RESUMO
MECP2 duplication syndrome (MDS; OMIM 300260) is an X-linked neurodevelopmental disorder caused by nonrecurrent duplications of the Xq28 region involving the gene methyl-CpG-binding protein 2 (MECP2; OMIM 300005). The core phenotype of affected individuals includes infantile hypotonia, severe intellectual disability, very poor-to-absent speech, progressive spasticity, seizures, and recurrent infections. The condition is 100% penetrant in males, with observed variability in phenotypic expression within and between families. Features of MDS in individuals of African descent are not well known. Here, we describe a male patient from Cameroon, with MDS caused by an inherited 610 kb microduplication of Xq28 encompassing the genes MECP2, IRAK1, L1CAM, and SLC6A8. This report supplements the public data on MDS and contributes by highlighting the phenotype of this condition in affected individuals of African descent.
Assuntos
Cromossomos Humanos X , Duplicação Gênica , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Proteína 2 de Ligação a Metil-CpG/genética , Camarões , Pré-Escolar , Humanos , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/genética , FenótipoRESUMO
Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22 , Síndrome de DiGeorge/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , MasculinoRESUMO
Current research in schizophrenia suggests that negative symptoms cannot be considered a unitary construct and should be divided in two dimensions: lack of motivation and impoverishment of expression. In addition, negative symptoms are particularly related to decreased daily-life functioning. In the present study, we aimed to replicate these results in a sample of participants with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition associated with high risk of developing schizophrenia. We also expected to observe an association between the COMT Val/Met polymorphism and negative symptoms. We examined the factorial structure of negative symptoms in a sample of 47 individuals with 22q11DS using the Structured Interview for Prodromal Symptoms (SIPS) and the Positive and Negative Syndrome Scale (PANSS). We also performed stepwise regression analyses to investigate the associations between negative symptoms, adaptive skills and the COMT Val/Met polymorphism. Negative symptoms were explained by a two-factor solution, namely the "amotivation and social withdrawal" and the "emotional withdrawal and expression" dimensions. The motivational dimension was significantly associated with daily-life functioning. Met carriers were rated as experiencing significantly more symptoms of amotivation. The results are interpreted in the light of existing cognitive models in the field of motivation and schizophrenia.
Assuntos
Transtornos Cognitivos/etiologia , Síndrome de DiGeorge/complicações , Adaptação Psicológica/fisiologia , Adolescente , Catecol O-Metiltransferase/genética , Criança , Transtornos Cognitivos/genética , Análise Fatorial , Feminino , Humanos , Inteligência , Masculino , Testes Neuropsicológicos , Polimorfismo Genético/genética , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVES: Congenital adrenal hyperplasia (CAH) remains one of the most challenging endocrine disorders to diagnose, manage, and treat, especially in Africa where there is lack of neonatal screening program, and limited access to care. Data on biomolecular anomaly are sparse, therefore type of mutations are unknown, increasing management challenges and genetic counseling. The present study aims to describe clinical, biomolecular aspects of a group of Cameroonian patients. METHODS: We did an observational retrospective study at the pediatric endocrinology unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde from May 2013 to December 2019, including all patients diagnosed with CAH. RESULTS: We consecutively included 31 patients aged less than 21 years, diagnosed CAH. Median age at diagnosis was 1.71 years (IQR 0.08-2.57 years). Abnormal genitalia was the main complain in 48.4%(n=15). The most prevalent genetic anomaly found in our study population (n=24) was on CYP11, found in 16 patients (66.6%) followed by CYP21A2 mutation found in 8 patients. Homozygous mutation of p.Q356X was found in half of patients with 11 hydroxylase deficiency. This mutation was mostly found in people from semi-Bantu tribes, declared non consanguineous. CONCLUSIONS: 11 hydroxylase deficiency is the most prevalent form of CAH found in this group of Cameroonian children.
Assuntos
Hiperplasia Suprarrenal Congênita , Adolescente , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/genética , Camarões/epidemiologia , Criança , Humanos , Recém-Nascido , Oxigenases de Função Mista/genética , Mutação , Estudos Retrospectivos , Esteroide 21-Hidroxilase/genéticaRESUMO
Approximately 1.1 billion people currently live in countries where consanguineous marriages are customary, and among them one in every three marriages is between cousins. Opinions diverge between those warning of the possible health risks to offspring and others who highlight the social benefits of consanguineous marriages. A consanguinity study group of international experts and counselors met at the Geneva International Consanguinity Workshop from May 3, 2010, to May 7, 2010, to discuss the known and presumptive risks and benefits of close kin marriages and to identify important future areas for research on consanguinity. The group highlighted the importance of evidence-based counseling recommendations for consanguineous marriages and of undertaking both genomic and social research in defining the various influences and outcomes of consanguinity. Technological advances in rapid high-throughput genome sequencing and for the identification of copy number variants by comparative genomic hybridization offer a significant opportunity to identify genotype-phenotype correlations focusing on autozygosity, the hallmark of consanguinity. The ongoing strong preferential culture of close kin marriages in many societies, and among migrant communities in Western countries, merits an equivalently detailed assessment of the social and genetic benefits of consanguinity in future studies.
Assuntos
Consanguinidade , Variações do Número de Cópias de DNA , Doença/genética , Feminino , Pesquisa em Genética , Humanos , Masculino , Casamento , Característica Quantitativa HerdávelRESUMO
Introduction According to the current classification of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) of Disorders of Sex Development (DSD), etiologies vary around the world. Ethnic or genetic diversity probably explains this variability. We therefore conducted the present study on etiologies of DSDs in a country from central Africa. Methods We carried out an observational retrospective study at the Pediatric Endocrinology Unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde, Cameroon from May 2013 to December 2019. All patients diagnosed with a DSD were included, and incomplete files excluded. Results We included 80 patients diagnosed with DSD during the study period. The 46,XX DSD were the most frequent in our study population (n = 41, 51.25%), with congenital adrenal hyperplasia (CAH) as the main diagnosis. The 46,XY DSD accounted for 33.75% and sex chromosome DSD group represented 15% of the study population. Conclusions DSDs are not an exceptional diagnosis in a Sub-Saharan context. 46,XX DSD are the most prevalent diagnosis in our setting. The diagnosis of all these affections is late compared to other centers, justifying advocacy for neonatal screening of DSDs in our context.
Assuntos
Transtornos do Desenvolvimento Sexual/epidemiologia , Adolescente , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/etiologia , Camarões , Criança , Pré-Escolar , Transtornos do Desenvolvimento Sexual/complicações , Feminino , Disgenesia Gonadal 46 XY/epidemiologia , Disgenesia Gonadal Mista/epidemiologia , Humanos , Lactente , Síndrome de Klinefelter/epidemiologia , Masculino , Prevalência , Estudos Retrospectivos , Aberrações dos Cromossomos Sexuais , Testículo/crescimento & desenvolvimento , Síndrome de Turner/epidemiologiaRESUMO
We report on a monochorionic/diamniotic twin pregnancy discordant for trisomy 21. Amniocentesis (at 13(5/7) weeks) was performed following ultrasound signs of hydrops and cystic hygroma in twin 1 (T1). Prenatal karyotype showed non-mosaic trisomy 21 in T1 (47,XX,+21[7]), and low-grade mosaic trisomy 21 in twin 2 (T2) (47,XX,+21[2]/46,XX[19]). Post mortem examination of fetal skin, kidneys and lungs confirmed trisomy 21 in T1 (47,XX,+21[548]) and the placenta (47,XX,+21[200]). T2 had a normal karyotype (46,XX[648]). Analysis of microsatellite polymorphisms in multiple samples from the placenta, hand, lungs, kidneys and the umbilical cords of both twins confirmed monozygosity for all loci tested, and trisomy 21 in T1. Unexpectedly, T1 and T2 inherited different maternal alleles for markers of the most distal 4 Mbp of 21q. At least four successive events are needed to explain the genetic status of both twins and include maternal MI premature chromatids separation or maternal II meiotic nondisjunction and post-zygotic events such as, chromosome rescue, nondisjunction, an/or recombination.
Assuntos
Cromossomos Humanos Par 21/genética , Doenças em Gêmeos , Síndrome de Down/genética , Diagnóstico Pré-Natal , Gêmeos Monozigóticos , Amniocentese , Feminino , Marcadores Genéticos , Genótipo , Humanos , Cariotipagem , Repetições de Microssatélites , Não Disjunção Genética , Polimorfismo Genético , GravidezRESUMO
We report on two patients with de novo subtelomeric terminal deletion of chromosome 6p. Patient 1 is an 8-month-old female born with normal growth parameters, typical facial features of 6pter deletion, bilateral corectopia, and protruding tongue. She has severe developmental delay, profound bilateral neurosensory deafness, poor visual contact, and hypsarrhythmia since the age of 6 months. Patient 2 is a 5-year-old male born with normal growth parameters and unilateral hip dysplasia; he has a characteristic facial phenotype, bilateral embryotoxon, and moderate mental retardation. Further characterization of the deletion, using high-resolution array comparative genomic hybridization (array-CGH; Agilent Human Genome kit 244 K), revealed that Patient 1 has a 8.1 Mb 6pter-6p24.3 deletion associated with a contiguous 5.8 Mb 6p24.3-6p24.1 duplication and Patient 2 a 5.7 Mb 6pter-6p25.1 deletion partially overlapping with that of Patient 1. Complementary FISH and array analysis showed that the inv del dup(6) in Patient 1 originated de novo. Our results demonstrate that simple rearrangements are often more complex than defined by standard techniques. We also discuss genotype-phenotype correlations including previously reported cases of deletion 6p.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Pré-Escolar , Inversão Cromossômica , Feminino , Genótipo , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , FenótipoRESUMO
PRINCIPLES: Human embryonic stem cells (hESC) hold enormous potential for regenerative medicine. So far, the majority of hESC lines have been derived from the isolated inner cell mass (ICM) of blastocysts of variable quality, and several of them from low-grade embryos. Moreover, most of the lines have been obtained in media containing animal components such as foetal bovine serum. We aimed to derive hESC lines in xeno-free conditions using spare embryos frozen in Switzerland before 2001. METHODS: In cooperation with Swiss IVF centres we collected up to 199 donated embryos frozen between 1988 and 2000 at different stages of development. RESULTS: Embryo quality at thawing showed wide variability, reduced quality and low survival upon culture. Using early arrested embryos (n=46), we report here the first Swiss hESC line, called CH-ES1, derived from a single blastomere of an arrested four-cell-stage embryo. Despite its polyploidy, already present at the third passage, CH-ES1 expressed ESC markers of pluripotency and differentiated into all three germ layers in embryoid bodies in vitro and in teratomas in vivo. CONCLUSIONS: As the destruction of viable developing embryos, even spare ones, raises serious ethical concerns, deriving hESC lines from arrested embryos may be an alternative approach to avoid embryo destruction. However, given the reduced derivation efficiency they should not be considered a unique and/or selective source of hESC lines.
Assuntos
Blastômeros/citologia , Linhagem Celular , Células-Tronco Embrionárias , Animais , Técnicas de Cultura de Células/métodos , Diferenciação Celular , Criopreservação , Destinação do Embrião , Células-Tronco Embrionárias/química , Células-Tronco Embrionárias/transplante , Expressão Gênica , Humanos , Imuno-Histoquímica , Injeções , Cariotipagem , Camundongos , Camundongos SCID , Células-Tronco PluripotentesRESUMO
BACKGROUND: The 22q11.2 deletion syndrome is amongst the most common microdeletion syndrome in humans. Its prevalence remains unknown in sub-Saharan Africa, and its clinical features are under-reported for people of African descent. OBJECTIVE: We have investigated the prevalence of the 22q11.2 deletion syndrome in patients with congenital heart defects in Cameroon. METHODS: A total of 70 of 100 cases of congenital cardiac malformation with echocardiographic evidence were examined prospectively and tested for the 22q11.2 deletion, using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. RESULTS: Two of 70 patients (2.8%) were found to have 22q11.2 deletion. Both cases had conotruncal heart defects and exhibited extracardiac features of the 22q11.2 deletion syndrome that were either classical (e.g., puffy upper eyelids, bulbous tip of the nose) or less identifiable (telecanthus, hooding of eyelids and prominent nasal bridge). CONCLUSIONS: The report shows that the prevalence of the 22q11.2 deletion syndrome in patients with heart malformations in Cameroon (2.8%) is similar to that of various world populations. The clinical phenotypes will contribute to the Global Atlas for dysmorphology. "Omics" technologies offer much promise in genetic/genomic screening of severe global health problems.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/epidemiologia , Testes Genéticos/métodos , Cardiopatias Congênitas/epidemiologia , Adolescente , Adulto , Camarões/epidemiologia , Criança , Pré-Escolar , Síndrome de DiGeorge/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Masculino , Fenótipo , Prevalência , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: Previous studies linking the catechol O-methyltransferase (COMT) functional polymorphism to the specific phenotype in 22q11.2 deletion syndrome (22q11.2DS) have yielded inconsistent results. The goal of the present study was to replicate a recent finding that executive function is higher in individuals hemizygous for the Met allele. METHOD: Thirty-four children and young adults with a 22q11.2 microdeletion, hemizygous for the Val (N=14) or Met (N=20) polymorphism, were tested on measures of executive function, IQ, and memory. RESULTS: No significant differences were detected between Met- and Val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. CONCLUSIONS: These results suggest either a small effect of the COMT polymorphism on executive function in 22q11.2DS or no effect at all. Further research is needed to characterize the implications of hemizygosity of COMT in 22q11.2DS for cognitive function.
Assuntos
Catecol O-Metiltransferase/genética , Transtornos Cognitivos/diagnóstico , Síndrome de DiGeorge/genética , Lobo Frontal/fisiologia , Polimorfismo Genético , Adolescente , Adulto , Catecol O-Metiltransferase/metabolismo , Criança , Transtornos Cognitivos/genética , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/enzimologia , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Metionina/genética , Metionina/metabolismo , Testes Neuropsicológicos , Valina/genética , Valina/metabolismoRESUMO
BACKGROUND: To open vaginal cavity to the pelvic floor is part of surgical treatment for urogenital sinus (UGS) in girls with congenital adrenal hyperplasia (CAH). For high UGS, this operative procedure can be challenging and may jeopardise urinary continence. Combined perineal and laparoscopic approaches could be useful to minimise perineal dissection and to facilitate the vaginal lowering. PATIENTS AND METHODS: We report the procedure of a laparoscopic-assisted vaginal pull-through for supra-sphincteric UGS in a 5-year-old girl with CAH. Laparoscopic dissection of the vagina from the posterior wall of the bladder and urethra, division of the confluence and vaginal pull-through to the perineum are described. DISCUSSION: The technique is derived from laparoscopic-assisted treatment for high ano-rectal malformations. Compared with current procedures for treatment for high UGS, laparoscopic-assisted approach allows mobilising vagina with minimal dissection of perineum and complete preservation of urethra. Another major advantage is to provide a direct vision for dissection of the space between rectum and urethra prior to vaginal pull-through. CONCLUSION: Laparoscopic-assisted vaginal pull-through appears to be an interesting approach for high UGS in CAH patients, reducing dissection and risk of urinary incontinence. This new approach needs to be strengthened by other cases.
Assuntos
Anormalidades Múltiplas , Hiperplasia Suprarrenal Congênita/cirurgia , Malformações Anorretais/cirurgia , Laparoscopia/métodos , Vagina/cirurgia , Hiperplasia Suprarrenal Congênita/diagnóstico , Malformações Anorretais/diagnóstico , Pré-Escolar , Feminino , HumanosRESUMO
In a search for potential infertility loci, which might be revealed by clustering of chromosomal breakpoints, we compiled 464 infertile males with a balanced rearrangement from Mendelian Cytogenetics Network database (MCNdb) and compared their karyotypes with those of a Danish nation-wide cohort. We excluded Robertsonian translocations, rearrangements involving sex chromosomes and common variants. We identified 10 autosomal bands, five of which were on chromosome 1, with a large excess of breakpoints in the infertility group. Some of these could potentially harbour a male-specific infertility locus. However, a general excess of breakpoints almost everywhere on chromosome 1 was observed among the infertile males: 26.5 versus 14.5% in the cohort. This excess was observed both for translocation and inversion carriers, especially pericentric inversions, both for published and unpublished cases, and was significantly associated with azoospermia. The largest number of breakpoints was reported in 1q21; FISH mapping of four of these breakpoints revealed that they did not involve the same region at the molecular level. We suggest that chromosome 1 harbours a critical domain whose integrity is essential for male fertility.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 1 , Infertilidade Masculina/genética , Inversão Cromossômica , Humanos , Masculino , Oligospermia/genética , Translocação GenéticaRESUMO
OBJECTIVE: To report parental decisions regarding pregnancy termination following the prenatal diagnosis of a sex chromosome abnormality (SCA) in the fetus. METHODS: Retrospective collection of data from records of 61 families receiving genetic counseling after prenatal diagnosis of a sex chromosome abnormality in the fetus in the Division of Medical Genetics, University Hospital of Geneva during the time period 1980-2001. RESULTS: Among 61 couples with a prenatal diagnosis of a sex chromosome abnormality (SCA), 44 couples (72.1%) decided to terminate pregnancy. Pregnancy termination rates were 100, 73.9, 70, 50 and 42.9% for Turner syndrome, Klinefelter syndrome, 47,XXX females, 47,XYY males, and mosaic cases, respectively. In all 11 cases with a fetal abnormality seen on ultrasound, pregnancy was terminated. Termination rates were higher among couples with a higher mean number of previous children. Maternal age and year of test did not influence parental decisions. CONCLUSIONS: Parental decision to terminate a pregnancy for a fetus with a SCA varied by type of sex chromosome abnormality, by presence of fetal ultrasound anomalies, and by the mean number of previous children.
Assuntos
Aborto Induzido/psicologia , Tomada de Decisões , Pais/psicologia , Transtornos dos Cromossomos Sexuais/diagnóstico , Adulto , Feminino , Aconselhamento Genético/psicologia , Testes Genéticos/psicologia , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , Estudos RetrospectivosRESUMO
Williams-Beuren syndrome (WBS) is a rare neurodevelopmental condition caused by a recurrent chromosomal microdeletion involving about 28 contiguous genes at 7q11.23. Most patients display a specific congenital heart defect, characteristic facial features, a particular behavior, and intellectual disability. Cases from sub-Saharan Africa have been seldom reported. The present study describes 3 Cameroonian patients affected by WBS, aged 19 months, 13 and 14 years, in whom the diagnosis was confirmed by fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH). The first patient presented with a congenital heart defect, the second and third with learning difficulties as well as developmental and behavioral issues. In the latter 2 cases, the facial phenotypes were similar to those of the unaffected population with the same ethnic background. However, the cardiovascular anomalies and friendly behavioral attitudes led to suspicion of WBS. FISH revealed the deletion of the WBS critical region in the first patient, and array-CGH detected a heterozygous â¼1.4-Mb deletion in the 7q11.23 region in the second and third patient. This preliminary report suggests that for sub-Saharan Africans clinical suspicion of WBS could be mostly based on behavioral phenotype and structural heart defects, and less on the classical facial dysmorphic signs.
RESUMO
Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contributes to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects.
Assuntos
Síndrome de Down/patologia , Síndrome de Down/terapia , Células-Tronco Pluripotentes Induzidas/transplante , Modelos Biológicos , Gêmeos Monozigóticos/genética , Animais , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células , Síndrome de Down/genética , Ontologia Genética , Genoma Humano/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neurais/patologia , Neurogênese/genética , Neurônios/metabolismo , Neurônios/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Transcriptoma/genética , Quinases DyrkRESUMO
Opitz G/BBB Syndrome (OS) is a multiple congenital anomaly disorder characterized by developmental defects of midline structures. The most relevant clinical signs are ocular hypertelorism, hypospadias, cleft lip and palate, laryngo-tracheo-esophageal abnormalities, imperforate anus, and cardiac defects. Developmental delay, intellectual disability and brain abnormalities are also present. The X-linked form of this disorder is caused by mutations in the MID1 gene coding for a member of the tripartite motif family of E3 ubiquitin ligases. Here, we describe 12 novel patients that carry MID1 mutations emphasizing that laryngo-tracheo-esophageal defects are very common in OS patients and, together with hypertelorism and hypospadias, are the most frequent findings among the full spectrum of OS clinical manifestations. Besides missense and nonsense mutations, small insertions and deletions scattered along the entire length of the gene, we found that a consistent number of MID1 alterations are represented by the deletion of single coding exons. Deep characterization of one of these deletions reveals, for the first time within the MID1 gene, a complex rearrangement composed of two deletions, an inversion and a small insertion that may suggest the involvement of concurrent non-homologous mechanisms in the generation of the observed structural variant.
Assuntos
Fissura Palatina/genética , Esôfago/anormalidades , Éxons , Doenças Genéticas Ligadas ao Cromossomo X/genética , Hipertelorismo/genética , Hipospadia/genética , Proteínas dos Microtúbulos/genética , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Translocação Genética , Adolescente , Criança , Pré-Escolar , Inversão Cromossômica , Ordem dos Genes , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Mutação Puntual , Deleção de Sequência , Ubiquitina-Proteína Ligases , Adulto JovemRESUMO
The aims of the present study were to assess (1) the parental origin of trisomy 21 and the stage in which nondisjunction occurs and (2) the relationship between altered genetic recombination and maternal age as risk factors for trisomy 21. The study included 102 cases with Down syndrome from the Croatian population. Genotyping analyses were performed by polymerase chain reaction using 11 short tandem repeat markers along chromosome 21q. The vast majority of trisomy 21 was of maternal origin (93%), followed by paternal (5%) and mitotic origin (2%). The frequencies of maternal meiotic I (MI) and meiotic II errors were 86% and 14%, respectively. The highest proportion of cases with zero recombination was observed among those with maternal MI derived trisomy 21. A higher proportion of telomeric exchanges were presented in cases with maternal MI errors and cases with young mothers, although these findings were not statistically significant. The present study is the first report examining parental origin and altered genetic recombination as a risk factor for trisomy 21 in a Croatian population. The results support that trisomy 21 has a universal genetic etiology across different human populations.
Assuntos
Síndrome de Down/etiologia , Síndrome de Down/genética , Padrões de Herança , Idade Materna , Recombinação Genética , Adolescente , Adulto , Croácia , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Meiose/genética , Meiose/fisiologia , Não Disjunção Genética/genética , Não Disjunção Genética/fisiologia , Pais , Gravidez , Recombinação Genética/fisiologia , Fatores de Risco , Adulto JovemRESUMO
We report a male patient, offspring of a consanguineous marriage between first cousins, with cognitive impairment, autistic-like behavior, deafness, postaxial polydactyly, and mild dysmorphic features. aCGH revealed a 600 kb homozygous deletion of 4p15.1 (from 33.553 to 34.159 Mb in NCBI36 hg18) encoding several transcripts of unknown function. Both parents are heterozygous for the deletion and the non-affected brother is homozygous for the normal alleles. We hypothesize that this deletion is likely to contribute to the phenotype of the patient. This case underlines the contribution of aCGH in discovering potentially pathogenic CNVs in consanguineous matings.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Sequência Conservada , Homozigoto , Fenótipo , Alelos , Transtorno Autístico/genética , Sequência de Bases , Pré-Escolar , Transtornos Cognitivos/genética , Hibridização Genômica Comparativa , Consanguinidade , Surdez/genética , Humanos , Masculino , Polidactilia/genéticaRESUMO
BACKGROUND: SRY, located on the Y chromosome, is one of the key genes involved in human sex determination. SRY mutations are responsible for 10-15% of all cases of 46,XY gonadal dysgenesis (GD) but are rarely implicated in the pathogenesis of mixed GD. METHODS: SRY was analyzed by sequence analysis of DNA extracted from blood leukocytes. SRY activity was evaluated by SOX9 immunostaining, one of the targets of SRY. RESULTS: We report a case of mixed GD due to a novel SRY point mutation in a patient with a 46,XY karyotype, without mosaicism or submicroscopic genomic imbalances. Hormonal studies showed low anti-müllerian hormone and histological examination of the gonads showed a streak gonad on the right side and a left dysgenetic testis, thus permitting the diagnosis of mixed GD. Immunostaining for SOX9, a target of SRY, was positive in nuclei of Sertoli and epididymal cells in the left gonad and negative on the right, thus indicating asymmetric activation of SRY. CONCLUSION: Mixed GD can result from SRY mutations without mosaicism, neither in peripheral blood, nor within the gonads. The asymmetric effect of the point mutation implies the presence of local factors modulating SRY expression or action.