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1.
Mol Genet Genomic Med ; 7(6): e660, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30950243

RESUMO

BACKGROUND: Early-onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by mutations in many genes. Nevertheless, to date, 30%-40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease. METHODS: Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit-lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay. RESULTS: Clinical assessment showed a typical early-onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift. CONCLUSION: Here, we report the first near-exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early-onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.

2.
Hum Genet ; 138(1): 61-72, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30535804

RESUMO

ATP2B2 encodes the PMCA2 Ca2+ pump that plays an important role in maintaining ion homeostasis in hair cells among others by extrusion of Ca2+ from the stereocilia to the endolymph. Several mouse models have been described for this gene; mice heterozygous for loss-of-function defects display a rapidly progressive high-frequency hearing impairment. Up to now ATP2B2 has only been reported as a modifier, or in a digenic mechanism with CDH23 for hearing impairment in humans. Whole exome sequencing in hearing impaired index cases of Dutch and Polish origins revealed five novel heterozygous (predicted to be) loss-of-function variants of ATP2B2. Two variants, c.1963G>T (p.Glu655*) and c.955delG (p.Ala319fs), occurred de novo. Three variants c.397+1G>A (p.?), c.1998C>A (p.Cys666*), and c.2329C>T (p.Arg777*), were identified in families with an autosomal dominant inheritance pattern of hearing impairment. After normal newborn hearing screening, a rapidly progressive high-frequency hearing impairment was diagnosed at the age of about 3-6 years. Subjects had no balance complaints and vestibular testing did not yield abnormalities. There was no evidence for retrocochlear pathology or structural inner ear abnormalities. Although a digenic inheritance pattern of hearing impairment has been reported for heterozygous missense variants of ATP2B2 and CDH23, our findings indicate a monogenic cause of hearing impairment in cases with loss-of-function variants of ATP2B2.


Assuntos
Biomarcadores/análise , Predisposição Genética para Doença , Perda Auditiva/genética , Mutação , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Prognóstico , Adulto Jovem
3.
Eur J Hum Genet ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291343

RESUMO

Clinical genomic sequencing can identify pathogenic variants unrelated to the initial clinical question, but of medical relevance to the patients and their families. With ongoing discussions on the utility of disclosing or searching for such variants, it is of crucial importance to obtain unbiased insight in the prevalence of these incidental or secondary findings, in order to better weigh potential risks and benefits. Previous studies have reported a broad range of secondary findings ranging from 1 to 9%, merely attributable to differences in study design, cohorts tested, sequence technology used and genes analyzed. Here, we analyzed WES data of 1640 anonymized healthy Dutch individuals to establish the frequency of medically actionable disease alleles in an outbred population of European descent. Our study shows that 1 in 38 healthy individuals (2.7%) has a (likely) pathogenic variant in one of 59 medically actionable dominant disease genes for which the American College of Medical Genetics and Genomics (ACMG) recommends disclosure. Additionally, we identified 36 individuals (2.2%) to be a carrier of a recessive pathogenic disease allele. Whereas these frequencies of secondary findings are in line with what has been reported in the East-Asian population, the pathogenic variants are differently distributed across the 59 ACMG genes. Our results contribute to the debate on genetic risk factor screening in healthy individuals and the discussion whether the potential benefits of this knowledge and related preventive options, outweigh the risk of the emotional impact of the test result and possible stigmatization.

4.
Am J Hum Genet ; 103(1): 74-88, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29961571

RESUMO

In a Dutch consanguineous family with recessively inherited nonsyndromic hearing impairment (HI), homozygosity mapping combined with whole-exome sequencing revealed a MPZL2 homozygous truncating variant, c.72del (p.Ile24Metfs∗22). By screening a cohort of phenotype-matched subjects and a cohort of HI subjects in whom WES had been performed previously, we identified two additional families with biallelic truncating variants of MPZL2. Affected individuals demonstrated symmetric, progressive, mild to moderate sensorineural HI. Onset of HI was in the first decade, and high-frequency hearing was more severely affected. There was no vestibular involvement. MPZL2 encodes myelin protein zero-like 2, an adhesion molecule that mediates epithelial cell-cell interactions in several (developing) tissues. Involvement of MPZL2 in hearing was confirmed by audiometric evaluation of Mpzl2-mutant mice. These displayed early-onset progressive sensorineural HI that was more pronounced in the high frequencies. Histological analysis of adult mutant mice demonstrated an altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti. In addition, we observed mild degeneration of spiral ganglion neurons, and this degeneration was most pronounced at the cochlear base. Although MPZL2 is known to function in cell adhesion in several tissues, no phenotypes other than HI were found to be associated with MPZL2 defects. This indicates that MPZL2 has a unique function in the inner ear. The present study suggests that deleterious variants of Mplz2/MPZL2 affect adhesion of the inner-ear epithelium and result in loss of structural integrity of the organ of Corti and progressive degeneration of hair cells, supporting cells, and spiral ganglion neurons.

5.
Hum Genet ; 2018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29754270

RESUMO

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein-protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.

6.
Genet Med ; 20(5): 480-485, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29121006

RESUMO

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole-genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (

Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Testes Genéticos , Diagnóstico Pré-Natal , Trissomia , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos/métodos , Genômica/métodos , Humanos , Placenta/metabolismo , Gravidez , Resultado da Gravidez , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Genoma
7.
JIMD Rep ; 40: 11-16, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28887793

RESUMO

A boy presented at the age of 3.5 months with a developmental delay. He developed infantile spasms with hypsarrhytmia on EEG 1 month later. Additional symptoms were delayed visual development, asymmetrical hearing loss, hypotonia, and choreoathetoid movements. He also had some dysmorphic features and was vulnerable for infections. He was treated successively with vigabatrin, prednisolone, valproic acid, nitrazepam, and lamotrigine without a lasting clinical effect, but showed a treatment response to levetiracetam. Cerebral MRI showed hypoplasia of the corpus callosum and a mild delay in myelination. Further investigations including metabolic screening and glycosylation studies by transferrin isoelectric focusing were all considered to be normal. Whole-exome sequencing identified a de novo mutation in the ALG13 gene (c.320A>G, p.(Asn107Ser)). Mutations in this gene, which is located on the X-chromosome, are associated with congenital disorders of glycosylation type I (CDG-I). Mass spectrometric analysis of transferrin showed minor glycosylation abnormalities. The c.320A>G mutation in ALG13 has until now only been described in girls and was thought to be lethal for boys. All girls with this specific mutation presented with a similar phenotype of developmental delay and severe early onset epilepsy. In two girls glycosylation studies were performed which showed a normal glycosylation pattern. This is the first boy presenting with an epileptic encephalopathy caused by the c.320A>G mutation in the ALG13 gene. Since glycosylation studies are near-normal in patients with this mutation, the diagnosis of ALG13-CDG can be missed if genetic studies are not performed.

8.
Hear Res ; 347: 56-62, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28089734

RESUMO

DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.


Assuntos
Códon sem Sentido , Mutação da Fase de Leitura , Perda Auditiva Neurossensorial/genética , Audição/genética , Proteínas dos Microfilamentos/genética , Limiar Auditivo , Análise Mutacional de DNA , Marcadores Genéticos , Predisposição Genética para Doença , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/fisiopatologia , Perda Auditiva Neurossensorial/psicologia , Testes Auditivos , Hereditariedade , Humanos , Linhagem , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença
9.
Eur J Hum Genet ; 25(3): 308-314, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28000701

RESUMO

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.


Assuntos
Exoma , Testes Genéticos/estatística & dados numéricos , Perda Auditiva/genética , Análise de Sequência de DNA/estatística & dados numéricos , Conexinas/genética , Variações do Número de Cópias de DNA , Proteínas da Matriz Extracelular/genética , Proteínas Ligadas por GPI/genética , Testes Genéticos/normas , Perda Auditiva/diagnóstico , Perda Auditiva/epidemiologia , Humanos , Proteínas de Membrana/genética , Mutação , Cadeias Pesadas de Miosina/genética , Miosinas/genética , Países Baixos , Análise de Sequência de DNA/normas
11.
Eur J Hum Genet ; 24(10): 1409-16, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27189020

RESUMO

Early in pregnancy women and their partners face the complex decision on whether or not to participate in prenatal testing for fetal chromosomal abnormalities. Several studies show that the majority of pregnant women currently do not make informed decisions regarding prenatal testing. As the range of prenatal tests is expanding due to the development of new techniques such as non-invasive prenatal testing (NIPT), autonomous reproductive decision-making is increasingly challenging. In this study, a randomised controlled trial was conducted to evaluate the effect of a web-based multimedia decision aid on decision-making regarding prenatal testing. The decision aid provided both written and audiovisual information on prenatal tests currently available, that is, prenatal screening by first-trimester combined testing, NIPT and invasive diagnostic testing through chorionic villus sampling or amniocentesis. Furthermore, it contained values clarification exercises encouraging pregnant women to reflect on the potential harms and benefits of having prenatal tests performed. The use of the decision aid improved informed decision-making regarding prenatal testing. Of pregnant women allocated to the intervention group (n=130) 82.3% made an informed choice compared with 66.4% of women in the control group (n=131), P=0.004. As the vast majority of pregnant women made decisions consistent with their attitudes towards having prenatal testing performed, this improvement in informed decision-making could be attributed mainly to an increase in decision-relevant knowledge. This study shows that the implementation of a web-based multimedia decision aid directly facilitates the ultimate goal of prenatal testing for fetal chromosomal abnormalities, which is enabling informed autonomous reproductive choice.


Assuntos
Consentimento Livre e Esclarecido , Educação de Pacientes como Assunto , Diagnóstico Pré-Natal/psicologia , Adulto , Tomada de Decisões , Feminino , Humanos , Internet , Gravidez
12.
Hum Mol Genet ; 25(5): 892-902, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26721934

RESUMO

Recently, we marked TRIO for the first time as a candidate gene for intellectual disability (ID). Across diverse vertebrate species, TRIO is a well-conserved Rho GTPase regulator that is highly expressed in the developing brain. However, little is known about the specific events regulated by TRIO during brain development and its clinical impact in humans when mutated. Routine clinical diagnostic testing identified an intragenic de novo deletion of TRIO in a boy with ID. Targeted sequencing of this gene in over 2300 individuals with ID, identified three additional truncating mutations. All index cases had mild to borderline ID combined with behavioral problems consisting of autistic, hyperactive and/or aggressive behavior. Studies in dissociated rat hippocampal neurons demonstrated the enhancement of dendritic formation by suppressing endogenous TRIO, and similarly decreasing endogenous TRIO in organotypic hippocampal brain slices significantly increased synaptic strength by increasing functional synapses. Together, our findings provide new mechanistic insight into how genetic deficits in TRIO can lead to early neuronal network formation by directly affecting both neurite outgrowth and synapse development.


Assuntos
Transtorno Autístico/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Mutação , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/genética , Agitação Psicomotora/genética , Sinapses/metabolismo , Adulto , Animais , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Criança , Feminino , Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/deficiência , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Neurogênese , Neurônios/patologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/deficiência , Agitação Psicomotora/metabolismo , Agitação Psicomotora/patologia , Ratos , Análise de Sequência de DNA , Índice de Gravidade de Doença , Sinapses/patologia
13.
Eur J Hum Genet ; 24(1): 2-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26508566

RESUMO

We present, on behalf of EuroGentest and the European Society of Human Genetics, guidelines for the evaluation and validation of next-generation sequencing (NGS) applications for the diagnosis of genetic disorders. The work was performed by a group of laboratory geneticists and bioinformaticians, and discussed with clinical geneticists, industry and patients' representatives, and other stakeholders in the field of human genetics. The statements that were written during the elaboration of the guidelines are presented here. The background document and full guidelines are available as supplementary material. They include many examples to assist the laboratories in the implementation of NGS and accreditation of this service. The work and ideas presented by others in guidelines that have emerged elsewhere in the course of the past few years were also considered and are acknowledged in the full text. Interestingly, a few new insights that have not been cited before have emerged during the preparation of the guidelines. The most important new feature is the presentation of a 'rating system' for NGS-based diagnostic tests. The guidelines and statements have been applauded by the genetic diagnostic community, and thus seem to be valuable for the harmonization and quality assurance of NGS diagnostics in Europe.


Assuntos
Acreditação/legislação & jurisprudência , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/normas , Proteínas/genética , Biomarcadores/metabolismo , Bases de Dados Genéticas , Europa (Continente) , Expressão Gênica , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Achados Incidentais , Disseminação de Informação/legislação & jurisprudência , Consentimento Livre e Esclarecido , Projetos de Pesquisa/normas , Sensibilidade e Especificidade
14.
Ear Hear ; 37(1): 103-11, 2016 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26331839

RESUMO

OBJECTIVES: Mutations in EYA4 can cause nonsyndromic autosomal dominant sensorineural hearing impairment (DFNA10) or a syndromic variant with hearing impairment and dilated cardiomyopathy. A mutation in EYA4 was found in a Dutch family, causing DFNA10. This study is focused on characterizing the hearing impairment in this family. DESIGN: Whole exome sequencing was performed in the proband. In addition, peripheral blood samples were collected from 23 family members, and segregation analyses were performed. All participants underwent otorhinolaryngological examinations and pure-tone audiometry, and 12 participants underwent speech audiometry. In addition, an extended set of audiometric measurements was performed in five family members to evaluate the functional status of the cochlea. Vestibular testing was performed in three family members. Two individuals underwent echocardiography to evaluate the nonsyndromic phenotype. RESULTS: The authors present a Dutch family with a truncating mutation in EYA4 causing a mid-frequency hearing impairment. This mutation (c.464del) leads to a frameshift and a premature stop codon (p.Pro155fsX). This mutation is the most N-terminal mutation in EYA4 found to date. In addition, a missense mutation, predicted to be deleterious, was found in EYA4 in two family members. Echocardiography in two family members revealed no signs of dilated cardiomyopathy. Results of caloric and velocity step tests in three family members showed no abnormalities. Hearing impairment was found to be symmetric and progressive, beginning as a mid-frequency hearing impairment in childhood and developing into a high-frequency, moderate hearing impairment later in life. Furthermore, an extended set of audiometric measurements was performed in five family members. The results were comparable to those obtained in patients with other sensory types of hearing impairments, such as patients with Usher syndrome type IIA and presbyacusis, and not to those obtained in patients with (cochlear) conductive types of hearing impairment, such as DFNA8/12 and DFNA13. CONCLUSIONS: The mid-frequency hearing impairment in the present family was found to be symmetric and progressive, with a predominantly childhood onset. The results of psychophysical measurements revealed similarities to other conditions involving a sensory type of hearing impairment, such as Usher syndrome type IIA and presbyacusis. The study results suggest that EYA4 is expressed in the sensory cells of the cochlea. This phenotypic description will facilitate counseling for hearing impairment in DFNA10 patients.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Família , Perda Auditiva Neurossensorial/fisiopatologia , Percepção da Fala , Adolescente , Adulto , Idoso , Audiometria da Fala , Criança , Progressão da Doença , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Transativadores/genética , Testes de Função Vestibular
15.
Prenat Diagn ; 35(10): 945-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25767004

RESUMO

OBJECTIVE: With a shift towards noninvasive testing, we have explored and validated the use of noninvasive prenatal diagnosis (NIPD) for Huntington disease (HD). METHODS: Fifteen couples have been included, assessing a total of n = 20 pregnancies. Fetal paternally inherited CAG repeat length was determined in total cell-free DNA from maternal plasma using a direct approach by PCR and subsequent fragment analysis. RESULTS: All fetal HD (n = 7) and intermediate (n = 3) CAG repeats could be detected in maternal plasma. Detection of repeats in the normal range (n = 10) was successful in n = 5 cases where the paternal repeat size could be distinguished from maternal repeat patterns after fragment analysis. In all other cases (n = 5), the paternal peaks coincided with the maternal peak pattern. All NIPD results were concordant with results from routine diagnostics on fetal genomic DNA from chorionic villi. CONCLUSION: In this validation study, we demonstrated that all fetuses at risk for HD could be identified noninvasively in maternal plasma. Additionally, we have confirmed results from previously described case reports that NIPD for HD can be performed using a direct approach by PCR. For future diagnostics, parental CAG profiles can be used to predict the success rate for NIPD prior to testing.


Assuntos
Doença de Huntington/diagnóstico , Testes para Triagem do Soro Materno , Proteínas do Tecido Nervoso/genética , Feminino , Humanos , Proteína Huntingtina , Doença de Huntington/sangue , Doença de Huntington/genética , Masculino , Gravidez
16.
Prenat Diagn ; 35(6): 549-57, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25644120

RESUMO

OBJECTIVE: This study evaluates pregnant women's and healthcare professionals' preferences regarding specific prenatal screening and diagnostic test characteristics. METHOD: A discrete choice experiment was developed to assess preferences for prenatal tests that differed in seven attributes: minimal gestational age, time to test results, level of information, detection rate, false positive rate, miscarriage risk and costs. RESULTS: The questionnaire was completed by 596 (70.2%) pregnant women and 297 (51.7%) healthcare professionals, of whom 507 (85.1%) and 283 (95.3%), respectively, were included in further analyses as their choice behavior indicated prenatal testing was an option to them. Comparison of results showed differences in relative importance attached to attributes, further reflected by differences in willingness to trade between attributes. Pregnant women are willing to accept a less accurate test to obtain more information on fetal chromosomal status or to exclude the risk of procedure-related miscarriage. Healthcare professionals consider level of information and miscarriage risk to be most important as well but put more emphasis on timing and accuracy. CONCLUSION: Pregnant women and healthcare professionals differ significantly in their preferences regarding prenatal test characteristics. Healthcare professionals should take these differences into consideration when counseling pregnant women on prenatal testing.


Assuntos
Atitude do Pessoal de Saúde , Comportamento de Escolha , Tocologia , Obstetrícia , Preferência do Paciente , Diagnóstico Pré-Natal/métodos , Aborto Espontâneo/etiologia , Adolescente , Adulto , Reações Falso-Positivas , Feminino , Idade Gestacional , Custos de Cuidados de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Diagnóstico Pré-Natal/efeitos adversos , Diagnóstico Pré-Natal/economia , Sensibilidade e Especificidade , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem
17.
Eur J Obstet Gynecol Reprod Biol ; 182: 53-61, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25238658

RESUMO

OBJECTIVE: Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy. Clinical trials have shown high sensitivity and specificity for trisomy 21 (T21) in both high-risk and average-risk populations. Although its great potential for prenatal medicine is evident, more information regarding the consequences of implementing NIPT in a national programme for prenatal screening is required. STUDY DESIGN: A decision-analytic model was developed to compare costs and outcomes of current clinical practice in The Netherlands using conventional screening only, with two alternatives: implementing NIPT as an optional secondary screening test for those pregnancies complicated by a high risk for T21, and implementing NIPT as primary screening test, replacing conventional screening. Probability estimates were derived from a systematic review of international literature. Costs were determined from a health-care perspective. Data were analysed to obtain outcomes, total costs, relative costs and incremental cost-effectiveness ratios (ICERs) for the different strategies. Sensitivity analysis was used to assess the impact of assumptions on model results. RESULTS: Implementing NIPT as an optional secondary, or as primary screening test will increase T21 detection rate by 36% (from 46.8% to 63.5%) and 54% (from 46.8% to 72.0%), simultaneously decreasing the average risk of procedure-related miscarriage by 44% (from 0.0168% to 0.0094% per pregnant woman) and 62% (from 0.0168% to 0.0064% per pregnant woman), respectively. None of the strategies clearly dominated: current clinical practice is the least costly, whereas implementing NIPT will cause total costs of the programme to increase by 21% (from €257.09 to €311.74 per pregnant woman), leading to an ICER of k€94 per detected case of T21, when utilised as an optional secondary screening test and by 157% (from €257.09 to €660.94 per pregnant woman), leading to an ICER of k€460 per detected case of T21, when utilised as primary screening test. However, implementing NIPT as triage test did result in the lowest expected relative costs per case of T21 diagnosed (k€141). CONCLUSION: NIPT should be implemented in national health care as an optional secondary screening test for those pregnancies complicated by a high risk for T21.


Assuntos
DNA/sangue , Síndrome de Down/diagnóstico , Testes Genéticos/economia , Política de Saúde/economia , Diagnóstico Pré-Natal/economia , Aborto Espontâneo/etiologia , Adulto , Amniocentese/efeitos adversos , Amniocentese/economia , Aneuploidia , Amostra da Vilosidade Coriônica/efeitos adversos , Amostra da Vilosidade Coriônica/economia , Análise Custo-Benefício , Árvores de Decisões , Feminino , Humanos , Países Baixos , Gravidez , Diagnóstico Pré-Natal/efeitos adversos , Diagnóstico Pré-Natal/métodos , Fatores de Risco , Ultrassonografia Pré-Natal
18.
J Clin Invest ; 124(3): 1214-27, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24487590

RESUMO

The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein­coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Síndrome de Kallmann/genética , Bulbo Olfatório/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Olfato , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Diferenciação Celular , Movimento Celular , Criança , Anormalidades Congênitas/genética , Orelha/anormalidades , Proteínas do Olho/metabolismo , Feminino , Expressão Gênica , Estudos de Associação Genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/patologia , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Peptídeos/metabolismo , Proteínas Repressoras/metabolismo , Transcriptoma
19.
Ear Hear ; 35(3): e84-91, 2014 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24378291

RESUMO

OBJECTIVES: Recently, OTOG and OTOGL were identified as human deafness genes. Currently, only four families are known to have autosomal recessive hearing loss based on mutations in these genes. Because the two genes code for proteins (otogelin and otogelin-like) that are strikingly similar in structure and localization in the inner ear, this study is focused on characterizing and comparing the hearing loss caused by mutations in these genes. DESIGN: To evaluate this type of hearing, an extensive set of audiometric and vestibular examinations was performed in the 13 patients from four families. RESULTS: All families show a flat to downsloping configuration of the audiogram with mild to moderate sensorineural hearing loss. Speech recognition scores remain good (>90%). Hearing loss is not significantly different in the four families and the psychophysical test results also do not differ among the families. Vestibular examinations show evidence for vestibular hyporeflexia. CONCLUSION: Because otogelin and otogelin-like are localized in the tectorial membrane, one could expect a cochlear conductive hearing loss, as was previously shown in DFNA13 (COL11A2) and DFNA8/12 (TECTA) patients. Results of psychophysical examinations, however, do not support this. Furthermore, the authors conclude that there are no phenotypic differences between hearing loss based on mutations in OTOG or OTOGL. This phenotype description will facilitate counseling of hearing loss caused by defects in either of these two genes.


Assuntos
Perda Auditiva Neurossensorial/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Emissões Otoacústicas Espontâneas/genética , Reflexo Anormal/genética , Reflexo Vestíbulo-Ocular/genética , Adolescente , Adulto , Audiometria de Tons Puros , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , Mutação , Fenótipo , Reflexo Acústico/genética , Teste do Limiar de Recepção da Fala , Testes de Função Vestibular , Adulto Jovem
20.
Mol Cytogenet ; 7(1): 6, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24428858

RESUMO

BACKGROUND: The aim of this study was to evaluate the best diagnostic approach for the genetic analysis of samples from first, second and third trimester intrauterine fetal deaths (IUFDs). We examined a total of 417 IUFD samples from fetuses with and without congenital anomalies. On 414 samples, karyotyping (N = 46) and/or rapid aneuploidy testing by QF-PCR (N = 371) was performed). One hundred sixty eight samples with a normal test result were subsequently tested by genome wide Single Nucleotide Polymorphism (SNP) array analysis. Three samples were only analyzed by array. RESULTS: In 50 (12.0%) samples an aneuploidy was detected by QF-PCR and/or karyotyping, representing 47.1% of first, 13.2% of second and 3.4% of third trimester pregnancies. Karyotyping and QF-PCR failed in 4 (8.7%) and 7 (1.9%) samples, respectively, concerning mostly contaminated amniotic fluid samples from third trimester pregnancies.Clinically relevant aberrations were identified in 4.2% (all fetuses with malformations) of the 168 samples tested by SNP array. Inherited copy number variants (CNVs) were detected in 5.4% and 8.9% showed CNVs of unknown clinical relevance as parental inheritance could not be studied yet. In a sample from a fetus suspect for Meckel-Grüber syndrome, the genotype information from the SNP array revealed various stretches of homozygosity, including one stretch encompassing the CEP290 gene. Subsequent CEP290 mutation analysis revealed a homozygous, pathogenic mutation in this gene. CONCLUSIONS: Based on our experience we recommend QF-PCR as the first-line test in IUFD samples of first and second trimester pregnancies to exclude aneuploidy before performing array analysis. The chance to detect aneuploidy in third trimester pregnancies is relatively low and therefore array analysis can be performed as a first-tier test. A tissue sample, instead of amniotic fluid, is preferred because of a higher success rate in testing.We emphasize the need for analysis of parental samples whenever a rare, unique CNV is detected to allow for better interpretation of such findings and to improve future pregnancy management. Furthermore, we illustrate the strength of SNP arrays for genotype analysis, even though we realize it is crucial to have detailed phenotypic information to make optimal use of the genotype data in finding candidate recessive genes that may be related to the fetal phenotype.

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