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Background More than 100 X-linked intellectual disability (X-LID) genes have been identified to be involved in 10–15% of intellectual disability (ID). Method To identify novel possible candidates, we selected 18 families with a male proband affected by isolated or syndromic ID. Pedigree and/or clinical presentation suggested an X-LID disorder. After exclusion of known genetic diseases, we identified seven cases whose mother showed a skewed X-inactivation (>80%) that underwent whole exome sequencing (WES, 50X average depth). Results WES allowed to solve the genetic basis in four cases, two of which (Coffin-Lowry syndrome, RPS6K3 gene; ATRX syndrome, ATRX gene) had been missed by previous clinical/genetics tests. One further ATRX case showed a complex phenotype including pontocerebellar atrophy (PCA), possibly associated to an unidentified PCA gene mutation. In a case with suspected Lujan-Fryns syndrome, a c.649C>T (p.Pro217Ser) MECP2 missense change was identified, likely explaining the neurological impairment, but not the marfanoid features, which were possibly associated to the p.Thr1020Ala variant in fibrillin 1. Finally, a c.707T>G variant (p.Phe236Cys) in the DMD gene was identified in a patient retrospectively recognized to be affected by Becker muscular dystrophy (BMD, OMIM 300376). Conclusion Overall, our data show that WES may give hints to solve complex ID phenotypes with a likely X-linked transmission, and that a significant proportion of these orphan conditions might result from concomitant mutations affecting different clinically associated genes. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to establish the optimal threshold of birth weight discordance for prediction of adverse outcome in liveborn, nonmalformed preterm twins. Study design: We accessed a cohort of twin gestations for the period 1990 through 2000 delivered at less than 37.0 weeks' gestation. Adverse neonatal outcome was defined as stillbirth or occurrence of major morbidities. Results: A total of 335 twin gestations (670 twins) were included, of which 104 (31%) experienced adverse neonatal outcome. The average birth weight discordance was 12.4% ± 10.6% versus 19.4% ± 14.8% in those with good versus adverse outcome (P < .001). Birth weight discordance was a significant predictor of adverse neonatal outcome that was independent of gestational age at delivery, small for gestational age, and chorionicity. Receiver operating characteristic curve analysis suggested that optimal thresholds of birth weight discordance for clinical use should take into account gestational age. Conclusion: Birth weight discordance is an independent predictor of adverse neonatal outcome in liveborn, nonmalformed preterm twins. [ABSTRACT FROM AUTHOR]

Objective: The study was undertaken to assess whether prenatal Doppler variables can identify cases of fetal growth restriction (FGR) approaching term who are at risk for adverse neonatal outcome.Study Design: From a cohort of FGR cases delivered at >or=34 weeks, fetal biometry and pulsatility indices (PI) of fetal arteries obtained less than 2 weeks before delivery were related to adverse neonatal outcome, defined as admission to the neonatal intensive care unit (NICU) for indications other than low birth weight alone.Results: Stepwise regression analysis showed that after controlling for gestational age at delivery and fetal biometry, only the last umbilical artery (UA) PI percentile was significantly predictive of adverse neonatal outcome (odds ratio=1.02, 95% CI 1.01-1.03, P=.02). Receiver operating characteristic curve analysis identified a UA PI at the 65th percentile as optimal predictor of adverse neonatal outcome (sensitivity=60%, false-positive rate=30%).Conclusion: In FGR cases delivered at >/=34 weeks' gestation, Doppler PI at the UA independently predicts the likelihood of admission to the NICU for reasons other than low birth weight alone. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this research was to study factors that are involved in centromeric hypomethylation in the pathogenesis of Down syndrome (DS). Study Design: This was a case-control study to evaluate the association between methyltetrahydrofolate reductase (MTHFR) C677T and methionine synthetase-reductase (MTRR) A66G polymorphisms and the risk of DS; we compared mothers in Italy who had children with DS and matched control subjects. Results: Seventy-four cases of DS caused by an error in maternal meiosis were compared with 184 matched control subjects. The frequencies of the MTHFR C677T polymorphism were similar between the 2 groups. As regards the MTRR A66G polymorphism, the presence of the mutated G allele either in the heterozygous or homozygous form was significantly more common among mothers of children with DS than among control subjects (odds ratio, 2.21; 95% CI, 1.11-4.40). Conclusion: In a population with a high prevalence of the mutated T allele, maternal MTRR A66G, but not MTHFR, polymorphisms are associated with Down syndrome. [Copyright &y& Elsevier]

Objective: To identify the classification protocol for stillbirth that minimizes the rate of unexplained causes. Study Design: All stillbirths at > 22 weeks from 1995-2007 underwent a workup inclusive of fetal ultrasonography, amniocentesis for karyotype and cultures, placental histology, fetal autopsy, skin biopsy, total body X-ray, maternal testing for thrombophilias, TORCH, Parvovirus spp, thyroid function, indirect Coombs, Kleiheuer-Betke test, and genital cultures. To such a cohort, we applied the 4 most commonly used classification protocols. Results: The stillbirth rate during the study period was 0.4% (154/37,958). The RoDeCo classification provided the lowest rate of unexplained stillbirth (14.3%) compared with Wigglesworth (47.4%), de Galan-Roosen (18.2%), and Tulip (16.2%) classifications. Mean gestational age at stillbirth in unexplained vs explained stillbirth was similar in the 4 protocols. Conclusion: Adoption of a consistent and appropriate workup protocol can reduce the rate of unexplained stillbirth to 14%. [Copyright &y& Elsevier]