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1.
Clín. investig. ginecol. obstet. (Ed. impr.) ; 46(4): 163-166, oct.-dic. 2019. tab, graf, ilus
Article in Spanish | IBECS | ID: ibc-184305

ABSTRACT

Los trastornos relacionados con mutaciones del gen IRF6, comprenden desde una afectación casi asintomática con la única presencia de hoyuelos labiales que son la manifestación más sutil del síndrome de van der Woude, hasta manifestaciones congénitas graves que incluyen anomalías faciales, musculoesqueléticas y genitourinarias que corresponden al síndrome de pterigium poplíteo. Pese a que existe cierta relación fenotipo-genotipo entre las mutaciones del gen IRF6, estas tienen una penetrancia incompleta y una expresión variable, inter e intrafamiliar


The disorders related to IRF6 encompass a spectrum from an almost asymptomatic affectation, with the only presence of isolated lip pits, which are a mild presentation of van der Woude syndrome, to the presence in the other extreme, of congenital manifestations that include facial anomalies, musculoskeletal and genitourinary malformations, corresponding to popliteal pterygium syndrome. Although there is a certain phenotype-genotype relationship between mutations of the IRF6 gene, such mutations have incomplete penetrance and variable inter-and intra-familial expression


Subject(s)
Humans , Female , Pregnancy , Adult , Abnormalities, Multiple/diagnosis , Cleft Lip/diagnosis , Fingers/abnormalities , Syndactyly/diagnosis , Mutation , Cleft Lip/genetics , Lower Extremity Deformities, Congenital/diagnosis , Fetus/abnormalities
2.
J Intellect Disabil Res ; 54(11): 1024-9, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20854288

ABSTRACT

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder usually caused by an anomaly in the maternally inherited chromosome 15. The main features are severe intellectual disability, speech impairment, ataxia, epilepsy, sleep disorder and a behavioural phenotype that reportedly includes happy disposition, attraction to/fascination with water and hypermotoric behaviour. METHOD: We studied the level of adaptive behaviour and the adaptive behavioural profile in the areas of 'motor skills', 'language and communication', 'personal life skills' and 'community life skills' in a group of 25 individuals with genetically confirmed AS, to determine whether there is a specific adaptive behaviour profile. RESULTS AND CONCLUSIONS: None of the individuals, whatever their chronological age, had reached a developmental age of 3 years. A specific adaptive behaviour profile was found, with 'personal life skills' emerging as relative strengths and 'social and communication skills' as weaknesses.


Subject(s)
Adaptation, Psychological , Angelman Syndrome/psychology , Intellectual Disability/psychology , Social Adjustment , Adolescent , Age Factors , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Male , Personality Inventory , Regression Analysis
3.
J Clin Endocrinol Metab ; 95(4): 1876-88, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20150575

ABSTRACT

BACKGROUND: Androgen receptor (AR) gene mutations are the most frequent cause of 46,XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). OBJECTIVE: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46,XY DSD in a series of Spanish patients. SETTING: We studied a series of 133 index patients with 46,XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis. METHODS: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients. RESULTS: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel. CONCLUSIONS: AR gene mutation is the most frequent cause of 46,XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel.


Subject(s)
Gonadal Dysgenesis, 46,XY/genetics , Receptors, Androgen/genetics , 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics , Adolescent , Child , Child, Preschool , Exons/genetics , Female , Fibroblasts/metabolism , Gonadal Dysgenesis, 46,XY/pathology , Heterozygote , Humans , Infant , Introns/genetics , Male , Mutation/genetics , Mutation/physiology , Phenotype , Receptors, Androgen/blood , Reverse Transcriptase Polymerase Chain Reaction , Sexual Behavior , Testis/pathology
4.
Mol Psychiatry ; 15(10): 1023-33, 2010 Oct.
Article in English | MEDLINE | ID: mdl-19528963

ABSTRACT

Copy number variants (CNVs) are a substantial source of human genetic diversity, influencing the variable susceptibility to multifactorial disorders. Schizophrenia is a complex illness thought to be caused by a number of genetic and environmental effects, few of which have been clearly defined. Recent reports have found several low prevalent CNVs associated with the disease. We have used a multiplex ligation-dependent probe amplification-based (MLPA) method to target 140 previously reported and putatively relevant gene-containing CNV regions in 654 schizophrenic patients and 604 controls for association studies. Most genotyped CNVs (95%) showed very low (<1%) population frequency. A few novel rare variants were only present in patients suggesting a possible pathogenic involvement, including 1.39 Mb overlapping duplications at 22q11.23 found in two unrelated patients, and duplications of the somatostatin receptor 5 gene (SSTR5) at 16p13.3 in three unrelated patients. Furthermore, among the few relatively common CNVs observed in patients and controls, the combined analysis of gene copy number genotypes at two glutathione S-transferase (GST) genes, GSTM1 (glutathione S-transferase mu 1) (1p13.3) and GSTT2 (glutathione S-transferase theta 2) (22q11.23), showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (odds ratio of 1.92; P=0.0008). Our data provide complementary evidences for low prevalent, but highly penetrant chromosomal variants associated with schizophrenia, as well as for common CNVs that may act as susceptibility factors by disturbing glutathione metabolism.


Subject(s)
Gene Dosage/genetics , Glutathione Transferase/genetics , Schizophrenia/genetics , Adult , Aged , Female , Gene Duplication/genetics , Genetic Predisposition to Disease/epidemiology , Genetic Variation , Genomics , Genotype , Humans , Male , Middle Aged , Prevalence , Risk Factors , Schizophrenia/epidemiology
5.
Eur J Med Genet ; 51(1): 81-6, 2008.
Article in English | MEDLINE | ID: mdl-17998172

ABSTRACT

In this study we report a female patient with an interstitial duplication of a region (10q22-q23) which is rarely reported in the literature. We fine mapped the aberration with array CGH, which revealed an 18.6-Mb duplication, covering 89 annotated genes, at 10q22.2-q23.33. There were no other deletions or duplications elsewhere in the genome. The main clinical features of the patient are microcephaly and congenital heart disease, which are likely to be caused by dosage effect of one or several genes in the duplicated region. Similar phenotypes have been found in other patients with 10q11-q22 duplications and in two out of three patients with 10q22-q25 duplications. However, most of the duplication cases were investigated only by conventional chromosome analyses, and fine mapping of these and other duplications of 10q22-q23 are warranted for genotype-phenotype comparisons.


Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 10/genetics , Genes, Duplicate , Heart Defects, Congenital/genetics , Microcephaly/genetics , Child, Preschool , Female , Humans
6.
Am J Med Genet A ; 136(2): 169-74, 2005 Jul 15.
Article in English | MEDLINE | ID: mdl-15948187

ABSTRACT

We applied comparative genomic hybridization (CGH) in six patients with de novo prenatal or postnatal extra marker chromosomes (MC). In four cases, MCs were mosaic and in one of them, the MC was detected in less than 50% of the cells. In three cases, CGH identified the origin of the extra MCs. In the other three, two prenatal cases and one child with an abnormal phenotype, CGH showed normal profiles. Among these cases, a normal profile and entirely C-band positive was identified suggesting that MC did not contain euchromatin. Genetic imbalances detected by CGH were as follow: a gain of 8p10-p12 in a boy with facial dysmorphism, hyperactivity and speech delay, a gain of 8q10-q12 in a healthy man with a history of spontaneous abortions, and a gain of 15q11-q13 in a girl with speech delay, and motor skill and object manipulation difficulties. Clinical data of these patients were compared with those reported in the literature. We conclude that CGH is a very useful and powerful tool for characterizing prenatal or postnatal MCs, even when the mosaicism is present and the MCs are present in less than 50% of the cells.


Subject(s)
Chromosome Aberrations , Nucleic Acid Hybridization/methods , Adolescent , Adult , Child, Preschool , Chromosome Banding , Female , Genome, Human , Humans , In Situ Hybridization, Fluorescence , Infant, Newborn , Karyotyping , Male
8.
Ann Genet ; 44(2): 83-8, 2001.
Article in English | MEDLINE | ID: mdl-11522246

ABSTRACT

The aim of the study was to carry out cytogenetic analyses in pregnancy losses. Samples of cartilage and placenta tissue were obtained prospectively from 237 pregnancy losses of more than 16 weeks of gestation (130 stillbirths, 97 induced abortions and 10 early neonatal deaths). Cartilage culture was performed in 222 samples and placental culture was initiated in 224. The overall culture success rate was 83.5%, 72.3% in stillbirths, 97% in induced abortions and 100% in early neonatal death. An abnormal karyotype was detected in 52 cases: 6.9% in stillbirths, 43.6% in induced abortions and 20% in early neonatal deaths. The rate of discrepancy between the prenatal cytogenetic results in amniotic fluid and the post-termination karyotype was 3%. The tissue of choice for cytogenetic analysis was cartilage in induced abortions and early neonatal death, and placenta in stillbirth. The majority of cases had a chromosome abnormality: multiple congenital anomalies in 74.6%, and a single major anomaly in 9.7%.


Subject(s)
Abortion, Induced , Chromosome Aberrations , Congenital Abnormalities/genetics , Fetal Death/genetics , Fetus/metabolism , Placenta/metabolism , Adult , Cartilage/metabolism , Chromosome Disorders/diagnosis , Chromosome Disorders/genetics , Congenital Abnormalities/diagnostic imaging , Culture Techniques , Female , Humans , Infant Mortality , Infant, Newborn , Karyotyping , Phenotype , Pregnancy , Ultrasonography
9.
Ann Genet ; 43(1): 23-8, 2000.
Article in English | MEDLINE | ID: mdl-10818217

ABSTRACT

We have carried out a population-based study on the origin of the extra chromosome 21 in 38 families with Down syndrome (DS) offspring in El Vallès (Spain). From 1991 to 1994, a higher prevalence of DS (22.7/10000 live births, stillbirths and induced abortions) was found compared to the majority of EUROCAT registries. The distribution of trisomy 21 by origin was 88% maternal (90.6% meiosis I, 6.2% meiosis II, 3.1% maternal mosaicism), 5.6% paternal (50% meiosis I, 50% meiosis II) and 5.6% mitotic. The percentage of parental mosaicism was 2.7%. These percentages are similar to those previously reported. Recombination study revealed a maternal meiosis I genetic map of 32.68 cM (approximately one-half the length of the normal female map). Mean maternal age among non-recombinant cases involving MI errors was significantly lower (31.1 years) than among those cases showing one observable crossover (36.1 years) (P<0.05); this could support the hypothesis that 'achiasmate' chromosomes may be subject to aberrant segregation regardless of maternal age.


Subject(s)
Chromosomes, Human, Pair 21 , Down Syndrome/epidemiology , Down Syndrome/genetics , Abortion, Induced , Adult , Chromosome Mapping , Congenital Abnormalities/epidemiology , Congenital Abnormalities/genetics , Female , Genetic Markers , Genomic Imprinting , Humans , Infant, Newborn , Male , Maternal Age , Microsatellite Repeats , Pregnancy , Prevalence , Registries , Spain/epidemiology
10.
Am J Hum Genet ; 63(4): 1067-72, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9758616

ABSTRACT

Between April 1991 and December 1994, epidemiological studies detected a population with a high prevalence of Down syndrome in El Vallès, Spain. Parallel double studies were carried out to determine the parental and the meiotic origins of the trisomy 21, by use of DNA polymorphisms, and to establish the incidence of disomy 21 in the spermatozoa of the fathers of affected children, by use of multicolor FISH. Results show that the overall incidence of chromosome 21 disomy in the fathers of affected children was not significantly different from that in the control population (0.31% vs. 0.37%). However, analysis of individual data demonstrates that two cases (DP-4 and DP-5) with significant increases of disomy 21 (0. 75% and 0.78% vs. 0.37%) correspond to the fathers of the two individuals with Down syndrome of paternal origin. DP-5 also had a significant increase of sex-chromosome disomies (0.69% vs. 0.37%) and of diploid spermatozoa (1.13% vs. 0.24%).


Subject(s)
Chromosome Aberrations/genetics , Chromosomes, Human, Pair 21/genetics , Down Syndrome/etiology , Spermatozoa/pathology , Down Syndrome/epidemiology , Down Syndrome/genetics , Fathers , Genetic Markers , Humans , In Situ Hybridization, Fluorescence , Male , Spain
11.
Med Clin (Barc) ; 107(9): 321-5, 1996 Sep 21.
Article in Spanish | MEDLINE | ID: mdl-8984233

ABSTRACT

BACKGROUND: Multiple endocrine neoplasm type 2A (MEN 2A) is an autosomal dominantly inherited disease characterized by medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. Mutations have been identified in the extracellular domain of the RET proto-oncogen product (10q11.2) in MEN 2A patients. In each case a single base pair substitution results in replacement of cysteine with another amino acid. Most MEN 2A patients have mutations of codon 634. PATIENTS AND METHODS: Sixty-five unrelated MEN 2A patients from seven families were studied. Polymerase chain reaction, segregation, sequence analysis and restriction enzyme digestion were performed. RESULTS: Of seven families, four had the TGC to TAC transition, two families the TGC to TGG transversion and one family the TGC to CGC transition in codon 634 of RET. CONCLUSIONS: We found all the mutations in codon 634. The characterization of MEN 2A mutations allows early and presymptomatic diagnosis in this syndrome.


Subject(s)
Drosophila Proteins , Multiple Endocrine Neoplasia Type 2a/genetics , Proto-Oncogene Proteins/analysis , Receptor Protein-Tyrosine Kinases/analysis , Base Sequence , Chromosomes, Human, Pair 10 , Codon , Female , Haplotypes , Humans , Male , Mutation , Pedigree , Polymerase Chain Reaction , Proto-Oncogene Proteins c-ret , Risk Factors , Sequence Analysis
12.
Am J Med Genet ; 64(2): 434-40, 1996 Aug 09.
Article in English | MEDLINE | ID: mdl-8844099

ABSTRACT

Very little is known about the phenotype of FRAXE-positive individuals and the relation between the genotype/phenotype and genotype/ cytogenetic expression. We describe three families with normal and mildly affected individuals and a severely retarded male expressing fragility at the FRAXE locus or presenting different expansions at the CGG FRAXE triplet. In addition, we analyze the FRAXE mutation in sperm DNA from a retarded male carrier with a handicapped daughter expressing fragility at the FRAXE locus. Mental status in FRAXE individuals is highly variable and, although mild mental retardation is observed in most cases, several carrier males are apparently normal. It seems that methylation is not as strictly associated with size of CGG triplets in the FRAXE locus as in FRAXA, and it is possible that normal carrier individuals with fully methylated increments in lymphocytes have a certain proportion of unmethylated alleles in the critical (i.e., neural) tissues, FRAXE mutation is apparently similar to FRAXA in that males with somatic large methylated increments are carriers of small unmethylated ones in germinal cells.


Subject(s)
Chromosome Fragility , Intellectual Disability/genetics , Sex Chromosome Aberrations/genetics , X Chromosome , Adolescent , Adult , Diagnosis, Differential , Female , Fragile X Syndrome/physiopathology , Fragile X Syndrome/psychology , Genotype , Humans , Intellectual Disability/physiopathology , Intellectual Disability/psychology , Intelligence Tests , Male , Pedigree , Phenotype , Sex Chromosome Aberrations/physiopathology , Sex Chromosome Aberrations/psychology , Spain
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