RESUMO
PURPOSE: The gold standard for identification of post-zygotic variants (PZVs) is droplet digital PCR (ddPCR) or high-depth sequencing across multiple tissues types. These approaches are yet to be systematically implemented for monogenic disorders. We developed PZV detection pipelines for correct classification of de novo variants. METHOD: Our pipelines detect PZV in parents (gonosomal mosaicism "pGoM") and children (somatic mosaicism, "M3"). We applied them to research exome sequencing (ES) data from The Australian Cerebral Palsy Biobank (ACPB, n=145 trios) and Simons Simplex Collection (SSC, n=405 families). Candidate mosaic variants were validated using deep amplicon sequencing or ddPCR. RESULTS: 69.2% (M3trio), 63.9% (M3single) and 92.7% (pGoM) of detected variants were validated, with 48.6%, 56.7% and 26.2% of variants respectively meeting strict criteria for mosaicism. In the ACPB, 16.6% of probands and 20.7% of parents had at least one true positive somatic or pGoM variant respectively. A large proportion of PZVs detected in SSC parents (79.8%) and child (94.5%) were not previously reported. We reclassified 3.7-8.0% of germline de novo variants as mosaic. CONCLUSION: Many PZVs were incorrectly classified as germline variants or missed by previous approaches. Systematic application of our pipelines could increase genetic diagnostic rate, improve estimates of recurrence risk in families, and benefit novel disease gene identification.
RESUMO
AIM: To conduct a systematic review of phenotypic definition and case ascertainment in published genetic studies of cerebral palsy (CP) to inform guidelines for the reporting of such studies. METHOD: Inclusion criteria comprised genetic studies of candidate genes, with CP as the outcome, published between 1990 and 2019 in the PubMed, Embase, and BIOSIS Citation Index databases. RESULTS: Fifty-seven studies met the inclusion criteria. We appraised how CP was defined, the quality of information on case ascertainment, and compliance with international consensus guidelines. Seven studies (12%) were poorly described, 33 studies (58%) gave incomplete information, and 17 studies (30%) were well described. Missing key information precluded determining how many studies complied with the definition by Rosenbaum et al. Only 18 out of 57 studies (32%) were compliant with the Surveillance of Cerebral Palsy in Europe (SCPE) international guidelines on defining CP. INTERPRETATION: Limited compliance with international consensus guidelines on phenotypic definition and mediocre reporting of CP case ascertainment hinders the comparison of results among genetic studies of CP (including meta-analyses), thereby limiting the quality, interpretability, and generalizability of study findings. Compliance with the SCPE guidelines is important for ongoing gene discovery efforts in CP, given the potential for misclassification of unrelated neurological conditions as CP.
Assuntos
Paralisia Cerebral/diagnóstico , Paralisia Cerebral/genética , Consenso , Bases de Dados Factuais , Guias como Assunto , Humanos , Fenótipo , Vigilância da População , Sistema de RegistrosRESUMO
Although prematurity and hypoxic-ischaemic injury are well-recognized contributors to the pathogenesis of cerebral palsy (CP), as many as one-third of children with CP may lack traditional risk factors. For many of these children, a genetic basis to their condition is suspected. Recent findings have implicated copy number variants and mutations in single genes in children with CP. Current studies are limited by relatively small patient numbers, the underlying genetic heterogeneity identified, and the paucity of validation studies that have been performed. However, several genes mapping to intersecting pathways controlling neurodevelopment and neuronal connectivity have been identified. Analogous to other neurodevelopmental disorders such as autism and intellectual disability, the genomic architecture of CP is likely to be highly complex. Although we are just beginning to understand genetic contributions to CP, new insights are anticipated to serve as a unique window into the neurobiology of CP and suggest new targets for intervention.
Assuntos
Paralisia Cerebral/genética , Variações do Número de Cópias de DNA/genética , Mutação/genética , Humanos , Fatores de RiscoRESUMO
Cerebral palsy (CP) is heterogeneous with different clinical types, comorbidities, brain imaging patterns, causes, and now also heterogeneous underlying genetic variants. Few are solely due to severe hypoxia or ischemia at birth. This common myth has held back research in causation. The cost of litigation has devastating effects on maternity services with unnecessarily high cesarean delivery rates and subsequent maternal morbidity and mortality. CP rates have remained the same for 50 years despite a 6-fold increase in cesarean birth. Epidemiological studies have shown that the origins of most CP are prior to labor. Increased risk is associated with preterm delivery, congenital malformations, intrauterine infection, fetal growth restriction, multiple pregnancy, and placental abnormalities. Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are heterogeneous and require function investigations to prove causation. Whole genome sequencing, fine scale copy number variant investigations, and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders.
Assuntos
Paralisia Cerebral/etiologia , Cardiotocografia , Anormalidades Congênitas , Medicina Defensiva , Distocia , Reações Falso-Positivas , Feminino , Retardo do Crescimento Fetal , Variação Genética , Humanos , Hipóxia-Isquemia Encefálica/complicações , Recém-Nascido , Infecções/complicações , Erros Inatos do Metabolismo/complicações , Mutação , Cordão Nucal , Complicações do Trabalho de Parto , Doenças Placentárias , Gravidez , Complicações na Gravidez , Gravidez Múltipla , Nascimento Prematuro , Fatores de Risco , Fatores SexuaisRESUMO
Cerebral palsy (CP) is the most common motor disability in children. To ascertain the role of major genetic variants in the etiology of CP, we conducted exome sequencing on a large-scale cohort with clinical manifestations of CP. The study cohort comprised 505 girls and 1,073 boys. Utilizing the current gold standard in genetic diagnostics, 387 of these 1,578 children (24.5%) received genetic diagnoses. We identified 412 pathogenic and likely pathogenic (P/LP) variants across 219 genes associated with neurodevelopmental disorders, and 59 P/LP copy number variants. The genetic diagnostic rate of children with CP labeled at birth with perinatal asphyxia was higher than the rate in children without asphyxia (P = 0.0033). Also, 33 children with CP manifestations (8.5%, 33 of 387) had findings that were clinically actionable. These results highlight the need for early genetic testing in children with CP, especially those with risk factors like perinatal asphyxia, to enable evidence-based medical decision-making.
Assuntos
Paralisia Cerebral , Variações do Número de Cópias de DNA , Sequenciamento do Exoma , Heterogeneidade Genética , Humanos , Paralisia Cerebral/genética , Feminino , Masculino , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Exoma/genética , Lactente , Testes Genéticos , Estudos de Coortes , Predisposição Genética para Doença , Recém-NascidoRESUMO
BACKGROUND: The aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at <37 completed weeks of gestation) and synthesize currently available evidence using meta-analysis. METHODS: Spontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥ 3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates. RESULTS: A cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4). CONCLUSION: Replication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.
Assuntos
Polimorfismo de Nucleotídeo Único/genética , Nascimento Prematuro/genética , População Branca/genética , Estudos de Casos e Controles , Estudos de Coortes , Fator V/genética , Feto , Humanos , Razão de ChancesRESUMO
BACKGROUND: To explore the additive effect of urinary incontinence, in people with comorbid depression, on health related quality of life. METHODS: Males and females, 15 to 95 years (n = 3010, response rate 70.2%) were interviewed face to face in the 1998 Autumn South Australian Health Omnibus Survey. RESULTS: Self-reported urinary incontinence was found in 20.3% (n=610), and depression as defined by the PRIME-MD in 15.2% (n=459) of the survey population. Urinary incontinence with comorbid depression was found in 4.3% of the overall population. Univariate analysis showed that respondents with urinary incontinence and comorbid depression were more likely to be aged between 15 and 34 years and never married when compared to those with incontinence only. Multivariate analysis demonstrated that in people with incontinence, the risk of having comorbid depression was increased by an overall health status of Fair or Poor, or the perception that their incontinence was moderately or very serious. Respondents reporting that they experienced incontinence with comorbid depression scored significantly lower than those experiencing incontinence without depression on all dimensions of the SF-36.The interaction of the presence of incontinence and the presence of depression was significantly associated with the dimensions of physical functioning. CONCLUSIONS: Depression and incontinence both reduce QOL. When they occur together there appears to be an additive effect which affects both physical and mental health, perhaps by increasing a person's negative perceptions of their illness. Clinicians should identify and manage comorbid depression when treating patients who have incontinence to improve their overall QOL.
Assuntos
Transtorno Depressivo/psicologia , Qualidade de Vida/psicologia , Incontinência Urinária/psicologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Estudos Transversais , Transtorno Depressivo/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Incontinência Urinária/epidemiologia , Adulto JovemRESUMO
AIM: This study aims to examine single nucleotide polymorphism (SNP) associations with cerebral palsy in a multi-variable analysis adjusting for potential clinical confounders and to assess SNP-SNP and SNP-maternal infection interactions as contributors to cerebral palsy. METHODS: A case control study including 587 children with cerebral palsy and 1154 control children without cerebral palsy. Thirty-nine candidate SNPs were genotyped in both mother and child. Data linkage to perinatal notes and cerebral palsy registers was performed with a supplementary maternal pregnancy questionnaire. History of known maternal infection during pregnancy was extracted from perinatal databases. RESULTS: Both maternal and fetal carriage of inducible nitric oxide synthase SNP rs1137933 were significantly negatively associated with cerebral palsy in infants born at less than 32 weeks gestation after adjustment for potential clinical confounders and correction for multiple testing (odds ratio 0.55, 95% confidence interval 0.38-0.79; odds ratio 0.57, 95% confidence interval 0.4-0.82, respectively). Analysis did not show any statistically significant SNP-SNP or SNP-maternal infection interactions after correction for multiple testing. CONCLUSIONS: Maternal and child inducible nitric oxide synthase SNPs are associated with reduced risk of cerebral palsy in infants born very preterm. There was no evidence for statistically significant SNP-SNP or SNP-maternal infection interactions as modulators of cerebral palsy risk.
Assuntos
Paralisia Cerebral/genética , Recém-Nascido Prematuro , Óxido Nítrico Sintase Tipo II/genética , Polimorfismo de Nucleotídeo Único , Fatores de Confusão Epidemiológicos , Citocinas/genética , Feminino , Técnicas de Genotipagem , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Lectina de Ligação a Manose/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Mães , Análise Multivariada , Trombofilia/genéticaRESUMO
BACKGROUND: Valproate use during pregnancy increases risk in malformations and neurodevelopmental disorders. Data from the experimental setting in mice showed valproate is a direct inhibitor of histone deacetylase, inducing histone hyperacetylation, histone methylation, and DNA demethylation causing congenital malformations with an epigenetic inheritance. We investigated potential transgenerational adverse effects of valproate. METHODS: We questioned 108 individuals (from 90 families) suffering complications due to valproate exposure in utero who were parents themselves (85 women and 23 men) about the occurrence of malformations and neurodevelopmental disorders in their children. All were member of Aide aux Parents d'Enfants souffrants du Syndrome de l'AntiConvulsivant (APESAC), a charity created in 2011 to provide personal assistance and support to families suffering complications due to valproate exposure during pregnancy. RESULTS: Among their 187 children they reported 43 (23%) children with malformation(s) (26 hand or foot malformations; 15 dysmorphic facial features; 10 renal/urologic malformations; 6 spina bifida; 4 cardiac malformation; 2 craniosynostosis; 2 cleft lip and palate) and 82 (44%) children with neurodevelopmental disorders (63 problematic behaviors and autism; 41 psychomotor disorders; 16 language problems; 16 attention deficit; 5 mental retardation). Only 88 (47%) children had neither malformation nor developmental disorders. CONCLUSION: These data add to the need for funding pharmacoepidemiological investigations of epigenetic inheritance caused by drugs causing malformations or neurodevelopmental disorders. Individuals exposed in utero to valproate must be informed about the risk, so they can consider fertility options, antenatal diagnosis, and adequate early surveillance.
Assuntos
Anormalidades Induzidas por Medicamentos , Fenda Labial , Fissura Palatina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsia , Complicações na Gravidez , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Anticonvulsivantes/uso terapêutico , Fenda Labial/induzido quimicamente , Fissura Palatina/induzido quimicamente , Epilepsia/induzido quimicamente , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Feminino , Histonas/uso terapêutico , Humanos , Masculino , Camundongos , Gravidez , Complicações na Gravidez/induzido quimicamente , Ácido Valproico/toxicidadeRESUMO
AIM: Previous studies have proposed a link between the presence of specific single nucleotide polymorphisms (SNPs) and cerebral palsy and the majority of these associations remain to be confirmed or rejected by prospective studies with sufficient statistical power. Prior studies have also given little attention to the interaction of genomic characteristics and clinical risk factors. METHODS: This paper describes the design of a prospective case-control study to test these genetic associations in conjunction with more stringent data collection in respect to clinical features associated with pregnancy, particularly maternal infection. Here we consider the ethical requirements, our hypothesis that genetic susceptibility modifies the risk of cerebral palsy in the presence of perinatal environmental triggers, a priori primary and secondary aims, power calculations, participant recruitment strategies, data linkage, sampling methods of genetic material and subsequent SNP analysis, collection of clinical data and the proposed final statistical analysis.
Assuntos
Paralisia Cerebral/etiologia , Paralisia Cerebral/genética , Comportamento Cooperativo , Complicações na Gravidez/genética , Projetos de Pesquisa , Adolescente , Austrália , Estudos de Casos e Controles , Criança , Pré-Escolar , DNA , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez , Nascimento Prematuro/genética , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Síndrome de Resposta Inflamatória Sistêmica/genética , Trombofilia/genéticaRESUMO
The Australian Federal Productivity Commission is proposing two new schemes to better support those with major disability. The main National Disability Insurance Scheme (NDIS) will provide long-term care and support for the disabled. A smaller scheme, the National Injury Insurance Scheme (NIIS), will provide 'no-fault 'support for those following an accident or 'medical injury'. It is proposed that cerebral palsy (CP) is part of the NIIS. While this brings quicker and more equitable benefits to CP families, the scheme labels CP as a 'medical accident' and infers preventability. Obstetricians will fund much of the system. Despite being labelled a 'no-fault' system, maternity staff can still be litigated for extensive 'head of damages', eg loss of earning capacity. An additional option is for federal/state legislation to introduce a true 'no-fault' lifetime pension specifically for all children on CP registers. This pension would be graded by degree of disability and dependent on waiving civil litigation. Savings in medico-legal costs and potentially a 7% reduction in caesarean delivery would cover the estimated annual cost of $50 000 per annum indexed life pension for severe CP cases and the total annual cost of AUD $93 million for Australia. This pension and the NDIS would help cover the needs of children with CP without recourse to prolonged litigation and without detriment to the maternity services of Australia, caused by defensive obstetrics and maternity hospital closure because of CP litigation.
Assuntos
Paralisia Cerebral/economia , Benefícios do Seguro/economia , Benefícios do Seguro/legislação & jurisprudência , Responsabilidade Legal , Austrália , Paralisia Cerebral/etiologia , Custos de Cuidados de Saúde , Humanos , PensõesRESUMO
BACKGROUND: Acute intrapartum hypoxia is an uncommon cause of cerebral palsy. The exclusion of acute intrapartum hypoxia utilizes two vital pieces of information that can be obtained at the time of birth: (i) cord blood gas to exclude a severe metabolic acidosis, and (ii) placental histology to suggest an alternative aetiology other than acute intrapartum hypoxia. Although recommendations exist to encourage this practice in high-risk deliveries, their compliance in an Australian setting is not known. AIMS: To evaluate the frequency and utility of cord blood gases and placental histology following delivery with an Apgar score ≤6 at five minutes. METHODS: A retrospective study of 12,887 consecutive deliveries at a tertiary obstetric centre, of which 100 live births had Apgar scores ≤6 at five minutes. Cord blood gases and placental histology were examined. There were also 132 stillbirths where placental histology was sought. RESULTS: Cord gases were measured in 52 of 100 live births with a low Apgar score. Seven of these had severe metabolic acidaemia and 26 had normal cord gases. Placental histology was requested in 40 of these births and 30 showed abnormal histology, suggesting alternative aetiologies. Of the 132 stillbirths, placental histology was available in 50. Abnormal histology was present in 39 of these stillbirths. CONCLUSIONS: Cord gases and placental histology should be sought in all babies with low Apgar scores for the benefit of understanding causation, counselling of the parents, research and professional liability assessment. Heightened awareness for adverse perinatal outcomes is required by health care professionals when a neonate requires resuscitation.
Assuntos
Índice de Apgar , Sangue Fetal/química , Oxigênio/sangue , Placenta/citologia , Acidose/diagnóstico , Acidose/epidemiologia , Austrália/epidemiologia , Gasometria , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Retrospectivos , Natimorto/epidemiologiaRESUMO
AIM: Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples. RESULTS: At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50-0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05-1.83). For infants born 32-36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34-80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21-14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13-0.76). CONCLUSION: Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection.
Assuntos
Paralisia Cerebral/genética , Paralisia Cerebral/virologia , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Complicações Infecciosas na Gravidez/virologia , Viroses/complicações , Estudos de Casos e Controles , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Interleucina-4/genética , Interleucina-6/genética , Razão de Chances , Gravidez , Sistema de Registros , Receptor 4 Toll-Like/genéticaRESUMO
[This corrects the article DOI: 10.1038/s41525-018-0073-4.].
RESUMO
High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as "cerebral palsy." This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology.
Assuntos
Paralisia Cerebral/diagnóstico , Paralisia Cerebral/etiologia , Paralisia Cerebral/genética , Sequenciamento de Nucleotídeos em Larga Escala , HumanosRESUMO
Apolipoprotein E (APOE) plays a significant role in lipid metabolism and has been implicated in the growth and repair of injured neurons. Two small studies have suggested an association between APOE genotype and cerebral palsy. We investigated if APOE genotype is associated with an increased risk for cerebral palsy, influences the type of cerebral palsy or interacts with prenatal viral infection to influence risk of cerebral palsy. The population-based case-control study comprised newborn screening cards of 443 Caucasian patients with cerebral palsy and 883 Caucasian matched controls. APOE genotyping was performed on DNA extracted from dried blood spots. Allelic and genotypic frequencies did not differ between cases and controls and combined frequencies were 0.10 (epsilon2), 0.76 (epsilon3), 0.14 (epsilon4), 0.03 (epsilon2/epsilon2), 0.10 (epsilon2/epsilon3), 0.03 (epsilon2/epsilon4), 0.02 (epsilon4/epsilon4), 0.21 (epsilon3/epsilon4), 0.61 (epsilon3/epsilon3). APOE genotype was correlated with cerebral palsy, type of cerebral palsy, gestation at birth and the presence of viral nucleic acids detected in previous work. Analysis by gestational age (all gestational ages, >/=37, 32-36 and <32 weeks) and type of cerebral palsy (all types, diplegia, hemiplegia and quadriplegia) showed no association between APOE genotype and cerebral palsy in this Caucasian population. An association between prenatal viral infection, APOE genotype and cerebral palsy was not demonstrated. These results did not confirm an association between APOE genotype, cerebral palsy, type of cerebral palsy and prenatal infection in a Caucasian population. Given the low frequency of APOE epsilon2 and some of the heterozygote and homozygote combinations in this study, a larger study is assessing this further.
Assuntos
Apolipoproteínas E/genética , Paralisia Cerebral/genética , População Branca/genética , Estudos de Casos e Controles , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/virologia , Feminino , Genótipo , Humanos , Reação em Cadeia da Polimerase , Gravidez , Diagnóstico Pré-NatalRESUMO
OBJECTIVE: The objective of the study was to investigate the associations between infection, polymorphisms in the mannose-binding lectin gene (MBL), and cerebral palsy (CP). STUDY DESIGN: This was a case-control study using deoxyribonucleic acid from newborn screening cards of 443 Caucasian CP cases and 883 Caucasian controls to screen for 6 polymorphisms within the MBL gene. These polymorphisms combine to create haplotypes with high (HYPA), intermediate (LYQA, LYPA), low (LXPA), and defective (HYPD, LYQC, LYPB) circulating MBL levels. RESULTS: chi(2) Analyses demonstrated significant differences between CP cases and controls (less than 37 weeks chi(2) 14.99, P = .02; less than 32 weeks chi(2) 13.62, P = .02). The MBL haplotype LYPA was associated with CP at all gestations (odds ratio [OR] 1.57, 95% confidence interval [CI], 1.00 to 2.46), less than 37 weeks (OR 2.43, 95% CI, 1.41 to 4.18), and less than 32 weeks (OR 2.54, 95% CI, 1.34 to 4.76). LYPA was also associated with hemiplegic CP for babies born at less than 37 weeks (OR 2.77, 95% CI, 1.02 to 7.26) and less than 32 weeks (OR 4.48, 95% CI, 1.55 to 12.65). HYPD was associated with quadriplegic CP at all gestations (OR 3.47, 95% CI, 1.41 to 8.31) as well as for babies born at less than 32 weeks (OR 7.86, 95% CI, 1.67 to 29.48). Subanalysis on samples previously testing positive for exposure to viral infection demonstrated similar patterns of significance as those presented above, whereas analysis on samples negative for exposure to viral infection showed no positive associations between any of the MBL haplotypes and CP. Potential type I error from multiple analyses is a caveat. CONCLUSION: MBL haplotypes LYPA or HYPD may be associated with an increased risk of CP in the presence of exposure to viral infection and may act as susceptibility factors for CP.