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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]

Abstract: Objectives: To estimate the risk of stillbirth in dichorionic and monochorionic twins compared with singletons, and to evaluate the relevant causes of stillbirth in each group. Study design: A retrospective cohort analysis of all pregnancies ≥22 weeks of gestation was performed at a tertiary care center from January 1995 to June 2011. The overall fetal survival and the prospective risk of stillbirth were compared in monochorionic diamniotic (MCDA) twins, dichorionic diamniotic (DCDA) twins, and singletons. Causes of stillbirth were classified using the ReCoDe classification and were compared among the three study groups. Results: A total of 46,200 singletons, 462 MCDA twins and 1108 DCDA twins were included in the study. Both Kaplan–Meier analysis and prospective risk calculation showed that MCDA twins had the highest risk of stillbirth (OR ranging between 13.5 95% CI 8.7–20.7 at 22.0–24.6 weeks and 4.0 95% CI 1.1–13.1 at 31.0–33.6 weeks, compared to singletons), while singletons had the lowest. Main causes of stillbirth were major congenital malformations in singletons (25.1%) and in DCDA twins (75%), and twin–twin transfusion syndrome in MCDA twins (81.5%). When excluding fetuses affected by major congenital anomalies, MCDA twins (p <0.001) but not DCDA twins (p =0.2) remained at increased risk for stillbirth compared with singletons. Conclusion: The risk of stillbirth is significantly higher both in MCDA and DCDA twins compared with singletons. Stillbirths are mainly due to twin–twin transfusion syndrome in MCDA twins and major congenital anomalies in DCDA twins. When major congenital anomalies are excluded, DCDA twins have a similar in utero mortality to singletons. [Copyright &y& Elsevier]

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]