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15024643

RESUMO

Classically, each parent of a child with an autosomal recessive disease has been considered to carry at least one copy of the abnormal allele. However, with the increasing ability to characterise the molecular basis of genetic diseases, several exceptions have been reported. The most frequent situation is that only one parent is a carrier of the mutation that is present in the patient in two copies either because of uniparental disomy or because of a de-novo mutation on the gene transmitted by the non-carrier parent. In order to give accurate genetic counselling, in particular when prenatal diagnosis is envisaged, molecular analysis of each of the parents of a child affected with an autosomal recessive disease must be routinely performed.


Assuntos
Genes Recessivos/genética , Aconselhamento Genético/métodos , Mutação/genética , Dissomia Uniparental/genética , Hiperplasia Suprarrenal Congênita/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Pais
14.
Prenat Diagn ; 22(12): 1102-6, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12454966

RESUMO

OBJECTIVE: To determine the importance of various factors on the decisions whether to terminate or continue a pregnancy after an abnormal result. METHODS: The decisions of 1467 women who had an abnormal result after an invasive prenatal test were examined according to their religion, the time of diagnosis and the severity of the disorder. RESULTS: When the examinations were performed by chorionic villus sampling (CVS) among both Jews and non-Jews most of the women opted to terminate the affected pregnancy. After amniocentesis the rate of termination of pregnancy was still very high among cases in which Down syndrome or other significant chromosomal aberrations were diagnosed among Jews. For all the other diagnostic groups either among Jews or non-Jews there was a significant proportion of the cases in which the women decided to continue the pregnancy. A significant exception about the decisions of the couples was in the case of hemoglobinopathy-affected pregnancies among Arabs since both after CVS and amniocentesis many women often decided to continue the pregnancy. CONCLUSION: The main factor in the decision to terminate or continue the pregnancy is the severity of the disorder diagnosed. However, among Arabs other factors are important, in particular the time at which the diagnosis is made.


Assuntos
Aborto Eugênico/psicologia , Árabes/psicologia , Anormalidades Congênitas/diagnóstico , Tomada de Decisões , Judeus/psicologia , Pais/psicologia , Diagnóstico Pré-Natal , Aborto Eugênico/estatística & dados numéricos , Adulto , Amniocentese , Amostra da Vilosidade Coriônica , Anormalidades Congênitas/etnologia , Feminino , Humanos , Israel/epidemiologia , Gravidez
15.
Lancet ; 360(9338): 1024; author reply 1024, 2002 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-12383694
16.
Isr Med Assoc J ; 4(12): 1111-4, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12516902

RESUMO

BACKGROUND: Open neural tube defects are among the most common malformations of the fetus. Secondary prevention by early diagnosis during pregnancy and abortion of affected fetuses result in a marked reduction of NTD incidence at birth. The dramatic effect of folic acid for primary prevention of these defects led to recommendations for folic acid supplementation in women of reproductive age. OBJECTIVE: To describe the epidemiologic features of NTD in Israel in 1999-2000. METHODS: A national registry of NTD was begun in 1999. During the years 1999-2000, a non-syndromic NTD was diagnosed in at least 394 pregnancies (166 anencephaly, 166 spina bifida, 43 encephalocele, and 19 with other types of NTD). The religious-ethnic affiliation was known in 392 cases (209 Jews and 183 non-Jews). RESULTS: Despite a marked decline in the rate of NTD at birth in the last few decades, the total rates during pregnancy did not change significantly, demonstrating that the changes were secondary to termination of affected pregnancies. At birth, NTD were almost four times more frequent among non-Jews (3.6 per 10,000 live births for anencephaly and 5.9 for spina bifida) than among Jews (anencephaly 1/10,000 live births, spina bifida 1.4/10,000 live births). The complete data of the registry showed an approximately twofold difference in the overall rates during pregnancy between Jews (anencephaly 5.3, spina bifida 4.6, total 11/10,000 live births) and non-Jews (anencephaly 8.8, spina bifida 10.3, total 22.3/10,000 live births). The registry demonstrated that the significant differences in NTD incidence observed at birth between Jews and non-Jews are secondary to a combined effect of a higher frequency of the malformations among non-Jews and a lower proportion of termination of affected pregnancies among non-Jews. CONCLUSIONS: The data presented here will serve as a basis for evaluating the impact of the Ministry of Health recommendations for folic acid supplementation on the incidence of NTD.


Assuntos
Defeitos do Tubo Neural/epidemiologia , Aborto Terapêutico/estatística & dados numéricos , Adulto , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Incidência , Israel/epidemiologia , Judeus/estatística & dados numéricos , Masculino , Defeitos do Tubo Neural/diagnóstico , Vigilância da População , Gravidez , Diagnóstico Pré-Natal , Sistema de Registros
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