RESUMO
A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be defined.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Nanismo/genética , Transtornos do Crescimento , Micrognatismo , Proteínas Serina-Treonina Quinases , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Códon sem Sentido , Microtia Congênita , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Nanismo/patologia , Orelha/anormalidades , Orelha/patologia , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Regulação da Expressão Gênica , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Heterozigoto , Humanos , Masculino , Microcefalia/genética , Microcefalia/patologia , Micrognatismo/genética , Micrognatismo/patologia , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Patela/anormalidades , Patela/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Splicing de RNA , Transdução de Sinais/genéticaRESUMO
The objective of the study is to investigate whether episodic binge pattern of alcohol consumption during pregnancy is independently associated with child mental health and academic outcomes. Using data from the prospective, population-based Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations between binge patterns of alcohol consumption during pregnancy (≥4 drinks per day) and child mental health [as rated by both parent (n = 4,610) and teacher (n = 4,274)] and academic outcomes [based on examination results (n = 6,939)] at age 11 years. After adjusting for prenatal and postnatal risk factors, binge pattern of alcohol consumption (≥4 drinks in a day on at least one occasion) during pregnancy was associated with higher levels of mental health problems (especially hyperactivity/inattention) in girls at age 11 years, according to parental report. After disentangling binge-pattern and daily drinking, binge-pattern drinking was independently associated with teacher-rated hyperactivity/inattention and lower academic scores in both genders. Episodic drinking involving ≥4 drinks per day during pregnancy may increase risk for child mental health problems and lower academic attainment even if daily average levels of alcohol consumption are low. Episodic binge pattern of drinking appears to be a risk factor for these outcomes, especially hyperactivity and inattention problems, in the absence of daily drinking.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Consumo Excessivo de Bebidas Alcoólicas/complicações , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Exposição Materna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estudos Prospectivos , Fatores de RiscoRESUMO
Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.
Assuntos
Predisposição Genética para Doença , Laminina/genética , Mutação/genética , Estudos de Associação Genética , Haplótipos/genética , Humanos , Laminina/química , FenótipoRESUMO
The factors that mediate chromosomal rearrangement remain incompletely defined. Among regions prone to structural variant formation, chromosome 6p25 is one of the few in which disease-associated segmental duplications and segmental deletions have been identified, primarily through gene dosage attributable ocular phenotypes. Using array comparative genome hybridization, we studied ten 6p25 duplication and deletion pedigrees and amplified junction fragments from each. Analysis of the breakpoint architecture revealed that all the rearrangements were non-recurrent, and in contrast to most previous examples the majority of the segmental duplications and deletions utilized coupled homologous and non-homologous recombination mechanisms. One junction fragment exhibited an unprecedented 367 bp insert derived from tandemly arranged breakpoint elements. While this accorded with a recently described replication-based mechanism, it differed from the previous example in being unassociated with template switching, and occurring in a segmental deletion. These results extend the mechanisms involved in structural variant formation, provide strong evidence that a spectrum of recombination, DNA repair and replication underlie 6p25 rearrangements, and have implications for genesis of copy number variations in other genomic regions. These findings highlight the benefits of undertaking the extensive studies necessary to characterize structural variants at the base pair level.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 6/genética , Dosagem de Genes , Glaucoma/genética , Quebra Cromossômica , Deleção Cromossômica , Fatores de Transcrição Forkhead , Haplótipos , Humanos , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Recombinação GenéticaRESUMO
OBJECTIVE: To investigate whether light drinking in pregnancy is associated with adverse child mental health and academic outcomes. DESIGN: Using data from the prospective, population-based Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations between light drinking in pregnancy (<1 glass per week in the first trimester) and child mental health (using both parent and teacher rated Strengths and Difficulties Questionnaires (SDQs)) and academic outcomes based on Key Stage 2 examination results at age 11 years. PARTICIPANTS: 11-year-old children from ALSPAC with parent (n=6587) and teacher (n=6393) completed SDQs and data from Key Stage 2 examination results (n=10 558). RESULTS: 39% of women had consumed <1 glass per week and 16% ≥1 glass per week of alcohol during the first trimester (45% abstaining). After adjustment, relative to abstainers, there was no effect of light drinking on teacher-rated SDQ scores or examination results. In girls, although there was a suggestion of worse outcomes (adjusted regression coefficient=0.38; 95% CI 0.01 to 0.74) on the parent-rated total SDQ score in those exposed to light drinking compared to abstainers, no dose-response relationship was evident. CONCLUSIONS: Although the pattern of findings involving parent ratings for girls exposed to light drinking is consistent with earlier findings from this cohort, the overall lack of any adverse effects of light drinking is similar to findings from other recent cohort studies. Light drinking in pregnancy does not appear to be associated with clinically important adverse effects for mental health and academic outcomes at the age of 11 years.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Deficiências da Aprendizagem/etiologia , Transtornos Mentais/etiologia , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Saúde Mental , Gravidez , Primeiro Trimestre da Gravidez , Estudos ProspectivosRESUMO
BACKGROUND: There is substantial debate as to whether moderate alcohol use during pregnancy could have subtle but important effects on offspring, by impairing later cognitive function and thus school performance. The authors aimed to investigate the unconfounded effect of moderately increased prenatal alcohol exposure on cognitive/educational performance. METHODS: We used mother-offspring pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) and performed both conventional observational analyses and Mendelian randomization using an ADH1B variant (rs1229984) associated with reduced alcohol consumption. Women of White European origin with genotype and self-reported prenatal alcohol consumption, whose offspring's IQ score had been assessed in clinic (N=4061 pairs) or Key Stage 2 (KS2) academic achievement score was available through linkage to the National Pupil Database (N=6268), contributed to the analyses. RESULTS: Women reporting moderate drinking before and during early pregnancy were relatively affluent compared with women reporting lighter drinking, and their children had higher KS2 and IQ scores. In contrast, children whose mothers' genotype predisposes to lower consumption or abstinence during early pregnancy had higher KS2 scores (mean difference +1.7, 95% confidence interval +0.4, +3.0) than children of mothers whose genotype predisposed to heavier drinking, after adjustment for population stratification. CONCLUSIONS: Better offspring cognitive/educational outcomes observed in association with prenatal alcohol exposure presumably reflected residual confounding by factors associated with social position and maternal education. The unconfounded Mendelian randomization estimates suggest a small but potentially important detrimental effect of small increases in prenatal alcohol exposure, at least on educational outcomes.
Assuntos
Logro , Consumo de Bebidas Alcoólicas/epidemiologia , Depressores do Sistema Nervoso Central/efeitos adversos , Cognição/efeitos dos fármacos , Etanol/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Causalidade , Criança , Estudos de Coortes , Avaliação Educacional/estatística & dados numéricos , Inglaterra/epidemiologia , Feminino , Genótipo , Humanos , Testes de Inteligência/estatística & dados numéricos , Modelos Lineares , Estudos Longitudinais , Comportamento Materno , Análise da Randomização Mendeliana , Gravidez , Primeiro Trimestre da Gravidez , Adulto JovemRESUMO
BACKGROUND: Observational studies have generated conflicting evidence on the effects of moderate maternal alcohol consumption during pregnancy on offspring cognition mainly reflecting problems of confounding. Among mothers who drink during pregnancy fetal alcohol exposure is influenced not only by mother's intake but also by genetic variants carried by both the mother and the fetus. Associations between children's cognitive function and both maternal and child genotype at these loci can shed light on the effects of maternal alcohol consumption on offspring cognitive development. METHODS: We used a large population based study of women recruited during pregnancy to determine whether genetic variants in alcohol metabolising genes in this cohort of women and their children were related to the child's cognitive score (measured by the Weschler Intelligence Scale) at age 8. FINDINGS: We found that four genetic variants in alcohol metabolising genes in 4167 children were strongly related to lower IQ at age 8, as was a risk allele score based on these 4 variants. This effect was only seen amongst the offspring of mothers who were moderate drinkers (1-6 units alcohol per week during pregnancy (per allele effect estimates were -1.80 (95% CI=â-2.63 to -0.97) p=0.00002, with no effect among children whose mothers abstained during pregnancy (0.16 (95%CI=â-1.05 to 1.36) p=0.80), p-value for interaction â=0.009). A further genetic variant associated with alcohol metabolism in mothers was associated with their child's IQ, but again only among mothers who drank during pregnancy.
Assuntos
Álcool Desidrogenase/genética , Cognição/efeitos dos fármacos , Etanol/farmacologia , Troca Materno-Fetal/fisiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Criança , Estudos de Coortes , Feminino , Genótipo , Humanos , Testes de Inteligência , Desequilíbrio de Ligação , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores de Risco , Sensibilidade e Especificidade , Inquéritos e Questionários , Reino Unido/epidemiologiaRESUMO
PURPOSE: To study the ocular phenotype of Pierson syndrome and to increase awareness among ophthalmologists of the diagnostic features of this condition. DESIGN: Retrospective, observational case series. METHODS: A multicenter study of 17 patients with molecularly confirmed Pierson syndrome. The eye findings were reviewed and compared to pertinent findings from the literature. RESULTS: The most characteristic ocular anomaly was microcoria. A wide range of additional abnormalities were found, including posterior embryotoxon, megalocornea, iris hypoplasia, cataract, abnormal lens shape, posterior lenticonus, persistent fetal vasculature, retinal detachment, variable axial lengths, and glaucoma. There was high interocular and intrafamilial variability. CONCLUSIONS: Loss-of-function mutations in laminin beta2 (LAMB2) cause a broad range of ocular pathology, emphasizing the importance of laminin beta2 in eye development. Patients with Pierson syndrome can initially present with ocular signs alone. In newborns with marked bilateral microcoria, Pierson syndrome should be considered and renal function investigated.