Background: Variants in DSP cause arrhythmogenic cardiomyopathy (ACM) and phenotype data derived largely from arrhythmogenic right ventricular cardiomyopathy (ARVC) patient cohorts. We hypothesised that patients with DSP truncating variants (DSPtv) express a wider phenotype spectrum. We report penetrance, phenotype spectrum and genetic architecture of DSPtv. Methods and Results: Unrelated patients with a DSPtv and any cardiac phenotype were sought from international centres (n = 98). Primary diagnosis for n = 32 included dilated cardiomyopathy (n = 19), ARVC (n = 10), ACM (n = 1), unexplained VF (n = 1) and Carvajal syndrome (n = 1). Fifteen (47%) experienced sudden cardiac death (SCD) events, including 7 (22%) with SCD as the presenting symptom. All had left ventricular (LV) involvement. A family history was reported in 22 (69%). In the total cohort (n = 98), there were 68 unique DSPtv (29 frameshift, 25 nonsense, 12 splice, two insertion/deletions) classified using ACMG criteria (5 pathogenic, 62 likely pathogenic, 1 uncertain significance). We investigated localisation of DSPtv to key functional gene regions (G1, CR and G2) in cases compared to controls. Case variants were more common in G1 and CR (84–72% vs 16–28%) while control variants were more frequent in G2 (58% vs 42%) (p < 0.0001). Event-free survival from SCD events was worse when DSPtv occurred in G1/CR, compared to G2 (log-rank p = 0.016). Conclusion: In the largest series of DSPtv carriers, we show a wide phenotype spectrum. It should be considered a distinct gene-specific cardiomyopathy characterised by LV dysfunction with high risk of ventricular arrhythmias. DSPtv are highly penetrant and gene location is associated with worse clinical outcomes.

Truncating variants in the TTN gene (TTNtv) are common in dilated cardiomyopathy (DCM) patients (15–20% cases) but are also present in unaffected individuals in DCM families and in the general population. Interpreting the clinical significance of these variants is challenging. Our aim was to determine DCM penetrance in a large cohort of kindreds with TTNtv-related familial DCM that were identified by a network of investigators in the Australian Genomics Cardiac Flagship. Eligible families were required to carry a high-impact TTNtv, with genetic testing offered in an unbiased way to affected and unaffected relatives. Probands from 65 families were identified from 8 clinical genetic testing or research services. 457 individuals were genotyped (mean age 52 years, range 13 to 93; 51% males). There were no differences in the relative distribution of TTNtv positive (n = 228, 50%) and TTNtv negative (n = 229, 50%) individuals, or in the numbers of male (n = 234, 51%) and female (n = 223, 49%) participants. The median age of DCM onset in TTNtv carriers was 51 years with DCM penetrance increasing from 34% at 40 years to 93% at 80 years. Male TTNtv carriers had a higher DCM penetrance (p < 0.0001; 59% vs 33% at 50 years) and lower median age of onset (45 vs 55 years) compared to females. Our data show that the overall penetrance of DCM in TTNtv carriers is high, but that a substantial proportion of relatives, particularly females, can remain asymptomatic until late in life. These findings have implications for screening surveillance and genetic counselling of asymptomatic TTNtv carriers.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks—the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes ( TUBA1A ( n =2), SCN8A ( n =1) and KDM5C ( n =1)) and in six novel candidate CP genes ( AGAP1 , JHDM1D , MAST1 , NAA35 , RFX2 and WIPI2 ) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1 . In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A ( DYRK1A ) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations ( P =0.00851) and an excess of de novo mutations ( P =2.53 × 10 −10 ) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel ( n =5) and recontacted ( n =3) cases with previous case reports, including larger CNV and translocation events ( n =7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

Multi-gene testing panels provided by clinical laboratories have become increasingly available and affordable and have been used since 2008 in South Australia. We audited consecutive patients diagnosed with cardiomyopathy or channelopathy and referred to the SA Clinical Genetics Service for genetic testing between 1 January 2008 and 31 December 2013. 66 probands with cardiac channelopathy were identified, 58 with Long QT syndrome (LQTS), 5 with Brugada syndrome, and 3 with other disorders. 62 of these probands were tested. The 60 completed tests identified 28% with pathogenic variants (All LQTS 29%, familial LQTS 43%, sporadic LQTS 20%) and 13% with variants of uncertain significance (VUS). Proband testing in channelopathy enabled cascade testing in 41 patients, 10 for confirmatory and 31 for predictive testing. 94 probands with cardiomyopathy were identified, 73 with hypertrophic cardiomyopathy (HCM), 10 with dilated cardiomyopathy, 4 with arrhythmogenic ventricular dysplasia, and 7 with other cardiomyopathies. 77 of these probands were tested. The 70 completed tests identified 47% with pathogenic variants (All HCM 46%, familial HCM 74%, sporadic HCM 22%) and 14% with a VUS. Proband testing in cardiomyopathy enabled cascade testing in 24 patients, 3 for confirmatory and 21 for predictive testing. We found that the yield of genetic testing for cardiomyopathies was similar to published rates, but our yield of genetic testing for cardiac channelopathies was lower than published rates. VUS were found in a considerable proportion of patients. In vivo functional data exist for few variants.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor ( FGFR ) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1 , FGFR2 , and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1 . Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1‐3 / TWIST1 ‐associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis. © 2013 Wiley Periodicals, Inc.

X-linked intellectual disability (XLID), defined as clinical ID combined with a pedigree consistent with X-linked inheritance, is a genetically heterogeneous condition that affects more than 10% of males with ID. Currently there are at least 92 genes known to cause XLID,1–3 yet a large proportion of XLID cases remain unexplained, as each of the XLID genes identified so far only accounts for a small fraction (< 1%) of affected individuals. Given that about one third of mutations affect gene expression levels,4 we reasoned that transcriptome profiling of lymphoblast cell lines from XLID patients may highlight genes harboring disease-causing mutations and may be an efficient follow-up method for rare sequence variants of unknown functional significance. We analyzed expression profiles of lymphoblast cell lines from 64 XLID patients, including 13 cases that were part of a recent X-chromosome exon re-sequencing study5 (Supplementary Methods, Supplementary Table 1). We found polyglutamine-binding protein 1 (PQBP1), a gene previously implicated in XLID,6,7 to be significantly downregulated in two cases (Supplementary Table 2), and confirmed an exon 4 (AG)2 deletion as the cause of mRNA downregulation in both instances. PQBP1 mutations cause a sydromic form of XLID commonly referred to as Renpenning syndrome.8 The specific mutation we describe here has been previously shown to cause XLID,6 and has also been proven to decrease mRNA levels by nonsense-mediated mRNA decay,7 thus being likely to be detected by assessment of gene expression. The cases for which we identified PQBP1 mutations were not part of the cohort studied by Tarpey et al. (Supplementary Table 1). We further asked whether any of the non-recurrent sequence variants identified by the exon re-sequencing study in the 13 overlapping cases was associated with a significant alteration of mRNA levels. We found that CCDC22, which encodes a coiled-coil domain protein of unknown function, was significantly downregulated (Figure 1c, Supplementary Figure 1) in one of our XLID patients. A CCDC22 non-recurrent sequence variant c.49A > G/p.T17A had been identified in a proband from the same family by the Sanger re-sequencing study, but its functional significance had not been determined.5 The proband belongs to a large family (55 individuals) with six affected males over three generations (Figure 1a). Notably, female carriers in this family show highly skewed X-chromosome inactivation (data not shown). Linkage analysis delineated a 58.4-Mb linkage interval (logarithm in base 10 of odds (LOD) score = 2.7). Whole X-chromosome exon re-sequencing identified four non-recurrent mis-sense variants within the linkage interval: CCDC22 c.49A> G/p.T17A, FAM121A (APOOL) c.40G> T/p.A14S, LOC402414 c.453T> A/p.S151R, ABCB7 c.941G> A/p.R314Q.5 Although these sequence variants were predicted to be neutral for protein function (Polyphen, data not shown), we found that the CCDC22 change was associated with a fivefold decrease in mRNA level (Figure 1c, Supplementary Figure 1 and Supplementary Table 3). No other gene in the 58.4-Mb linkage interval showed significant downregulation of mRNA levels (Supplementary Figure 2a). We sequenced CCDC22 in all available family members and found that the c.49A>G change segregates with the disease consistent with its location within the linkage interval. Figure 1 CCDC22 mutation causes X-linked intellectual disability (XLID) in a large pedigree. (a) The pedigree of the IGOLD #586 family shows six affected males over three generations. The case analyzed by expression profiling in this study (ID11) is the case from ... The c.49A >G sequence variant is located within exon 1, two base pairs away from the 5′ splice site of intron 1 of CCDC22 (Figure 1b) and is predicted to significantly decrease the splicing efficiency at the corresponding 5′ splice site (splice site score decrease from 0.9 to 0.7, using NNsplice9; http://www.fruitfly.org/seq_tools/splice.html). We found abnormally spliced transcripts retaining intron 1 to be much more abundant in cases harboring the c.49A >G mutation than in controls (Figure 1c, Supplementary Methods, Supplementary Figure 1), demonstrating that the mutation impedes efficient alternative splicing at the 5′ splice site. The abnormally spliced transcripts with intron 1 retention contain several in-frame premature terminal codons, which would likely cause the transcript to be degraded by nonsense-mediated mRNA decay surveillance (NMD). Alternatively, the splicing defect could have a negative impact on the transcription efficiency of CCDC22.10–12 Inhibition of NMD by cyclohexamide did not significantly affect the total CCDC22 mRNA level or the abundance of the abnormally spliced isoform (Supplementary Figure 1), indicating that NMD did not have a major role in CCDC22 mRNA downregulation. Recent studies have suggested that abnormal transcripts with retained intron(s), having failed the nuclear quality control mechanism, are not exported into the cytoplasm and thus are not degraded by NMD.13–17 In addition, splicing events proximal to the transcription start sites have been shown to be important for efficient recruitment of basal transcription factors.10–12 We thus suspect that the c.49A >G change near the first splice site removes the positive feedback necessary for efficient transcription of CCDC22. To test whether CCDC22 downregulation occurred frequently in the general population we analyzed CCDC22 expression level in 52 age-matched control males using genome-wide expression data from lymphoblast cell lines from an AGRE cohort (Methods). None of the controls showed significant downregulation of CCDC22 mRNA level (Supplementary Figure 2b). The phenotype of the IGOLD #586 family is consistent with syndromic XLID. In addition to intellectual disability, affected individuals have cardiac abnormalities (atrial septal defect, ventricular septal defect, dextrocardia), skeletal abnormalities (hypoplastic distal phalanges, syndactyly, hip subluxation, scoliosis) and specific facial features (Table 1). Table 1 Phenotype characterization of the IGOLD 586 family CCDC22 is a ubiquitously expressed coiled-coil domain protein (Supplementary Figure 3). Although the function of CCDC22 is currently poorly defined, CCDC22 has been shown to interact in vitro with copines, a family of calcium-dependent membrane-binding proteins, via its coiled-coil domain18 as well as the Nance–Horan syndrome protein.19 In the rat brain, CCDC22 is expressed in multiple regions including the prefrontal and somatosensory cortex, dentate gyrus and thalamus,20 and CCDC22-specific antibodies stain primarily axons.20,21 In the rat spinal cord, CCDC22 is primarily expressed in the dorsal columns, as well as in ipsilateral motor neurons after sciatic nerve trans-section,21 suggesting a role for this gene in neuronal injury response. To gain further insight into the function of CCDC22, we took a bioinformatics approach. To identify genes that are functionally related to, or potentially interact with CCDC22 in the developing human brain, we used a recently published human fetal brain transcriptome dataset22 and queried which are the nearest neighbors of CCDC22 by co-expression topological overlap.23 Figure 1d shows the genes co-expressed with CCDC22 in the human fetal brain. Remarkably, this module contains genes that have been implicated in hereditary cardiac and skeletal disorders, the main classes of extra-central nervous system pathological changes observed in family IGOLD #586. The IGOLD #586 case was the only one in the X-chromosome re-sequencing cohort of 208 with a CCDC22 mutation, suggesting that mutations of CCDC22 are a rare cause of XLID. Here we highlight CCDC22 as a novel XLID candidate gene for future targeted re-sequencing studies and propose that the mRNA downregulation associated with the described mutation likely results from reduced transcriptional efficiency rather than nonsense-mediated mRNA decay.

Children with intellectual disability, dysmorphic features, malformations and/or growth abnormalities frequently display normal karyotypes. Recent studies have shown that genome-wide single nucleotide polymorphism (SNP) arrays can be effective in detecting abnormalities involving copy number variation (CNV), deletions, duplications and loss of heterozygosity (LOH) that routine cytogenetic tests fail to identify. Five patients with various degrees of intellectual disability and/or dysmorphic features and other malformations were whole-genome genotyped using the Human-1 Genotyping BeadChip--Exon-Centrix 100K SNP arrays (Illumina). All patients had undergone routine cytogenetic testing; four patients had normal karyotypes, while one patient had an apparently balanced complex translocation involving chromosomes 1q25, 1q32, 2q23, 7q22 and 16q24. We detected deletions on chromosome 1q44 and 13q31.1 in one patient, and LOH of the entire chromosome 2 in another patient, both with cytogenetically normal karyotypes. The patient with the complex translocation had a deletion on chromosome 7q22.2-22.3, which is in conjunction with one of the translocation breakpoints. Our findings provide further evidence of there being a critical region for the development of microcephaly and corpus callosum abnormalities in children with distal 1q deletions. We have also shown that apparently balanced complex translocations might not be balanced at the DNA level, and we report the fourth case of paternal uniparental disomy of chromosome 2. The results of this study suggest that it may be desirable to investigate idiopathic mental retardation using genome-wide SNP arrays, in conjunction with other cytogenetic and molecular techniques.

Objective: To describe the epidemiology of cases of fetal alcohol syndrome (FAS) seen by Australian paediatricians. Methods: Active, national case-finding using the Australian Paediatric Surveillance Unit (APSU). Monthly reporting of incident cases aged <15 years by paediatricians between January 2001 and December 2004. Results: Over 1150 paediatricians submitted reports each month to the APSU. Of 169 reported cases, 92 fulfilled the study criteria for FAS. There was a significant increase in the number of children reported each year from 2001 to 2004. Of 92 children, 53.3% were male, 35.7% were preterm (<37 weeks’ gestation) and 64.6% were of low birth weight (<2.5 kg). Most (94.4%) had high risk exposure to alcohol in utero and 78.3% were exposed to one or more additional drugs. The median age at diagnosis was 3.3 years (range: newborn to 11.9 years): 6.5% were diagnosed at birth and 63% by 5 years of age. Of the 92 cases, 56% had growth deficiency, 53.2% had microcephaly, 85.9% had evidence of central nervous system dysfunction, 24% had additional birth defects, 5.4% had sensorineural deafness and 4.3% had visual impairment. Of children with FAS, 65% were Indigenous, 51% had a sibling with FAS, and only 40.2% lived with a biological parent. Conclusion: Our data are the only prospective national data available on FAS throughout the world. These findings highlight the severity, complexity and impact of FAS, the need for effective strategies for prevention, and the necessity for education to facilitate earlier diagnosis, referral and reporting of cases.

Objective: The purpose of this study was to investigate associations between inherited cytokine polymorphisms and cerebral palsy.Study design: This was a case-control study that used DNA from the newborn infant screening cards of 443 white infants with cerebral palsy and 883 white control infants to test for the following cytokine polymorphisms: tumor necrosis factor-alpha-308, mannose-binding lectin-221, and 3 polymorphisms in exon-1 of the mannose-binding lectin gene at codon-52, -54, and -57.Results: At all gestational ages mannose-binding lectin codon-54 increased the risk of the development of diplegia (homozygous or heterozygous odds ratio, 1.55; 95% CI, 1.03-2.32). For babies who were born at term, the risk of the development of quadriplegia was associated with heterozygous tumor necrosis factor-alpha (odds ratio, 1.82; 95% CI, 1.04-3.15), and mannose-binding lectin codon-54 was associated with diplegia (homozygous or heterozygous odds ratio, 2.12; 95% Cl, 1.10-4.05). The presence of any polymorphism in mannose-binding lectin exon-1 at term approximately doubled the risk of the development of diplegia (odds ratio, 1.94; 95% CI, 1.05-3.62). Homozygous or heterozygous tumor necrosis factor-a was associated with hemiplegia for babies who were born at < 32 weeks of gestation (odds ratio, 2.38; 95% CI, 1.02-5.58). Overall, the presence of any cytokine polymorphism was associated with cerebral palsy (odds ratio, 1.37; 95% CI, 1.02-1.84).Conclusion: Carriage of polymorphisms in the tumor necrosis factor-alpha and mannose-binding lectin genes are associated with an increased risk of cerebral palsy. (c) 2006 Mosby, Inc. All rights reserved.

ADVERSE PREGNANCY OUTCOMES CATHERINE GIBSON, NARD JANSSEN, WILLEM KIST, ALASTAIR MACLENNAN, BILL HAGUE, ERIC HAAN, PAUL GOLDWATER, KEVIN PRIEST, GUSTAAF DEKKER, Adelaide University, Obstetrics and Gynaecology, Adelaide, South Australia, Australia, VU University Medical Center, Obstetrics and Gynaecology, Amsterdam, Netherlands, Women’s and Children’s Hospital, Adelaide, North Adelaide, South Australia, Australia, Women’s andChildren’sHospital,DepartmentofGeneticMedicine, Adelaide, South Australia, Australia, Women’s and Children’s Hospital, Microbiology and Infectious Diseases, Adelaide, South Australia, Australia, Department of Health, Epidemiology Branch, Adelaide, South Australia, Australia, AdelaideUniversity,MaternalMedicine, Adelaide, SouthAustralia, Australia OBJECTIVE: To investigate the role of fetal inherited thrombophilia in the development of a range of adverse pregnancy outcomes, including pregnancyinduced hypertensive disorders (PIHD), antepartum haemorrhage (APH), intrauterine growth restriction!10th percentile (IUGR) andpretermbirth (PTB). STUDY DESIGN: 717 cases and 609 controls were genotyped for Factor V Leiden (FVL, G1691A), Prothrombin gene mutation (PGM, G20210A), and Methylenetetrahydrofolate reductase (MTHFR) C677T and MTHFR A1298C using genomic DNA extracted from newborn screening cards. RESULTS: For babies born!28 weeks gestation, PGM was associated with an increased risk of IUGR(OR6.40, 1.66-24.71) andAPHwith IUGR(OR6.35, 1.63-24.75). Homozygous PGM also increased the risk of PIHD with IUGR for term-born babies (OR 50.81, 1.75-1476.90). Homozygosity for MTHFR A1298C was associated with an increased risk of IUGR for babies born 28-31 weeks gestation (OR 4.00, 1.04-15.37), and with APH and IUGR for babies born !32 weeks gestation (OR 3.57, 1.09-11.66). MTHFR C677T was associated with a reduced risk of PTB and IUGR (OR 0.52, 0.28-0.96) for babies born 32-36 weeks gestation. Homozygous FVL was associated with an increased risk of PIHD with IUGR for term-born babies (OR 37.15, 1.33-1041.30), but decreased the risk of PTB!32 weeks gestation (OR 0.55, 0.31-0.98). There were no associations with any thrombophilic polymorphism and APH alone. CONCLUSION: These results suggest that some fetal thrombophilic polymorphisms may be related to adverse pregnancy outcomes, in particular IUGR, but this may not be the only association. Further studies matching maternal and fetal genotypes are required to investigate if both are needed for the adverse pregnancy outcome phenotype to be expressed. S14 SMFM Abstracts