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1.
Eur J Endocrinol ; 183(2): R29-R40, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32580146

RESUMO

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter's syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.


Assuntos
Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/fisiopatologia , Desidratação/prevenção & controle , Diabetes Insípido Nefrogênico/terapia , Feminino , Triagem de Portadores Genéticos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Testes Genéticos , Humanos , Hipernatremia , Recém-Nascido , Glomérulos Renais/fisiopatologia , Masculino , Mutação , Neurofisinas/sangue , Neurofisinas/fisiologia , Concentração Osmolar , Gravidez , Diagnóstico Pré-Natal , Precursores de Proteínas/sangue , Precursores de Proteínas/fisiologia , Receptores de Vasopressinas/genética , Receptores de Vasopressinas/fisiologia , Vasopressinas/sangue , Vasopressinas/fisiologia
3.
Acta Obstet Gynecol Scand ; 99(6): 802-808, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32242916

RESUMO

INTRODUCTION: The Israeli population, encompassing 9 million citizens, is comprised of diverse communities. The Ministry of Health genetic screening program for reproductive purposes was introduced in 2013. This program is mainly aimed at severe incurable diseases with high rates of infant and childhood morbidity and/or mortality, with a carrier frequency of at least 1:60 and/or a disease frequency of 1 in 15 000 live births. In this paper, we present the results of the national genetic carrier-screening program implementation. MATERIAL AND METHODS: Data acquisition for this study was performed by retrospectively searching Ministry of Health database, which includes the reports of 18 genetic laboratories performing genetic screening tests. RESULTS: During 2015-2017, a total of 919 820 carrier-screening genetic tests were executed. The overall number rose by 14.9% over these years. For about two-thirds of the presented disorders, carrier frequency was within the expected range. A decrease of 57% was noted in the observed number of patients with spinal muscular atrophy born during 2014-2017, compared with the expected rate. Familial dysautonomia, Canavan and Tay-Sachs diseases yielded a very low prevalence. CONCLUSIONS: Our results highlight the impact of a national genetic carrier-screening program. Couples at risk of an affected fetus mostly choose to perform preconception or prenatal diagnosis and to act accordingly. Our country has several characteristics enabling us to achieve this success, including considerable rates of endogamy and consanguineous marriages, increased frequency of founder mutations, and high fertility rates. In addition, wide accessibility of the tests and good compliance of the population must be noted. Still, raising the awareness and continuing education of population and caregivers about the importance and efficiency of carrier screening remains an important issue. Finally, expanding the existing tests into a uniform, wide genetic panel seems to be the next goal.


Assuntos
Triagem de Portadores Genéticos/estatística & dados numéricos , Aborto Induzido/estatística & dados numéricos , Grupos Étnicos/genética , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Israel , Gravidez , Estudos Retrospectivos
4.
Acta méd. costarric ; 62(1): 38-42, ene.-mar. 2020. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1088534

RESUMO

Resumen La enfermedad por hemoglobina H es un cuadro clínico que se presenta en las alfa talasemias, las cuales son enfermedades que cursan con anemia microcítica hipocrómica, debidas principalmente a deleciones en el gen de alfaglobina, lo que disminuye la producción de la cadena de alfa globina y promueve la formación de variantes de hemoglobina. Cuando se detectan variantes de hemoglobina en las alfa talasemias, por lo general, se debe a genotipos homocigotas o dobles heterocigotas para mutaciones y deleciones del gen de alfa globina coheredadas. En este artículo se describe el primer caso en Costa Rica, de dos hermanos con enfermedad por hemoglobina H, que fenotípicamente presentaron las variantes de hemoglobina H y hemoglobina Constant Spring en el análisis electroforético de la hemoglobina, y cuyo análisis molecular del gen de alfa globina detectó tanto la deleción sudeste asiático como la mutación para hemoglobina Constant Spring, siendo diagnosticados como dobles heterocigotos por alfa talasemia (genotipo --SEA/ααCS).


Abstract Hemoglobin H disease occurs in patients with alpha thalassemia, diseases associated with hypochromic microcytic anemia, mainly due to deletions in the alpha globin gene, which decreases the production of the alpha globin chain and promotes the formation of hemoglobin variants. When hemoglobin variants are detected in alpha thalassemias it is usually due to homozygoys or doublé heterozygous genotypes, for mutations and deletions of the alpha globin gene. This article describes the first case in Costa Rica of two siblings with hemoglobin H disease, who phenotypically presented the hemoglobin H and Constant Spring hemoglobin variants in the electrophoretic analysis of the hemoglobin, and whose molecular DNA analysis of the alpha globin gene detected both, the Southeast Asian deletion and the mutation for Constant Spring Hemoglobin, being diagnosed as compound heterozygous for alpha thalassemia (genotipe --SEA/ααCS).


Assuntos
Humanos , Feminino , Lactente , Hemoglobina H , Talassemia alfa , Costa Rica , Hemoglobinopatias/genética , Triagem de Portadores Genéticos , Anemia Hipocrômica
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 384-388, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219818

RESUMO

OBJECTIVE: To perform carrier screening for spinal muscular atrophy (SMA) among 3049 reproductive-age individuals from Yunnan region and determine the copy number of survival motor neuron (SMN) gene and carrier frequencies. METHODS: Multiplex ligation-dependent probe amplification (MLPA) was used to determine the copy number of exon 7 of SMN1 and SMN2 genes and identify those with a single copy of SMN1 gene. Prenatal diagnosis was performed for couples whom were both found to be SMA carriers. RESULTS: In total 62 SMA carriers were identified among the 3049 subjects, which yielded a carrier frequency of 1 in 49 (2.03%). No statistical difference was found in the carrier frequency between males and females (1.91% vs. 2.30%, P>0.05). Respectively, 1.3% (41/3049) and 0.69% (21/3049) of the carriers were caused by heterozygous deletion and conversion of the SMN1 gene. The average copy number for SMN1 alleles was 1.99. Two couples were found to be both as SMA carriers, for whom the birth of an affected fetus was avoided by prenatal diagnosis. CONCLUSION: No difference was found in the carrier frequency of SMA-related mutations between the two genders in Yunnan region, which was in keeping to an autosomal recessive inheritance pattern. Determination of the carrier frequency for SMA and SMN gene variants may provide a basis for genetic counseling and prenatal diagnosis for the disease.


Assuntos
Triagem de Portadores Genéticos , Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , China , Feminino , Aconselhamento Genético , Variação Genética , Heterozigoto , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , Proteína 2 de Sobrevivência do Neurônio Motor/genética
6.
BMC Med Genet ; 21(1): 20, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005174

RESUMO

BACKGROUND: X-linked ichthyosis (XLI; OMIM# 308100) is a recessive keratinization disorder characterized by the presence of dark brown, polygonal, adherent scales on different parts of the body surface. It almost exclusively affects males and the estimated prevalence ranges from 1:2000-6000 in males worldwide. Extracutaneous manifestations are frequent including corneal opacities, cryptorchidism, neuropsychiatric symptoms or others. Up to 90% of XLI cases are caused by recurrent hemizygous microdeletion encompassing entire STS gene on chromosome Xp22.3, while only a minority of patients shows partial deletions or loss of function point mutations in STS. Larger deletions also involving contiguous genes are identified in syndromic patients. METHODS: Here, we report clinical and genetic findings of a large Pakistani family having 16 affected individuals including 2 females with XLI. Molecular karyotyping and direct DNA sequencing of coding region of the STS gene was performed. RESULTS: The clinical manifestations in affected individuals involved generalized dryness and scaling of the skin with polygonal, dark scales of the skin on scalp, trunk, limbs, and neck while sparing face, palms and soles. There were no associated extra-cutaneous features such as short stature, cryptorchidism, photophobia, corneal opacities, male baldness, and behavioral, cognitive, or neurological phenotypes including intellectual disability, autism or attention deficit hyperactivity disorder. Molecular karyotyping was normal and no copy number variation was found. Sanger sequencing identified a novel hemizygous nonsense mutation (c.287G > A; p.W96*), in exon 4 of STS gene in all affected male individuals. In addition, two XLI affected females in the family were found to be homozygous for the identified variant. CONCLUSIONS: This study is useful for understanding the genetic basis of XLI in the patients studied, for extending the known mutational spectrum of STS, diagnosis of female carriers and for further application of mutation screening in the genetic counseling of this family.


Assuntos
Triagem de Portadores Genéticos , Ictiose Ligada ao Cromossomo X/genética , Pele/metabolismo , Esteril-Sulfatase/genética , Adolescente , Adulto , Códon sem Sentido/genética , Variações do Número de Cópias de DNA/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Ictiose Ligada ao Cromossomo X/fisiopatologia , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Fenótipo , Deleção de Sequência/genética , Pele/patologia , Adulto Jovem
7.
Acta Obstet Gynecol Scand ; 99(6): 696-706, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32039470

RESUMO

INTRODUCTION: In assisted reproductive technology, aneuploidy is considered a primary cause of failed embryo implantation. This has led to the implementation of preimplantation genetic testing for aneuploidy in some clinics. The prevalence of aneuploidy and the use of aneuploidy screening during preimplantation genetic testing for inherited disorders has not previously been reviewed. Here, we systematically review the literature to investigate the prevalence of aneuploidy in blastocysts derived from patients carrying or affected by an inherited disorder, and whether screening for aneuploidy improves clinical outcomes. MATERIAL AND METHODS: PubMed and Embase were searched for articles describing preimplantation genetic testing for monogenic disorders and/or structural rearrangements in combination with preimplantation genetic testing for aneuploidy. Original articles reporting aneuploidy rates at the blastocyst stage and/or clinical outcomes (positive human chorionic gonadotropin, gestational sacs/implantation rate, fetal heartbeat/clinical pregnancy, ongoing pregnancy, miscarriage, or live birth/delivery rate on a per transfer basis) were included. Case studies were excluded. RESULTS: Of the 26 identified studies, none were randomized controlled trials, three were historical cohort studies with a reference group not receiving aneuploidy screening, and the remaining were case series. In weighted analysis, 34.1% of 7749 blastocysts were aneuploid. Screening for aneuploidy reduced the proportion of embryos suitable for transfer, thereby increasing the risk of experiencing a cycle without transferable embryos. In pooled analysis the percentage of embryos suitable for transfer was reduced from 57.5% to 37.2% following screening for aneuploidy. Among historical cohort studies, one reported significantly improved pregnancy and birth rates but did not control for confounding, one did not report any statistically significant difference between groups, and one properly designed study concluded that preimplantation genetic testing for aneuploidy enhanced the chance of achieving a pregnancy while simultaneously reducing the chance of miscarriage following single embryo transfer. CONCLUSIONS: On average, aneuploidy is detected in 34% of embryos when performing a single blastocyst biopsy derived from patients carrying or affected by an inherited disorder. Accordingly, when screening for aneuploidy, the risk of experiencing a cycle with no transferable embryos increases. Current available data on the clinical effect of preimplantation genetic testing for aneuploidy performed concurrently with preimplantation genetic testing for inherited disorders are sparse, rendering the clinical effect from preimplantation genetic testing for aneuploidy difficult to access.


Assuntos
Aneuploidia , Triagem de Portadores Genéticos , Testes Genéticos , Diagnóstico Pré-Implantação , Transferência Embrionária , Humanos , Mosaicismo , Prevalência
8.
Sci Rep ; 10(1): 1413, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996704

RESUMO

A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking. Therefore, genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.


Assuntos
Genes Recessivos/genética , Triagem de Portadores Genéticos/métodos , Transtornos do Neurodesenvolvimento/genética , Adolescente , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Triagem de Portadores Genéticos/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , República da Coreia/epidemiologia , Sequenciamento Completo do Exoma , Adulto Jovem
9.
J Clin Pathol ; 73(8): 488-492, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31980563

RESUMO

AIMS: Thalassaemia is one of the most common genetics disorders in the world, especially in southern China. The aim of the present study was to investigate the feasibility of combining the gap-PCR and next-generation sequencing (NGS) for thalassaemia carrier screening in the Chinese population. METHODS: Blood samples were obtained from 944 prepregnancy couples; thalassaemia carrier screening was performed by using a routine haematological method and a combination of gap-PCR and NGS method. RESULTS: We found that the α thalassaemia carrier rate was 11% (207/1888); the ß thalassaemia carrier rate was 3.7% (70/1888); the composite α thalassaemia and ß thalassaemia carrier rate was 0.4% (8/1888). We also identified seven novel mutations, including HBA1: c.412A>G, -50 (G>A), HBB: c.*+129T>A, HBB: c.-64G>C, HBB: c.-180G>C, HBB: c.*+5G>A and HBB: c.-113A>G. By comparing the combined gap-PCR and NGS method, the MCV+MCH and HbA2 detection strategy showed a lower sensitivity of 61.05% (105/172) and a higher missed diagnosis ratio of 38.95% (67/172) for α thalassaemia mutations. The sensitivity was improved with the MCV+MCH and HbA2 detection screen when compared with MCV+MCH detection for ß thalassaemia (98.51% vs 85.90%). CONCLUSIONS: Our study suggests the combined gap-PCR and NGS method is a cost-effective method for the thalassaemia carrier screening, particularly for the α thalassaemia mutation carriers.


Assuntos
Talassemia alfa/genética , Talassemia beta/genética , Adulto , China , Feminino , Triagem de Portadores Genéticos/métodos , Triagem de Portadores Genéticos/normas , Genótipo , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Mutação/genética , Reação em Cadeia da Polimerase/métodos , Cuidado Pré-Concepcional , Sensibilidade e Especificidade , Adulto Jovem , alfa-Globinas/genética , Globinas beta/genética
10.
Sci Data ; 7(1): 8, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913291

RESUMO

Cystic fibrosis (CF) is one of the most common genetic diseases worldwide with high carrier frequencies across different ethnicities. Next generation sequencing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has proven to be an effective screening tool to determine carrier status with high detection rates. Here, we evaluate the performance of the Swift Biosciences Accel-Amplicon CFTR Capture Panel using CFTR-positive DNA samples. This assay is a one-day protocol that allows for one-tube reaction of 87 amplicons that span all coding regions, 5' and 3'UTR, as well as four intronic regions. In this study, we provide the FASTQ, BAM, and VCF files on seven unique CFTR-positive samples and one normal control sample (14 samples processed including repeated samples). This method generated sequencing data with high coverage and near 100% on-target reads. We found that coverage depth was correlated with the GC content of each exon. This dataset is instrumental for clinical laboratories that are evaluating this technology as part of their carrier screening program.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Triagem de Portadores Genéticos , Composição de Bases , Humanos , Análise de Sequência de DNA
11.
Proc Natl Acad Sci U S A ; 117(3): 1621-1627, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31882447

RESUMO

Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.


Assuntos
Fibrose Cística/genética , Triagem de Portadores Genéticos , Heterozigoto , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/epidemiologia , Feminino , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Prevalência , Estudos Retrospectivos , Estados Unidos , Adulto Jovem
13.
Acta méd. costarric ; 61(4): 190-194, oct.-dic. 2019. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1054731

RESUMO

Resumen En este reporte de caso se describe el primer paciente doble heterocigoto para alfa+-talasemia tipo -3,7 y rasgo heterocigoto por hemoglobina S en Costa Rica, diagnosticado desde su nacimiento por medio del tamizaje neonatal como heterocigoto para hemoglobina S. Luego de la detección de la hemoglobina S por tamizaje, el paciente fue referido al servicio de Hematología del Hospital Nacional de Niños para su seguimiento, en donde se observa hemograma con índices y morfología de glóbulos rojos sugestivos de alfa talasemia, con presentación de electroforesis de hemoglobina con patrón AS cuya expresión relativa de HbS era menor de lo esperado, lo que motivó a efectuar estudio molecular del gen de alfa globina, que confirmó el diagnóstico de alfa talasemia con deleción heterocigota de tipo -3,7 en herencia conjunta con la heterocigosis de hemoglobina S.


Abstract In this case report we describe the first patient compound heterozygous for type -3.7 alpha+ thalassemia and sickle cell trait in Costa Rica, who was diagnosed from birth by neonatal screening as heterozygous for hemoglobin S. After detection of hemoglobin S by screening, the patient was referred to the Hematology service of the National Children`s Hospital for follow-up, where hemogram with indexes and morphology of red blood cells suggestive of alpha thalassemia is observed, presenting hemoglobin electrophoresis with AS pattern whose relative expression of hemoglobin S was lower tan expected, which led to a molecular study of the alpha globin gene confirming the diagnosis of alpha thalassemia with heretozygous deletion of type -3.7, in co-inheritance with hemoglobin S heterozygosis.


Assuntos
Humanos , Masculino , Recém-Nascido , Hemoglobina A , Hemoglobina Falciforme , Triagem Neonatal , Talassemia alfa , Costa Rica , Hemoglobinopatias , Triagem de Portadores Genéticos
14.
Genes (Basel) ; 10(11)2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718017

RESUMO

X-linked Emery-Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers-25 familial and 5 sporadic cases-seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.


Assuntos
Arritmias Cardíacas/diagnóstico , Triagem de Portadores Genéticos , Proteínas de Membrana/genética , Distrofia Muscular de Emery-Dreifuss/genética , Proteínas Nucleares/genética , Inativação do Cromossomo X/genética , Adulto , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Doenças Assintomáticas , Linhagem Celular Tumoral , Feminino , Aconselhamento Genético , Átrios do Coração/fisiopatologia , Heterozigoto , Humanos , Pessoa de Meia-Idade , Distrofia Muscular de Emery-Dreifuss/sangue , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Mutação , Fenótipo , Adulto Jovem
15.
BMC Med Genet ; 20(1): 165, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660881

RESUMO

BACKGROUND: Treatment of steroid-resistant nephrotic syndrome (SRNS) remains a challenge for paediatricians. SRNS accounts for 10~20% of childhood cases of nephrotic syndrome (NS). Individuals with SRNS overwhelmingly progress to chronic kidney disease (CKD) and end-stage kidney disease (ESRD). Genetic research is of great significance for diagnosis and treatment. More than 39 recessive or dominant genes have been found to cause human SRNS, including COQ2. COQ2 gene mutations not only cause primary coenzyme Q10 deficiency but also cause SRNS without extrarenal manifestations. The concept of COQ2 nephropathy has been proposed for a long time. Mutations in the COQ2 gene have rarely been reported. Worldwide, only 5 cases involving 4 families have been reported. CASE PRESENTATION: We present the case of a 6-month-old girl with steroid-resistant glomerulopathy due to a COQ2 defect with no additional systemic symptoms. The patient was identified as a homozygote for the c.832 T > C (p. Cys278Arg) missense mutation and a single base homozygous mutation in ARSB gene in c.1213 + 1G > A. The father and mother were heterozygous mutation carriers in both COQ2 and ARSB, and her healthy sister was only a heterozygous mutation carrier in COQ2. In this case, hormone therapy was ineffective, and progressive deterioration of renal function occurred within 1 week after onset, leading to acute renal failure and eventual death. CONCLUSIONS: We reported a consanguinity married family which had COQ2 and ARSB dual mutant. Kidney diseases caused by COQ2 gene mutations can manifest as SRNS, with poor prognosis. The C. 832 T > c (p.csc 278arg) is a new mutation site. Genetic assessment for children with steroid-resistant nephrotic syndrome, especially in infancy, is very important. Families with a clear family history should receive genetic counselling and prenatal examinations, and children without a family phenotype should also receive genetic screening as early as possible.


Assuntos
Alquil e Aril Transferases/genética , Consanguinidade , Casamento , Metilprednisolona/uso terapêutico , Mutação , N-Acetilgalactosamina-4-Sulfatase/genética , Síndrome Nefrótica/genética , Resistência a Medicamentos , Evolução Fatal , Feminino , Triagem de Portadores Genéticos , Homozigoto , Humanos , Lactente , Masculino , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/terapia , Linhagem , Diálise Peritoneal
16.
PLoS Genet ; 15(10): e1008409, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31589614

RESUMO

Limited translational genomic research data have been reported on the application of exome sequencing and parallel gene testing for preconception carrier screening (PCS). Here, we present individual-level data from a large PCS program in which exome sequencing was routinely performed on either gamete donors (5,845) or infertile patients (8,280) undergoing in vitro fertilization (IVF) treatment without any known family history of inheritable genetic conditions. Individual-level data on pathogenic variants were used to define conditions for PCS based on criteria for severity, penetrance, inheritance pattern, and age of onset. Fetal risk was defined based on actual carrier frequency data accounting for the specific inheritance pattern (fetal disease risk, FDR). In addition, large-scale application of exome sequencing for PCS allowed a deep investigation of the incidence of medically actionable secondary findings in this population. Exome sequencing achieved remarkable clinical sensitivity for reproductive risk of highly penetrant childhood-onset disorders (1/337 conceptions) through analysis of 114 selected gene-condition pairs. A significant contribution to fetal disease risk was observed for rare (carrier rate < 1:100) and X-linked conditions (16.7% and 41.2% of total FDR, respectively). Subgroup analysis of 776 IVF couples identified 37 at increased reproductive risk (4.8%; 95% CI = 3.4-6.5). Further, two additional couples had increased risk for very rare conditions when both members of a parental pair were treated as a unit and the search was extended to the entire exome. About 2.3% of participants showed at least one pathogenic variant for genes included in the updated American College of Medical Genetics and Genomics v2.0 list of secondary findings. Gamete donors and IVF couples showed similar carrier burden for both carrier screening and secondary findings, indicating no causal relationship to fertility. These translational research data will facilitate development of more effective PCS strategies that maximize clinical sensitivity with minimal counterproductive effects.


Assuntos
Genes Recessivos , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Infertilidade/genética , Adulto , Criança , Pré-Escolar , Doação Dirigida de Tecido , Exoma/genética , Feminino , Testes Genéticos , Genoma Humano/genética , Genômica , Heterozigoto , Humanos , Lactente , Recém-Nascido , Infertilidade/epidemiologia , Infertilidade/fisiopatologia , Masculino , Mutação/genética , Pesquisa Médica Translacional , Sequenciamento Completo do Exoma
17.
Rev. esp. enferm. dig ; 111(10): 775-788, oct. 2019. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-190451

RESUMO

Background and aims: heterozygous ABCB4, ABCB11 and ATP8B1 sequence variants were previously reported to be associated with low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis and biliary lithiasis. The present study aimed to identify the presence of sequence variations in genes responsible for Mendelian liver disorders in patients with cholestatic liver disease. Methods: targeted massive parallel sequencing of a panel of genes involved in bile acid homeostasis was performed in 105 young and adult patients with cholestatic liver disease in our laboratory for molecular diagnosis. The effects of novel variants were evaluated using bioinformatics prediction tools and the Protter and Phyre2 software programs were used to create 2D, 3D topology protein modeling. Genotype-phenotype correlation was established according to molecular analysis and clinical records. Results: twenty novel heterozygous ABCB4 sequence variations, one heterozygous ABCB4 large intragenic deletion and only one novel missense variant in ABCB11 and ATP8B1 were identified. Interestingly, heterozygous and homozygous SLC4A2 missense variants were detected in patients with low phospholipid-associated cholelithiasis. Two patients harbored heterozygous GPBAR1 variants. Common variants such as homozygous ABCB11 p.Val444Ala and heterozygous ABCG8 p.Asp19His were also identified in 12 cases. Conclusions: forty-eight variants were identified in five genes including ABCB4, ABCB11, ATP8B1, SLC4A2 and GPBAR1, twenty-five of which were novel. This study expands the phenotypic and mutational spectrum in genes involved in bile acid homeostasis and highlights the genetic and phenotypic heterogeneity in patients with inherited liver disorders


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Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Colestase/genética , Doenças Genéticas Inatas/diagnóstico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Colestase/diagnóstico , Predisposição Genética para Doença , Marcadores Genéticos , Triagem de Portadores Genéticos/métodos
18.
Obstet Gynecol ; 134(4): 756-758, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31503151

RESUMO

BACKGROUND: Genetic carrier screening of individuals with a history of hematopoietic stem cell (HSC) transplant is not always straightforward. CASE: We present the case of a couple who underwent prepregnancy genetic screening before fertility treatment. The genetics laboratory flagged the male partner's blood sample because there was a discrepancy between the sex of the patient and the sex chromosome markers, ultimately leading to the discovery of a prior HSC transplant. CONCLUSION: A history of HSC transplant may confound results of serum-based genetic carrier screening. Hematopoietic stem cell transplant recipients are at risk for misinterpreted genetic carrier screening because the results of such screening may not actually be reflective of their own DNA.


Assuntos
Triagem de Portadores Genéticos , Transplante de Células-Tronco Hematopoéticas , Feminino , Humanos , Masculino , Adulto Jovem
20.
Trans Am Clin Climatol Assoc ; 130: 216-234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31516187

RESUMO

In the first half of the 20th century, the US was swept up in a multifaceted movement to enhance the genetic makeup of the country's population. This eugenics movement, based on flawed scientific principles promulgated by Galton in the UK and Davenport in the US included legally mandated compulsory sterilization in 27 states in the US and sharply restricted immigration from many parts of the world. Compulsory sterilization legislation was upheld by the Supreme Court in 1927. The American eugenics movement was a model for the compulsory sterilization implemented by the Nazis after they took power in Germany in 1933. The movement waned in America only following World War II when the US public became aware of the full extent of the Nazi Aryan racial superiority program. With the advent of major advances in molecular and cellular biology that are already being applied to clinical medicine in the 21st century, we have entered a new eugenics era. It is critical that we learn the lessons of our earlier eugenics movement if we are to avoid making the same flawed decisions now.


Assuntos
Eugenia (Ciência)/história , Emigração e Imigração/história , Fertilização In Vitro/história , Terapias Fetais , Edição de Genes , Triagem de Portadores Genéticos , Terapia Genética , Sequenciamento de Nucleotídeos em Larga Escala , História do Século XX , História do Século XXI , Humanos , Recém-Nascido , Socialismo Nacional/história , Triagem Neonatal , Diagnóstico Pré-Implantação , Diagnóstico Pré-Natal , Análise de Sequência de DNA , Esterilização Involuntária/história , Estados Unidos
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