<b><i>Objective:</i></b> The aim of the study wasto describe the past med... more <b><i>Objective:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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; <i>p</i> = 0.021) and Latin American origin (OR 6.66; 95% CI 1.73–25.66; <i>p</i> = 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; <i>p</i> = 0.013) and a favorable opinion about termination of pregnancy (OR 0.23; 95% CI: 0.06–0.92; <i>p</i> = 0.037) were related with a lower uptake. <b><i>Conclusion:</i></b> Half of the pregnant women at high risk for fetal aneuploidy opted for cfDNA testing. The main reason to choose [...]
ABSTRACTObjectiveTo estimate the increased test success rate and incremental yield of chromosomal... more ABSTRACTObjectiveTo estimate the increased test success rate and incremental yield of chromosomal microarray analysis (CMA) over conventional karyotyping in detection of pathogenic copy number variants (CNVs) and variants of unknown significance (VOUS) in early pregnancy loss.MethodThis was a systematic review conducted in accordance with PRISMA criteria. All articles identified in PubMed, Ovid MEDLINE and Web of Science, between January 2000 and April 2017, that described CNVs in early pregnancy losses (up to 20 weeks) were included. Risk differences were pooled to estimate the incremental yield of CMA over karyotyping overall, and after stratification. In addition, test success rate, defined as the proportion of informative results, was compared in series in which CMA and karyotyping were performed concurrently.ResultsTwenty‐three studies, reporting on 5507 pregnancy losses up to 20 weeks with full data available, met the inclusion criteria for analysis. In the series in which CMA...
A large number of nevi (LNN) is a high risk phenotypic trait for developing cutaneous malignant m... more A large number of nevi (LNN) is a high risk phenotypic trait for developing cutaneous malignant melanoma (CMM). In this study, the breakpoints of a t(9;12)(p21;q13) balanced chromosome translocation were finely mapped in a family with LNN and CMM. Molecular characterization of the 9p21 breakpoint identified a novel gene C9orf14 expressed in melanocytes disrupted by the translocation. Integrative analysis of functional genomics data was applied to determine the role of C9orf14 in CMM development. An analysis of genome-wide DNA copy number alterations in melanoma tumors revealed the loss of the C9orf14 locus, located proximal to CDKN2A, in approximately one-fourth of tumors. Analysis of gene expression data in cancer cell lines and melanoma tumors suggests a loss of C9orf14 expression in melanoma tumorigenesis. Taken together, our results indicate that C9orf14 is a candidate tumor-suppressor for nevus development and late stage melanoma at 9p21, a region frequently deleted in different types of human cancers.
Congenital erythropoietic porphyria (CEP) is a rare inborn error of metabolism that results from ... more Congenital erythropoietic porphyria (CEP) is a rare inborn error of metabolism that results from a deficient activity of uroporphyrinogen III synthase (URO-synthase). We report four Spanish CEP cases studied at a clinical, biochemical and molecular level. The patients harbored missense mutations in the URO-synthase gene showing the following genotypes: C73R/T228M; C73R/P248Q; and P248Q/P248Q (two patients). The last allelic combination had never been reported in a CEP patient. The compound heterozygote patients presented both a moderate-to-severe disease with hematological and dermatological involvement. The two homozygote P248Q/P248Q cases showed, however, a very different phenotype. One patient presented signs of hemolysis, cutaneous scarring and severe deformities, while the other showed only mild hyperpigmentation and no signs of hemolysis. Biochemical study showed that the former patient presented a higher erythrocytic concentration and a higher urinary excretion of porphyrins with the residual activity of URO-synthase in red blood cells being similar in both cases. Differences in stimulation of erythropoiesis; long-term divergences in life-style and inadequate protection from sunlight may explain, in part, the drastic clinical divergence and the lack of genotype-phenotype correlation among these CEP patients.
Within the past few years, there has been a significant change in identifying and characterizing ... more Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that B20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.
X-linked mental retardation (XLMR) is an extremely heterogeneous condition that account for 15-25... more X-linked mental retardation (XLMR) is an extremely heterogeneous condition that account for 15-25% of all mentally retarded patients. The number of genes newly reported in relation with this condition has been rapidly increased in the past years. One of the latest is called Jumonji AT-rich interactive domain 1C (JARID1C). This gene encodes for a member of a recently discovered protein family that harbours DNA-binding motifs, suggesting a possible role in transcriptional regulation and in the modification of chromatin structure. In this work we describe the results obtained by screening JARID1C gene in 24 mentally retarded males with history of at least two affected males. Remarkably, we have found a novel missense mutation in exon 10 of the gene that results in a Serine-to-arginine change at amino-acid 451 (S451R). This nucleotide change appears to be restricted to mentally retarded patients, since it has not been detected in control samples. Familial analysis has confirmed the segregation of this mutation with mental retardation. Furthermore, sequence alignment analysis with the different members of the human JARID1 family and with homologous proteins of mouse and fruit fly has revealed that the affected amino acid is conserved. Our data highlights the importance of reporting mutations in this gene since it might support the recent findings that implicates JARID1C with XLMR.
Background Aproximately 5–10% of cases of mental retardation in males are due to copy number vari... more Background Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions w...
We describe a fetus with confined placental mosaicism for 46,XY,dup(18)(q21q23)/46,XY, del(18)(q2... more We describe a fetus with confined placental mosaicism for 46,XY,dup(18)(q21q23)/46,XY, del(18)(q21) in which finally the 18q- cell line formed the embryo. This prenatal diagnosis was performed on a pregnant woman carrying a premutation in the FMR1 gene. The purpose of the current study was to characterise the final fetus genotype and to discuss how this chromosomal abnormality was originated. Conventional cytogenetic analyses were performed from chorionic villi, amniocytes, and fetal blood samples in order to establish the fetal chromosome constitution. Molecular studies with microsatellite markers and CGH were carried out to this end. PCR and Southern blot were used to analyse the CGG-repeat region of the FMR1 gene. An initial chorionic villi sample analysis showed a normal allele for the fragile X syndrome, but an abnormal 46,XY,dup(18)(q21q23) karyotype. Amniocentesis was subsequently performed, and a different 46,XY,del(18)(q21) cell line was detected. Re-examination of original chorionic villi sample evidenced a mosaicism for 46,XY,dup(18)(q21q23)/46,XY,del(18)(q21). Molecular findings allowed us to determine that the deletion expands at least 20 Mb and that it is paternally inherited. Two different cell lines with structural abnormalities on chromosome 18 were formed as a consequence of an unequal sister chromatid exchange during the first post-zygotic division. This case reinforces the necessity of performing a karyotype in all prenatal diagnosis even when the indication is for a monogenic disease.
from the Autonomous Catalan Government [2014 SGR603 and 2017 SGR1134] from the Generalitat de Cat... more from the Autonomous Catalan Government [2014 SGR603 and 2017 SGR1134] from the Generalitat de Catalunya. The 'CIBER de Enfermedades Raras' is an initiative of the ISCIII. AUTHOR CONTRIBUTIONS MIAM, MM, IM, LRR contributed to the conception and design of the study. MIAM, PSV, FM, MIT, SIA, AC, OV, BRS, LAPJ, MM contributed to the acquisition and analysis of data. MIAM, MM, IM, LRR contributed to drafting the text and preparing the figures.
SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 o... more SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.
Résumé/Abstract Introduction. The study of mental retardation is one of the most complex fields i... more Résumé/Abstract Introduction. The study of mental retardation is one of the most complex fields in human genetics due to its high degree of clinical and genetic heterogeneity. About 50% of cases of mental retardation remain undiagnosed. It is known that about 6-10% of ...
FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficien... more FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically sign...
American journal of medical genetics. Part A, 2007
Norrie disease (ND) is an X-linked disorder, inherited as a recessive trait that, therefore, most... more Norrie disease (ND) is an X-linked disorder, inherited as a recessive trait that, therefore, mostly affects males. The gene responsible for ND, called NDP, maps to the short arm of chromosome X (Xp11.4-p11.3). We report here an atypical case of ND, consisting of a patient harboring a large submicroscopic deletion affecting not only the NDP gene but also the MAOA, MAOB, and EFHC2 genes. Microarray comparative genomic hybridization (CGH) analysis showed that 11 consecutive bacterial artificial chromosome (BAC) clones, mapping around the NDP gene, were deleted. These clones span a region of about 1 Mb on Xp11.3. The deletion was ascertained by fluorescent in situ hybridization (FISH) analysis with different BAC clones located within the region. Clinical features of the proband include bilateral retinal detachment, microcephaly, severe psychomotor retardation without verbal language skills acquired, and epilepsy. The identification and molecular characterization of this case reinforces ...
The study of mental retardation is one of the most complex fields in human genetics due to its hi... more The study of mental retardation is one of the most complex fields in human genetics due to its high degree of clinical and genetic heterogeneity. About 50% of cases of mental retardation remain undiagnosed. It is known that about 6-10% of cases are due to subtelomeric rearrangements. Some of these are responsible for a clinically recognized phenotype, i.e. 1p36 or 22q13.33 microdeletion syndromes, but others affect few patients and are not well characterized. We have analyzed 300 consecutive mentally retarded patients for subtelomeric rearrangements by MLPA. About 5.3% of patients presented subtelomeric rearrangements; from these, 75% contained de novo rearrangements and 18.7% included inherited aberrations from a healthy parent. In 14 cases, aberrations were likely related to disease and in two cases were putative polymorphisms. This study confirms the high frequency of subtelomeric rearrangements in mental retardation and reinforces the idea of a routine subtelomeric screening in ...
AimsThe causes of intellectual disability, which affects 1%–3% of the general population, are hig... more AimsThe causes of intellectual disability, which affects 1%–3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases.MethodsWhole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes.ResultsWe present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose.ConclusionsThe accessibility to next-generation sequencing allows cl...
It has been estimated that 1:1233 males and 1:411 females are FMR1 premutated carriers. This gene... more It has been estimated that 1:1233 males and 1:411 females are FMR1 premutated carriers. This gene is responsible for the fragile X syndrome. Among 398 fragile X syndrome families, we evaluated 112 premutated carriers older than 50 year. FXTAS penetrance among fragile X families was 10.7% for female premutated carriers and 29.7% for male premutated carriers. In the general population, it was estimated that 1:4,000 females and 1:5,000 males will develop the FXTAS syndrome. Besides the risk for fragile X syndrome, the genetic counseling in premutation carriers should mention the risk for FXTAS. This syndrome should also be taken into account among spinocerebelar ataxia patients with an unknown etiology.
Friedreich ataxia (FRDA) is the most common hereditary ataxia that is caused mainly by an unstabl... more Friedreich ataxia (FRDA) is the most common hereditary ataxia that is caused mainly by an unstable GAA trinucleotide expansion in the first intron of the frataxin gene. Molecular tests for FRDA diagnosis and carrier detection include polymerase chain reaction (PCR) for the GAA expansion, triplet repeat primed PCR (TP-PCR), and/or Southern blotting. TP-PCR is a method developed to detect trinucleotide expansions successfully applied to FRDA diagnosis. In our laboratory, we have included a PCR for the GAA expansion using fluorescent primers polymerase chain reaction (F-PCR) to identify normal heterozygous and affected individuals unambiguously. The purpose of our study was to reanalyze 310 samples previously diagnosed in our laboratory and compare the results with those obtained by F-PCR and TP-PCR. Eight percent of the discrepancies between the carrier and the normal individuals were identified correctly by this protocol. No discrepancy was detected in the affected individuals. These techniques are effective, and compared with Southern blotting, they are less labor-intensive and suitable for automation. We suggest a new routine protocol for FRDA diagnosis that includes F-PCR and TP-PCR.
<b><i>Objective:</i></b> The aim of the study wasto describe the past med... more <b><i>Objective:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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; <i>p</i> = 0.021) and Latin American origin (OR 6.66; 95% CI 1.73–25.66; <i>p</i> = 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; <i>p</i> = 0.013) and a favorable opinion about termination of pregnancy (OR 0.23; 95% CI: 0.06–0.92; <i>p</i> = 0.037) were related with a lower uptake. <b><i>Conclusion:</i></b> Half of the pregnant women at high risk for fetal aneuploidy opted for cfDNA testing. The main reason to choose [...]
ABSTRACTObjectiveTo estimate the increased test success rate and incremental yield of chromosomal... more ABSTRACTObjectiveTo estimate the increased test success rate and incremental yield of chromosomal microarray analysis (CMA) over conventional karyotyping in detection of pathogenic copy number variants (CNVs) and variants of unknown significance (VOUS) in early pregnancy loss.MethodThis was a systematic review conducted in accordance with PRISMA criteria. All articles identified in PubMed, Ovid MEDLINE and Web of Science, between January 2000 and April 2017, that described CNVs in early pregnancy losses (up to 20 weeks) were included. Risk differences were pooled to estimate the incremental yield of CMA over karyotyping overall, and after stratification. In addition, test success rate, defined as the proportion of informative results, was compared in series in which CMA and karyotyping were performed concurrently.ResultsTwenty‐three studies, reporting on 5507 pregnancy losses up to 20 weeks with full data available, met the inclusion criteria for analysis. In the series in which CMA...
A large number of nevi (LNN) is a high risk phenotypic trait for developing cutaneous malignant m... more A large number of nevi (LNN) is a high risk phenotypic trait for developing cutaneous malignant melanoma (CMM). In this study, the breakpoints of a t(9;12)(p21;q13) balanced chromosome translocation were finely mapped in a family with LNN and CMM. Molecular characterization of the 9p21 breakpoint identified a novel gene C9orf14 expressed in melanocytes disrupted by the translocation. Integrative analysis of functional genomics data was applied to determine the role of C9orf14 in CMM development. An analysis of genome-wide DNA copy number alterations in melanoma tumors revealed the loss of the C9orf14 locus, located proximal to CDKN2A, in approximately one-fourth of tumors. Analysis of gene expression data in cancer cell lines and melanoma tumors suggests a loss of C9orf14 expression in melanoma tumorigenesis. Taken together, our results indicate that C9orf14 is a candidate tumor-suppressor for nevus development and late stage melanoma at 9p21, a region frequently deleted in different types of human cancers.
Congenital erythropoietic porphyria (CEP) is a rare inborn error of metabolism that results from ... more Congenital erythropoietic porphyria (CEP) is a rare inborn error of metabolism that results from a deficient activity of uroporphyrinogen III synthase (URO-synthase). We report four Spanish CEP cases studied at a clinical, biochemical and molecular level. The patients harbored missense mutations in the URO-synthase gene showing the following genotypes: C73R/T228M; C73R/P248Q; and P248Q/P248Q (two patients). The last allelic combination had never been reported in a CEP patient. The compound heterozygote patients presented both a moderate-to-severe disease with hematological and dermatological involvement. The two homozygote P248Q/P248Q cases showed, however, a very different phenotype. One patient presented signs of hemolysis, cutaneous scarring and severe deformities, while the other showed only mild hyperpigmentation and no signs of hemolysis. Biochemical study showed that the former patient presented a higher erythrocytic concentration and a higher urinary excretion of porphyrins with the residual activity of URO-synthase in red blood cells being similar in both cases. Differences in stimulation of erythropoiesis; long-term divergences in life-style and inadequate protection from sunlight may explain, in part, the drastic clinical divergence and the lack of genotype-phenotype correlation among these CEP patients.
Within the past few years, there has been a significant change in identifying and characterizing ... more Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that B20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.
X-linked mental retardation (XLMR) is an extremely heterogeneous condition that account for 15-25... more X-linked mental retardation (XLMR) is an extremely heterogeneous condition that account for 15-25% of all mentally retarded patients. The number of genes newly reported in relation with this condition has been rapidly increased in the past years. One of the latest is called Jumonji AT-rich interactive domain 1C (JARID1C). This gene encodes for a member of a recently discovered protein family that harbours DNA-binding motifs, suggesting a possible role in transcriptional regulation and in the modification of chromatin structure. In this work we describe the results obtained by screening JARID1C gene in 24 mentally retarded males with history of at least two affected males. Remarkably, we have found a novel missense mutation in exon 10 of the gene that results in a Serine-to-arginine change at amino-acid 451 (S451R). This nucleotide change appears to be restricted to mentally retarded patients, since it has not been detected in control samples. Familial analysis has confirmed the segregation of this mutation with mental retardation. Furthermore, sequence alignment analysis with the different members of the human JARID1 family and with homologous proteins of mouse and fruit fly has revealed that the affected amino acid is conserved. Our data highlights the importance of reporting mutations in this gene since it might support the recent findings that implicates JARID1C with XLMR.
Background Aproximately 5–10% of cases of mental retardation in males are due to copy number vari... more Background Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions w...
We describe a fetus with confined placental mosaicism for 46,XY,dup(18)(q21q23)/46,XY, del(18)(q2... more We describe a fetus with confined placental mosaicism for 46,XY,dup(18)(q21q23)/46,XY, del(18)(q21) in which finally the 18q- cell line formed the embryo. This prenatal diagnosis was performed on a pregnant woman carrying a premutation in the FMR1 gene. The purpose of the current study was to characterise the final fetus genotype and to discuss how this chromosomal abnormality was originated. Conventional cytogenetic analyses were performed from chorionic villi, amniocytes, and fetal blood samples in order to establish the fetal chromosome constitution. Molecular studies with microsatellite markers and CGH were carried out to this end. PCR and Southern blot were used to analyse the CGG-repeat region of the FMR1 gene. An initial chorionic villi sample analysis showed a normal allele for the fragile X syndrome, but an abnormal 46,XY,dup(18)(q21q23) karyotype. Amniocentesis was subsequently performed, and a different 46,XY,del(18)(q21) cell line was detected. Re-examination of original chorionic villi sample evidenced a mosaicism for 46,XY,dup(18)(q21q23)/46,XY,del(18)(q21). Molecular findings allowed us to determine that the deletion expands at least 20 Mb and that it is paternally inherited. Two different cell lines with structural abnormalities on chromosome 18 were formed as a consequence of an unequal sister chromatid exchange during the first post-zygotic division. This case reinforces the necessity of performing a karyotype in all prenatal diagnosis even when the indication is for a monogenic disease.
from the Autonomous Catalan Government [2014 SGR603 and 2017 SGR1134] from the Generalitat de Cat... more from the Autonomous Catalan Government [2014 SGR603 and 2017 SGR1134] from the Generalitat de Catalunya. The 'CIBER de Enfermedades Raras' is an initiative of the ISCIII. AUTHOR CONTRIBUTIONS MIAM, MM, IM, LRR contributed to the conception and design of the study. MIAM, PSV, FM, MIT, SIA, AC, OV, BRS, LAPJ, MM contributed to the acquisition and analysis of data. MIAM, MM, IM, LRR contributed to drafting the text and preparing the figures.
SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 o... more SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.
Résumé/Abstract Introduction. The study of mental retardation is one of the most complex fields i... more Résumé/Abstract Introduction. The study of mental retardation is one of the most complex fields in human genetics due to its high degree of clinical and genetic heterogeneity. About 50% of cases of mental retardation remain undiagnosed. It is known that about 6-10% of ...
FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficien... more FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically sign...
American journal of medical genetics. Part A, 2007
Norrie disease (ND) is an X-linked disorder, inherited as a recessive trait that, therefore, most... more Norrie disease (ND) is an X-linked disorder, inherited as a recessive trait that, therefore, mostly affects males. The gene responsible for ND, called NDP, maps to the short arm of chromosome X (Xp11.4-p11.3). We report here an atypical case of ND, consisting of a patient harboring a large submicroscopic deletion affecting not only the NDP gene but also the MAOA, MAOB, and EFHC2 genes. Microarray comparative genomic hybridization (CGH) analysis showed that 11 consecutive bacterial artificial chromosome (BAC) clones, mapping around the NDP gene, were deleted. These clones span a region of about 1 Mb on Xp11.3. The deletion was ascertained by fluorescent in situ hybridization (FISH) analysis with different BAC clones located within the region. Clinical features of the proband include bilateral retinal detachment, microcephaly, severe psychomotor retardation without verbal language skills acquired, and epilepsy. The identification and molecular characterization of this case reinforces ...
The study of mental retardation is one of the most complex fields in human genetics due to its hi... more The study of mental retardation is one of the most complex fields in human genetics due to its high degree of clinical and genetic heterogeneity. About 50% of cases of mental retardation remain undiagnosed. It is known that about 6-10% of cases are due to subtelomeric rearrangements. Some of these are responsible for a clinically recognized phenotype, i.e. 1p36 or 22q13.33 microdeletion syndromes, but others affect few patients and are not well characterized. We have analyzed 300 consecutive mentally retarded patients for subtelomeric rearrangements by MLPA. About 5.3% of patients presented subtelomeric rearrangements; from these, 75% contained de novo rearrangements and 18.7% included inherited aberrations from a healthy parent. In 14 cases, aberrations were likely related to disease and in two cases were putative polymorphisms. This study confirms the high frequency of subtelomeric rearrangements in mental retardation and reinforces the idea of a routine subtelomeric screening in ...
AimsThe causes of intellectual disability, which affects 1%–3% of the general population, are hig... more AimsThe causes of intellectual disability, which affects 1%–3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases.MethodsWhole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes.ResultsWe present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose.ConclusionsThe accessibility to next-generation sequencing allows cl...
It has been estimated that 1:1233 males and 1:411 females are FMR1 premutated carriers. This gene... more It has been estimated that 1:1233 males and 1:411 females are FMR1 premutated carriers. This gene is responsible for the fragile X syndrome. Among 398 fragile X syndrome families, we evaluated 112 premutated carriers older than 50 year. FXTAS penetrance among fragile X families was 10.7% for female premutated carriers and 29.7% for male premutated carriers. In the general population, it was estimated that 1:4,000 females and 1:5,000 males will develop the FXTAS syndrome. Besides the risk for fragile X syndrome, the genetic counseling in premutation carriers should mention the risk for FXTAS. This syndrome should also be taken into account among spinocerebelar ataxia patients with an unknown etiology.
Friedreich ataxia (FRDA) is the most common hereditary ataxia that is caused mainly by an unstabl... more Friedreich ataxia (FRDA) is the most common hereditary ataxia that is caused mainly by an unstable GAA trinucleotide expansion in the first intron of the frataxin gene. Molecular tests for FRDA diagnosis and carrier detection include polymerase chain reaction (PCR) for the GAA expansion, triplet repeat primed PCR (TP-PCR), and/or Southern blotting. TP-PCR is a method developed to detect trinucleotide expansions successfully applied to FRDA diagnosis. In our laboratory, we have included a PCR for the GAA expansion using fluorescent primers polymerase chain reaction (F-PCR) to identify normal heterozygous and affected individuals unambiguously. The purpose of our study was to reanalyze 310 samples previously diagnosed in our laboratory and compare the results with those obtained by F-PCR and TP-PCR. Eight percent of the discrepancies between the carrier and the normal individuals were identified correctly by this protocol. No discrepancy was detected in the affected individuals. These techniques are effective, and compared with Southern blotting, they are less labor-intensive and suitable for automation. We suggest a new routine protocol for FRDA diagnosis that includes F-PCR and TP-PCR.
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Papers by I. Madrigal