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1.
Prenat Diagn ; 44(1): 77-80, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38110236

RESUMEN

At 16 + 6-weeks a fetal scan performed in the second pregnancy of a 42 y.o. woman identified a right multicystic dysplastic kidney, left renal agenesis, absent urinary bladder, myocardial hypertrophy, increased nuchal fold, a single umbilical artery, and oligohydramnios. Trio exome sequencing analysis detected a novel pathogenic NONO variant. Postmortem examination after the termination of pregnancy confirmed the ultrasound findings and also revealed pulmonary hypoplasia, retrognathia and low-set ears. The variant was a novel de novo hemizygous pathogenic loss-of-function variant in NONO [NM_007363.5], associated with a rare X-linked recessive neurodevelopmental disorder, named intellectual developmental disorder, X-linked syndromic 34 (OMIM#300967). The postnatal characteristic features of this disorder include intellectual disability, developmental delay, macrocephaly, structural abnormalities involving the corpus callosum and/or cerebellum, left ventricular noncompaction and other congenital heart defects. In the prenatal setting, the phenotype has been poorly described, with all described cases presenting with heart defects. This case highlights the need of further clinical delineation to include renal abnormalities in the prenatal phenotype spectrum.


Asunto(s)
Cardiopatías Congénitas , Discapacidad Intelectual , Enfermedades Renales , Anomalías Urogenitales , Embarazo , Femenino , Humanos , Riñón/diagnóstico por imagen , Riñón/anomalías , Feto/anomalías , Enfermedades Renales/diagnóstico por imagen , Enfermedades Renales/genética , Discapacidad Intelectual/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ARN/genética
2.
J Med Genet ; 60(7): 644-654, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36446582

RESUMEN

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.


Asunto(s)
Anomalías Múltiples , Trastorno del Espectro Autista , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , Anomalías Dentarias , Masculino , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Anomalías Múltiples/diagnóstico , Enfermedades del Desarrollo Óseo/genética , Anomalías Dentarias/genética , Facies , Trastorno del Espectro Autista/genética , Variaciones en el Número de Copia de ADN , Proteínas Represoras/genética , Deleción Cromosómica , Fenotipo , Factores de Transcripción/genética
3.
Fetal Diagn Ther ; 48(1): 9-14, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32906126

RESUMEN

OBJECTIVE: The aim of the study wasto describe the past medical history, sociodemographic, and pregnancy characteristics of women at high risk for aneuploidy and to determine which factors are related to her choice of cell-free DNA (cfDNA) testing instead of invasive diagnostic testing. METHODS: We conducted a prospective descriptive study including pregnant women from the Western Barcelona public health area at high risk for fetal aneuploidy, defined as a trisomy 21 or 18 risk between 1/10 and 1/250 at the combined first-trimester or at the second-trimester biochemical screening. During 1 year (December 2018 to November 2019), these women were asked to fill in a confidential questionnaire about her past medical history, demographic and pregnancy characteristics, and her opinion about termination of the pregnancy after a counseling consultation with a maternal-fetal medicine specialist in which advantages and disadvantages of both testing methods, cfDNA or diagnostic testing, were discussed. Logistic regression analysis was used to determine which factors were related with cfDNA uptake. RESULTS: During the study period, 82 pregnant women filled the questionnaire. The median maternal age was 39.6 years (interquartile range [IQR] 37.3-40.9 years), and 73 (89%) of them were 35 years or older. Forty-three (52%) women opted for cfDNA testing, while 39 (48%) chose invasive diagnosis. In a logistic regression analysis, the use of assisted reproductive techniques (OR 13.03; 95% CI: 1.47-115.56; p = 0.021) and Latin American origin (OR 6.66; 95% CI 1.73-25.66; p = 0.006) were shown to be related to a higher cfDNA uptake. In contrast, nonreligious women (OR 0.21; 95% CI: 0.06-0.72; p = 0.013) and a favorable opinion about termination of pregnancy (OR 0.23; 95% CI: 0.06-0.92; p = 0.037) were related with a lower uptake. CONCLUSION: Half of the pregnant women at high risk for fetal aneuploidy opted for cfDNA testing. The main reason to choose cfDNA was avoiding the risk of pregnancy loss. Women using assisted reproductive techniques and those of Latin American origin preferred cfDNA testing, while nonreligious women and those with a favorable opinion on termination pregnancy preferred invasive testing.


Asunto(s)
Ácidos Nucleicos Libres de Células , Síndrome de Down , Adulto , Femenino , Humanos , Embarazo , Primer Trimestre del Embarazo , Estudios Prospectivos , Trisomía
4.
Fetal Diagn Ther ; 48(11-12): 849-856, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34872079

RESUMEN

INTRODUCTION: The introduction of prenatal cell-free DNA as a screening test has surpassed traditional combined first-trimester screening (cFTS) in the detection of common trisomies. However, its current limitation in detecting only common trisomies is affecting the diagnostic yield for other clinically significant chromosomal abnormalities. METHODS: In efforts to optimize the detection of fetuses with genetic abnormalities, we have analyzed the relationship between the cFTS risk score and biomarkers with atypical chromosomal abnormalities. Furthermore, we have evaluated the impact of prenatal cell-free DNA screening on the detection of chromosomal abnormalities in our population. For these purposes, we performed a retrospective study of 877 singleton pregnancies who underwent chromosomal microarray analysis (CMA) between 2013 and 2020 and for whom cFTS data were available. RESULTS: The results demonstrated that low levels of free beta-human chorionic gonadotropin (ß-hCG) (≤0.37 multiples of the median) and increased fetal nuchal translucency (NT) (≥3.5 mm) were statistically associated with the presence of atypical chromosomal abnormalities. In fact, the risk of pathogenic CMA results increased from 6 to 10% when fetal NT was increased and from 6 to 20% when a low serum ß-hCG level was detected in the high-risk cFTS group. Moreover, our results showed that altered serum levels of ß-hCG can have a substantial impact on the early detection of clinically relevant copy number variants. DISCUSSION/CONCLUSION: Traditional cFTS can potentially identify a substantial proportion of atypical chromosomal aberrations, and women with increased NT or low maternal serum ß-hCG levels are at increased risk of having pathogenic CMA results. Our results may help clinicians and women decide whether invasive testing or prenatal cell-free DNA screening testing is more appropriate for each situation.


Asunto(s)
Gonadotropina Coriónica Humana de Subunidad beta , Síndrome de Down , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Aberraciones Cromosómicas , Síndrome de Down/diagnóstico , Síndrome de Down/epidemiología , Síndrome de Down/genética , Femenino , Humanos , Medida de Translucencia Nucal , Embarazo , Primer Trimestre del Embarazo , Proteína Plasmática A Asociada al Embarazo , Diagnóstico Prenatal/métodos , Estudios Retrospectivos
5.
Clin Genet ; 98(4): 379-383, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32632923

RESUMEN

Chromosomal microarray analysis (CMA) has now replaced karyotyping in the analysis of prenatal cases with a fetal structural anomaly, whereas in those pregnancies undergoing invasive prenatal diagnosis with a normal fetal ultrasound, conventional karyotyping is still performed. The aims of this study were to establish the diagnostic yield of CMA in prenatal diagnosis, and to provide new data that might contribute to reconsider current practices. We reviewed 2905 prenatal samples with a normal rapid aneuploidy detection test referred for evaluation by CMA testing. Our study revealed pathogenic and reported susceptibility copy number variants associated with syndromic disorders in 4.8% (n = 138/2905) of cases, being 2.8% (n = 81/2905) the estimated added diagnostic value of CMA over karyotyping. Clinically significant CMA abnormality was detected in 5.4% (107/1975) of the fetuses with ultrasound anomalies and in 1.4% (5/345) of those considered as low-risk pregnancies. Our series shows that in prenatal samples, CMA increases 2-fold the diagnostic yield achieved by conventional karyotyping.


Asunto(s)
Cromosomas/genética , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas , Diagnóstico Prenatal , Aneuploidia , Variaciones en el Número de Copia de ADN/genética , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/patología , Humanos , Análisis por Micromatrices/tendencias , Embarazo , Síndrome
6.
J Med Genet ; 56(7): 481-490, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30894412

RESUMEN

BACKGROUND: Mapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 (BMPR2) gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic BMPR2 mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%. METHODS: We performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family. RESULTS: We identified a candidate chromosome region in 2q24.3, 38 Mb upstream from BMPR2, with significant linkage (LOD=4.09) under a PAH susceptibility model. This region contains common variants associated with vascular aetiology and shows functional evidence that the putative genetic modifier is located in the upstream distal promoter of the fidgetin (FIGN) gene. CONCLUSION: Our results suggest that the genetic modifier acts through FIGN transcriptional regulation, whose expression variability would contribute to modulating heritable PAH. This finding may help to advance our understanding of RP in PAH across families sharing the p.Arg491Gln pathogenic mutation in BMPR2.


Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Hipertensión Pulmonar Primaria Familiar/diagnóstico , Hipertensión Pulmonar Primaria Familiar/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad , Proteínas Asociadas a Microtúbulos/genética , Penetrancia , Alelos , Sustitución de Aminoácidos , Presión Sanguínea , Cromosomas Humanos Par 2 , Familia , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Hemodinámica , Heterocigoto , Humanos , Desequilibrio de Ligamiento , Mutación , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple
7.
Fetal Diagn Ther ; 47(4): 315-320, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31955157

RESUMEN

BACKGROUND: Chromosomal anomalies are a recognized cause of stillbirth, accounting for 6-17% of the cases. As a diagnostic laboratory method in this setting, conventional karyotyping has two main drawbacks: the need for viable fetal cells in a dead fetus and its limited resolution as compared to alternative techniques. OBJECTIVE: To assess the effectiveness of cytogenetic analysis in stillbirths between different testing methods and different sampled tissues. METHODS: From 2011 to 2017, 145 stillborn fetuses (defined as fetal losses after 22 weeks) were delivered in our center. The stillbirth protocol includes genetic testing by means of a karyotype, QF-PCR, or chromosomal microarray analysis (CMA), depending on the presence of fetal structural anomalies and the study time period. The success rates were compared between tests and between different sampled tissues. RESULTS: Consent was granted for cytogenetic analysis in 136 stillbirths. Test success rate was 100% (38/38) for CMA independent of the sampled tissue, 99% (65/66) for QF-PCR, and 66% (65/98) for karyotyping. The success rate for karyotyping was 48% (69/145) of the total tissues samples, showing great variation according to the tissue sampled: 83% (40/48) in amniotic fluid, 78% (21/27) in the placenta, 13% (7/54) in fetal skin, and 6.3% (1/16) in fetal blood. Four full or partial aneuploidies (trisomy 9, trisomy 22, tetrasomy 18p, and monosomy X) and 2 microdeletions (del2p16.3 and del1q13.2q13.4) were found, resulting in a 3.9% (4/103) prevalence for full or partial aneuploidy and a 5.3% prevalence (2/38) for submicroscopic abnormalities. CONCLUSIONS: Amniotic fluid should be the preferred tissue source in the cytogenetic analysis of stillbirth due to its high success rate. Between tests, CMA is a preferable method because of its higher test success rate, independent of the sampled tissue, and higher diagnostic yield including chromosomal and submicroscopic anomalies.


Asunto(s)
Aberraciones Cromosómicas , Cariotipo , Cariotipificación , Mortinato/genética , Análisis Citogenético , Humanos , Diagnóstico Prenatal/métodos
8.
Hum Mutat ; 39(8): 1126-1138, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29851191

RESUMEN

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.


Asunto(s)
Epilepsia/metabolismo , Exones/genética , Trastornos del Crecimiento/metabolismo , Discapacidad Intelectual/metabolismo , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Niño , Preescolar , Epilepsia/genética , Femenino , Trastornos del Crecimiento/genética , Células HEK293 , Células HeLa , Humanos , Discapacidad Intelectual/genética , Masculino , Mutación Missense/genética , Isoformas de Proteínas/genética , Transporte de ARN/genética , Transporte de ARN/fisiología , Proteínas de Unión al ARN/genética
9.
Am J Med Genet A ; 173(10): 2795-2797, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28815939

RESUMEN

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and autism. In most of cases, the molecular basis of this syndrome is a CGG repeat expansion in the 5' untranslated region of the FMR1 gene. It is inherited as an X linked dominant trait, with a reduced penetrance (80% for males and 30% for females). Full mutation (FM) expansion from premutated alleles (PM) is only acquired via maternal meiosis, while paternal transmission always remains in the PM range. We present a 16-year-old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation-full mutation with an unmethylated uninterrupted allele (175, >200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation-full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry a premutation, the possibility of paternal transmission should be considered.


Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Mutación , Herencia Paterna , Adolescente , Adulto , Femenino , Síndrome del Cromosoma X Frágil/patología , Humanos , Masculino , Adulto Joven
10.
Cytogenet Genome Res ; 149(4): 258-261, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27653741

RESUMEN

The patient was referred for prenatal diagnosis due to the sonographic finding of a polymalformed male fetus, and an amniocentesis was performed before termination of pregnancy. The pathological study of the placenta did not show morphological alterations. In her next pregnancy, sonographic examination disclosed a missed abortion with a visible embryo, and a chorionic villi sample was obtained for cytogenetic analysis before evacuation. Macroscopic examination of the villi sample did not reveal molar vesicular appearance. QF-PCR and cytogenetic analyses were performed on amniotic fluid (first pregnancy) and chorionic villi samples (second pregnancy). A 69,XXY and 92,XXXY karyotype was found, respectively. QF-PCR results disclosed 2 maternal and 1 paternal alleles in the first pregnancy (digynic triploidy), and double maternal and double paternal contribution to the tetraploid pregnancy. Among the few reported cases of 92,XXXY tetraploidy, those associated with partial moles show a PPPM genotype (3 paternal and 1 maternal alleles), and the only case with a PPMM genotype was found in a spontaneously aborted fetus similar to our case. We are not aware of other cases with combination of a digynic triploid pregnancy and a tetraploid pregnancy with a PPMM contribution. Our case adds evidence to the influence of the balance between paternal and maternal genomic doses on the phenotype.


Asunto(s)
Aborto Espontáneo/genética , Feto/anomalías , Tetraploidía , Triploidía , Alelos , Amniocentesis , Muestra de la Vellosidad Coriónica , Femenino , Humanos , Mola Hidatiforme/genética , Masculino , Herencia Materna/genética , Repeticiones de Microsatélite , Herencia Paterna/genética , Embarazo
11.
Cerebellum ; 15(5): 570-7, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27315125

RESUMEN

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. The prevalence of FMR1 premutation carriers in the general population is relatively high, and although rare, a premutation in both X chromosomes may occur in females inheriting a premutation allele from each of both parent carriers. Here, we report the first female with an autozygous (homozygous by descendent) FMR1 premutation allele, who fulfills neurological and radiological FXTAS findings/criteria. Molecular characterization included CGG repeat length, AGG interruption pattern, FMR1 messenger RNA (mRNA), fragile X mental retardation protein (FMRP) level quantification, and single-nucleotide polymorphism (SNP) microarray. Neuroradiological assessment of 3-T magnetic resonance imaging and neurological and cognitive/neuropsychological evaluations were performed. Neurological and neuroradiological examination of the female with the same FMR1 allele in the premutation range (77 CGGs) demonstrated FXTAS features. Further familial evaluation showed a similar neuropsychiatric profile, with impairments in cognitive flexibility and visuospatial function, mainly. A unique family with an autozygous FMR1 premutation female is presented. Neurological/cognitive and neuroradiological examinations revealed FXTAS-specific findings in the female with the autozygous FMR1 premutation allele. The consistent molecular and cognitive/psychiatric phenotype in family members suggests that carrying one or two FMR1 premutation alleles has no effect on illness severity.


Asunto(s)
Ataxia/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Dosificación de Gen , Temblor/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Ataxia/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Familia , Femenino , Síndrome del Cromosoma X Frágil/diagnóstico por imagen , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Temblor/diagnóstico por imagen
12.
Neurodegener Dis ; 16(3-4): 290-2, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26609701

RESUMEN

BACKGROUND: Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a late-onset multisystem neurological disorder characterized by intention tremor and cerebellar ataxia. OBJECTIVE: We hypothesized that in FMR1 premutation females with FXTAS, a normal X chromosome might more frequently be inactivated; therefore, the aim of this study was to determine the relationship between skewed X chromosome inactivation (XCI) and FXTAS. METHODS: We studied the XCI patterns of cases of FMR1 premutation in 10 women with FXTAS and 21 without FXTAS. RESULTS: The distribution of XCI patterns in the FXTAS and no-FXTAS groups showed differences regarding the allele presenting severe skewed XCI. In the FXTAS group, all cases preferentially inactivated the non-expanded X chromosome, whereas in the no-FXTAS group, all inactivated the expanded X chromosome. Nevertheless, no significant differences were found on comparing XCI frequencies among FMR1 premutation carriers with and without FXTAS. As expected, we found statistically significant differences in the skewed XCI on comparing FMR1 premutation women and controls. CONCLUSION: Although the reduced sample size and blood XCI patterns are two limitations of this study, our results suggest that the skewed XCI of the normal FMR1 allele may be a risk factor for the development of FXTAS. Furthermore, our findings also support the protective effect of the expression of a normal FMR1 allele.


Asunto(s)
Ataxia/sangre , Ataxia/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/sangre , Síndrome del Cromosoma X Frágil/genética , Temblor/sangre , Temblor/genética , Inactivación del Cromosoma X , Análisis Químico de la Sangre , Metilación de ADN , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Persona de Mediana Edad
13.
Neurobiol Dis ; 65: 43-54, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24418349

RESUMEN

Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5'-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.


Asunto(s)
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Regulación de la Expresión Génica/genética , Infertilidad/genética , Enfermedades Neurodegenerativas/sangre , Expansión de Repetición de Trinucleótido/genética , Adulto , Anciano , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Análisis por Micromatrices , Proteínas de Microfilamentos , Persona de Mediana Edad , Neuroblastoma/patología , Enfermedades Neurodegenerativas/genética , Fenotipo , Proteínas/genética , Proteínas/metabolismo , Securina/genética , Securina/metabolismo
14.
J Clin Med ; 13(16)2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39201029

RESUMEN

Background/Objectives: Cell-free DNA (cfDNA) is a non-invasive prenatal test used to screen for common trisomies (target cfDNA) that can be expanded to assess all autosomal chromosomes (genome-wide cfDNA). As cfDNA testing gains popularity, it is crucial to examine the factors influencing the decision-making process of pregnant individuals when choosing between these two approaches. Methods: In this prospective cohort study, 190 individuals undergoing cfDNA testing for aneuploidy screening, according to the current screening protocol, were allowed to make their own choice between target and genome-wide cfDNA testing. They were asked to complete a first survey at 11-13 weeks, designed to explore their characteristics, preferences, and satisfaction with the prenatal genetic counseling session, as well as a Decisional Conflict Scale. A postnatal survey was administered three months after delivery, including the Decisional Regret Scale and two open questions. Results: 84% of participants opted for genome-wide cfDNA. However, 17% found the decision challenging, and 14% felt that the results might increase anxiety. No significant differences in participant characteristics were found when comparing decisions between genome-wide and target cfDNA. However, significant differences were observed regarding ethnicity (p = <0.001), educational level (p = 0.029), previous cfDNA experience (p = 0.004), and having sufficient information when comparing termination options (p = 0.002). After delivery, only 4% would have changed their decision. Conclusions: Individuals, regardless of their characteristics, prefer genome-wide cfDNA; however, the complexity of the results necessitates enhanced genetic education for prenatal care clinicians.

15.
Genet Med ; 15(8): 639-42, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23492875

RESUMEN

PURPOSE: Fragile X-associated tremor/ataxia syndrome is a late-onset neurodegenerative disorder that occurs in FMR1 premutation carriers. It is well known that the apolipoprotein E ε4 allele is a risk factor for neurodegenerative disease. The main goal of this work was to evaluate the apolipoprotein E genotypes and allelic distribution among patients with fragile X-associated tremor/ataxia syndrome. METHODS: A total of 44 unrelated FMR1 premutation carriers (22 presenting with fragile X-associated tremor/ataxia syndrome and 22 without fragile X-associated tremor/ataxia syndrome) were genotyped. RESULTS: All the apolipoprotein E ε4/4 genotype carriers detected (100%), and six of the seven apolipoprotein E ε4/3 genotype carriers (85.7%) are patients presenting with fragile X-associated tremor/ataxia syndrome symptoms, whereas only 40% of the apolipoprotein E ε3/3 genotype carriers belong to the fragile X-associated tremor/ataxia syndrome group. The results showed that the presence of the apolipoprotein E ε4 allele increases the risk of developing fragile X-associated tremor/ataxia syndrome (odds ratio = 12.041; P = 0.034). CONCLUSION: On the basis of these results, we conclude that the presence of at least one apolipoprotein E ε4 allele might act as a genetic factor predisposing individuals to develop fragile X-associated tremor/ataxia syndrome.


Asunto(s)
Apolipoproteína E3/genética , Apolipoproteína E4/genética , Ataxia/genética , Síndrome del Cromosoma X Frágil/genética , Temblor/genética , Anciano , Anciano de 80 o más Años , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , España , Población Blanca/genética
16.
Genes (Basel) ; 14(9)2023 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-37761902

RESUMEN

Neurodevelopmental disorders are a group of neurological disorders that may give rise to delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills [...].

17.
JIMD Rep ; 64(1): 10-16, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36636600

RESUMEN

Acute intermittent porphyria (AIP) is a rare disease caused by a deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme of the heme-synthesis pathway. Decreased enzymatic activity in the liver induces an overproduction of heme-precursors and acute neurological attacks. We report a 36-years-old female with AIP with a long-term history of severe, disabling, recurrent attacks, who underwent curative liver transplantation. Tissue samples from the explant were obtained for transcriptome analysis. Whole RNA was extracted and 16 gene-transcripts were selected and investigated by quantitative polymerase chain reaction. These included nine genes encoding enzymes that consecutively catalyze heme-synthesis and catabolism in the liver (ALAS1; ALAD; HMBS; UROS; UROD; CPOX; PPOX; FECH; HMOX1). Additionally, we studied genes related to inflammation (IL6; TNF) insulin signaling (PGC-1α; IGF-1; FOXO-1) and tryptophan metabolism (TDO2; IDO). Transcripts of eight house-keeping genes were co-measured for normalization. All transcripts were also measured in five control samples from healthy living liver donors. The transcriptome of the controls showed important differences between the various genes, with the first two genes of the heme-synthesis pathway, ALAS1 and ALAD showing strikingly high mRNA levels compared to the consecutive HMBS gene. Transcripts of several genes significantly differed in the AIP liver compared to controls. Transcripts of HMOX1 and UROS were increased in the AIP liver whereas transcripts of UROD; CPOX, PPOX, and TDO2 were decreased. ALAS1 expression was not increased, possibly due to hemin administered to the patient before transplantation. These results highlight several transcriptomic changes related to heme homeostasis in AIP.

18.
Genes (Basel) ; 14(4)2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-37107571

RESUMEN

Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson's disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing (NGS) as a first-line test in patients with these disorders. Whole exome sequencing (WES) is widely regarded as the current technology of choice for diagnosing monogenic ND. The introduction of NGS allows for rapid and inexpensive large-scale genomic analysis and has led to enormous progress in deciphering monogenic forms of various genetic diseases. The simultaneous analysis of several potentially mutated genes improves the diagnostic process, making it faster and more efficient. The main aim of this report is to discuss the impact and advantages of the implementation of WES into the clinical diagnosis and management of ND. Therefore, we have performed a retrospective evaluation of WES application in 209 cases referred to the Department of Biochemistry and Molecular Genetics of the Hospital Clinic of Barcelona for WES sequencing derived from neurologists or clinical geneticists. In addition, we have further discussed some important facts regarding classification criteria for pathogenicity of rare variants, variants of unknown significance, deleterious variants, different clinical phenotypes, or frequency of actionable secondary findings. Different studies have shown that WES implementation establish diagnostic rate around 32% in ND and the continuous molecular diagnosis is essential to solve the remaining cases.


Asunto(s)
Epilepsia , Exoma , Humanos , Secuenciación del Exoma , Estudios Retrospectivos , Exoma/genética , Fenotipo , Epilepsia/diagnóstico , Epilepsia/genética
19.
Am J Hum Genet ; 85(6): 809-22, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20004760

RESUMEN

We report on the identification of a 0.3 Mb inherited recurrent but variable copy-number gain at Xq28 in affected males of four unrelated families with X-linked mental retardation (MR). All aberrations segregate with the disease in the families, and the carrier mothers show nonrandom X chromosome inactivation. Tiling Xq28-region-specific oligo array revealed that all aberrations start at the beginning of the low copy repeat LCR-K1, at position 153.20 Mb, and end just distal to LCR-L2, at 153.54 Mb. The copy-number gain always includes 18 annotated genes, of which RPL10, ATP6AP1 and GDI1 are highly expressed in brain. From these, GDI1 is the most likely candidate gene. Its copy number correlates with the severity of clinical features, because it is duplicated in one family with nonsyndromic moderate MR, is triplicated in males from two families with mild MR and additional features, and is present in five copies in a fourth family with a severe syndromic form of MR. Moreover, expression analysis revealed copy-number-dependent increased mRNA levels in affected patients compared to control individuals. Interestingly, analysis of the breakpoint regions suggests a recombination mechanism that involves two adjacent but different sets of low copy repeats. Taken together, our data strongly suggest that an increased expression of GDI1 results in impaired cognition in a dosage-dependent manner. Moreover, these data also imply that a copy-number gain of an individual gene present in the larger genomic aberration that leads to the severe MECP2 duplication syndrome can of itself result in a clinical phenotype as well.


Asunto(s)
Cromosomas Humanos X , Dosificación de Gen , Discapacidad Intelectual/genética , Recombinación Genética , Adulto , Encéfalo/metabolismo , Niño , Preescolar , Aberraciones Cromosómicas , Mapeo Cromosómico , Femenino , Humanos , Masculino , Modelos Genéticos , Hibridación de Ácido Nucleico , Linaje , Fenotipo
20.
Am J Med Genet A ; 158A(5): 1071-6, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22488686

RESUMEN

Congenital balanced reciprocal translocations are one of the most frequent structural chromosomal aberrations in the population. We report a familial translocation t(12;22)(p13.3;pter) responsible for intellectual disabilities and congenital anomalies characterized by FISH and array CGH. Two patients carried a der(12)t(12;22)(p13.3;pter), resulting in a 6 Mb 12pter deletion. Patients presented with intellectual disabilities, pre- and post-natal growth retardation, ponderal development delay, global hypotonia, feeding problems and dysmorphic features. Two relatives presented with the reciprocal 12pter duplication, which had no clinical manifestations associated. For this translocation, we propose a mechanism based on a non-allelic recombination model, in which recombination of direct oriented segmental duplications between non-homologous chromatids leads to the reciprocal translocation. The characterization of this translocation has been critical for the family. Translocation carriers have a risk of 40% of having offspring carrying unbalanced products. 12p13.3 deletion carriers present with a recognizable syndrome and on the contrary, 12p13.3 duplication carriers present without clinical manifestations. Other published cases of 12p13.3 duplication show that this syndrome has a variable phenotype. It is advisable to delineate the duplication size and to discard other genetic aberrations, in order to give an accurate genetic counseling in patients carrying 12pter duplications.


Asunto(s)
Cromosomas Humanos Par 12/genética , Reordenamiento Génico , Discapacidad Intelectual/genética , Eliminación de Secuencia , Familia , Humanos , Duplicaciones Segmentarias en el Genoma , Translocación Genética
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