RESUMO
Background In 2017/2018, the Health Products Regulatory Authority issued new guidance on the prescription of Sodium Valproate (VPA) to female patients of reproductive age. A review was initiated of VPA exposed individuals to identify whether previously unascertained cases of VPA related Embryopathy could be identified. Methods Forty patients under twenty-three years of age were reviewed. Results Eleven (27.5%) new cases of Fetal Valproate Spectrum Disorder (FVSD) were identified. Twenty-four (60%) cases were felt not to satisfy diagnostic threshold for this teratogenic disorder. Five (12.5%) cases were indeterminate. Six of the forty patients (15%) had an alternative genetic cause of developmental delay established. Conclusion There is increased awareness regarding avoidance of VPA use in women of childbearing age. An equal awareness is warranted that developmental delay in the context of VPA exposure in pregnancy does not necessarily constitute a diagnosis of FVSD but that other competing diagnostic hypotheses have to be considered.
Assuntos
Anormalidades Induzidas por Medicamentos , Ácido Valproico , Anormalidades Induzidas por Medicamentos/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Feminino , Humanos , Gravidez , Ácido Valproico/efeitos adversosRESUMO
PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.
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Deficiência Intelectual , Complexo Mediador/genética , Deficiência Intelectual Ligada ao Cromossomo X , Transtornos do Neurodesenvolvimento , Feminino , Genes Ligados ao Cromossomo X , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Fenótipo , SíndromeRESUMO
Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.
Assuntos
Duplicação Gênica , Deficiência Intelectual/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adolescente , Adulto , Criança , Cromossomos Humanos X/genética , Feminino , Aconselhamento Genético , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/fisiopatologia , Linhagem , FenótipoRESUMO
Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.
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Metilação de DNA/genética , Genoma Humano , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Síndrome de Sotos/genética , Regulação da Expressão Gênica , Histona Metiltransferases , Histona-Lisina N-Metiltransferase , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Proteínas Nucleares/genéticaRESUMO
Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
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Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Estudos de Associação Genética , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Mutação , Proteínas de Neoplasias/genética , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/genética , Fácies , Feminino , Humanos , Masculino , Fenótipo , Análise de Sequência de DNARESUMO
Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.
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BACKGROUND: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. METHODS: Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. RESULTS: The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. CONCLUSION: A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 3 , Deficiências do Desenvolvimento/genética , Fácies , Genitália Masculina/anormalidades , Transtornos do Crescimento/genética , Deficiências do Desenvolvimento/diagnóstico , Feminino , Estudos de Associação Genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Receptores de Dopamina D3/genética , Síndrome , Fatores de Transcrição/genéticaRESUMO
The objective of this study was to determine the association of single nucleotide polymorphisms (SNP) in selected candidate genes with sensory and technological meat quality traits in commercial cattle. SNP in seven candidate genes were genotyped in 130 crossbred Bos taurus cattle using PCR-RFLP. Reported associations between calpastatin (CAST) and Warner-Bratzler shear force and carboxypeptidase E (CPE) and intra-muscular fat were not confirmed. However, SNP in CAST, amp-activated protein kinase, gamma-3 subunit (PRKAG3), growth hormone receptor (GHR) and stearoyl coA desaturase (SCD) genes were significantly associated with colour traits (p<0.05). The PRKAG3 SNP was additionally associated with cook loss in M. longissimus thoracis et lumborum (p<0.05) and tended towards association in M. semimembranosus (p<0.1). An association with pH was identified for the SCD SNP (p<0.001). The GHR polymorphism was influential on moisture and intra-muscular fat in M. semimembranosus and protein content in both muscles (p<0.05). Only CPE was associated with sensory traits (flavour in M. longissimus, p<0.01).
Assuntos
Cor , Ácidos Graxos/análise , Genes , Carne/normas , Músculo Esquelético/química , Polimorfismo de Nucleotídeo Único , Água/análise , Proteínas Quinases Ativadas por AMP/genética , Animais , Proteínas de Ligação ao Cálcio/genética , Bovinos , Tecnologia de Alimentos , Genótipo , Concentração de Íons de Hidrogênio , Receptores da Somatotropina/genética , Estearoil-CoA Dessaturase/genética , PaladarRESUMO
Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion.
Assuntos
Blefarofimose/genética , Variações do Número de Cópias de DNA/genética , Fatores de Transcrição Forkhead/genética , Deleção de Genes , Mutação/genética , Adolescente , Pré-Escolar , Feminino , Proteína Forkhead Box L2 , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , PrognósticoRESUMO
A 17-month-old boy was referred with profound sensorineural hearing loss (SNHL), severe visual impairment and developmental delay. Neuroimaging identified hypomyelination and cochlear nerve aplasia. He was noted to have fair skin and hair and multiple areas of cutaneous hyperpigmentation. Previous investigations including karyotype, array comparative genomic hybridization (aCGH) and a full metabolic screen were normal. A novel missense mutation of the highly conserved high mobility group (HMG) domain of SOX10 was identified (Q174P:c.521A>C). This case represents the first description of aplasia of the cochlear nerve due to a SOX10 mutation.
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Nervo Coclear/patologia , Mutação , Bulbo Olfatório/patologia , Fatores de Transcrição SOXE/genética , Anormalidades Múltiplas , Nervo Coclear/diagnóstico por imagem , Perda Auditiva Neurossensorial/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Bulbo Olfatório/diagnóstico por imagem , Radiografia , Análise de Sequência de DNARESUMO
It is essential to isolate high-quality DNA from muscle tissue for PCR-based applications in traceability of animal origin. We wished to examine the impact of cooking meat to a range of core temperatures on the quality and quantity of subsequently isolated genomic (specifically, nuclear) DNA. Triplicate steak samples were cooked in a water bath (100 degrees C) until their final internal temperature was 75, 80, 85, 90, 95, or 100 degrees C, and DNA was extracted. Deoxyribonucleic acid quantity was significantly reduced in cooked meat samples compared with raw (6.5 vs. 56.6 ng/microL; P < 0.001), but there was no relationship with cooking temperature. Quality (A(260)/A(280), i.e., absorbance at 260 and 280 nm) was also affected by cooking (P < 0.001). For all 3 genes, large PCR amplicons (product size >800 bp) were observed only when using DNA from raw meat and steak cooked to lower core temperatures. Small amplicons (<200 bp) were present for all core temperatures. Cooking meat to high temperatures thus resulted in a reduced overall yield and probable fragmentation of DNA to sizes less than 800 bp. Although nuclear DNA is preferable to mitochondrial DNA for food authentication, it is less abundant, and results suggest that analyses should be designed to use small amplicon sizes for meat cooked to high core temperatures.
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Núcleo Celular/genética , DNA/genética , Tecnologia de Alimentos , Temperatura Alta , Carne/análise , DNA/análise , DNA/normas , Reação em Cadeia da PolimeraseRESUMO
BACKGROUND: Increasing use of fertility therapy has elicited concerns regarding adverse effects for expectant mothers and the health of children thus conceived. AIMS: To study the risk of adverse perinatal outcomes, birth defects and pregnancy complications following assisted reproductive technology (ART). METHODS: Questionnaire-based study involving 1,524 children and 1,182 pregnancies conceived following in vitro fertilisation (IVF) in two units. Outcomes were compared with the general population. RESULTS: In the study group versus the general population; multi-foetal gestations, 26 versus 2%; singleton preterm delivery and low birth weight, 8.7 and 6.4 versus 4.3 and 4%, respectively; non-lethal congenital malformation rate, 2.6 versus 2.1%; placenta praevia, 2.8 versus 0.5%. CONCLUSIONS: Multi-foetal gestations remain the principal cause of adverse perinatal outcomes after ART. Singleton ART pregnancies have an increased risk of preterm delivery and low birth weight at term. Non-lethal congenital malformation rates are not increased following ART. Placenta praevia is increased following ART.
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Complicações na Gravidez/epidemiologia , Complicações na Gravidez/etiologia , Resultado da Gravidez , Técnicas de Reprodução Assistida/efeitos adversos , Adulto , Distribuição de Qui-Quadrado , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Irlanda/epidemiologia , Placenta Prévia/epidemiologia , Placenta Prévia/etiologia , Gravidez , Gravidez Múltipla , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects, as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. OBJECTIVE: To describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and to report on the molecular characterisation of the deletion size. RESULTS AND CONCLUSIONS: The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in 10 of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalities to a 360 kb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.
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Agenesia do Corpo Caloso , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Família , Feminino , Humanos , Lactente , Masculino , SíndromeRESUMO
Awareness of the rare condition of Job syndrome is low among both paediatricians and geneticists. Consequently, observation of the recurrent fractures in the majority of such cases can result in misdiagnosis of non-accidental injury in young children who have the syndrome. The case we report here represents an example of this diagnostic pitfall, which deserves wide recognition due to the serious consequences for children, families and paediatricians acting as experts in legal actions in such circumstances.
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Fraturas Ósseas/etiologia , Síndrome de Job/diagnóstico , Maus-Tratos Infantis/diagnóstico , Suturas Cranianas/anormalidades , Diagnóstico Diferencial , Eczema/complicações , Eczema/etiologia , Feminino , Fraturas Ósseas/complicações , Sopros Cardíacos/complicações , Humanos , Imunoglobulina E/sangue , Lactente , Síndrome de Job/complicações , Molusco Contagioso/complicações , RecidivaRESUMO
Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant syndrome characterized by canine teeth with extremely large roots (radiculomegaly), congenital cataract, dysmorphic facial features and congenital heart disease. A case of mother-daughter vertical transmission of OFCD is reported. Dental findings were important in confirming the diagnosis in the mother.
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Anormalidades Múltiplas/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Anormalidades Dentárias/diagnóstico , Adulto , Anormalidades do Olho/diagnóstico , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Recém-Nascido , Doenças Raras/diagnóstico , SíndromeRESUMO
We report a series of neonates and foetuses with trisomy 18 and abnormally low cholesterol levels and propose that down regulation of cholesterol synthesis in trisomy 18 is, in part, responsible for its phenotype. Cholesterol is a major structural lipid of cell membranes, as well as the precursor of steroid hormones and bile acids. Several human malformation syndromes have been identified biochemically as disorders of cholesterol biosynthesis. Trisomy 18, a multi-system malformation syndrome, has clinical features that overlap with those of disorders of cholesterol biosynthesis and dysregulation of this pathway may have a role in the developmental pathology.
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Colesterol/biossíntese , Cromossomos Humanos Par 18/metabolismo , Trissomia/genética , Líquido Amniótico/metabolismo , Colesterol/deficiência , Humanos , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/metabolismo , Trissomia/diagnósticoRESUMO
BACKGROUND: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. METHODS: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. RESULTS: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. CONCLUSIONS: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.
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Anormalidades Múltiplas/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/genética , Proto-Oncogene Mas , SíndromeRESUMO
IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X linked syndrome) is a rare disorder which usually results in death in early infancy or childhood. Clinical awareness remains the cornerstone of diagnosis, and provided that the diagnosis is entertained, mutation analysis for FOXP3 gene mutations can be confirmatory. Two new patients in whom IPEX was diagnosed retrospectively are reported.
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Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Poliendocrinopatias Autoimunes/diagnóstico , Sequência de Bases , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Recém-Nascido , Masculino , Dados de Sequência Molecular , Mutação , Poliendocrinopatias Autoimunes/genética , SíndromeRESUMO
MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.