A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

Primary Ovarian Insufficiency (P01) affects 1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic P01 revealed a homozygous mutation in FANCM, leading to a truncated protein (p.GIn1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancrril- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation

A genome-wide approach reveals novel imprinted genes expressed in the human placenta

Genomic imprinting characterizes genes with a monoallelic expression, which is dependent on the parental origin of each allele. Approximately 150 imprinted genes are known to date, in humans and mice but, though computational searches have tried to extract intrinsic characteristics of these genes to identify new ones, the existing list is probably far from being comprehensive. We used a high-throughput strategy by diverting the classical use of genotyping microarrays to compare the genotypes of mRNA/cDNA vs. genomic DNA to identify new genes presenting monoallelic expression, starting from human placental material. After filtering of data, we obtained a list of 1,082 putative candidate monoallelic SNPs located in more than one hundred candidate genes. Among these, we found known imprinted genes, such as IPW, GRB10, INPP5F and ZNF597, which contribute to validate the approach. We also explored some likely candidates of our list and identified seven new imprinted genes, including ZFAT, ZFAT-AS1, GLIS3, NTM, MAGI2, ZC3H12Cand LIN28B, four of which encode zinc finger transcription factors. They are, however, not imprinted in the mouse placenta, except for Magi2. We analyzed in more details the ZFAT gene, which is paternally expressed in the placenta (as ZFAT-AS1, a non-coding antisense RNA) but biallelic in other tissues. The ZFAT protein is expressed in endothelial cells, as well as in syncytiotrophoblasts. The expression of this gene is, moreover, downregulated in placentas from complicated pregnancies. With this work we increase by about 10% the number of known imprinted genes in humans

Predictors of retinochoroiditis in children with congenital toxoplasmosis : European, prospective cohort study

OBJECTIVE. By school age, 20% of children infected with congenital toxoplasmosis will have > 1 retinochoroidal lesion. We determined which children are most at risk and whether prenatal treatment reduces the risk of retinochoroiditis to help clinicians decide about treatment and follow-up. PATIENTS AND METHODS. We prospectively studied a cohort of children with congenital toxoplasmosis identified by prenatal or neonatal screening in 6 European countries. We determined the effects of prenatal treatment and prognostic markers soon after birth on the age at first detection of retinochoroiditis. RESULTS. Of 281 children with congenital toxoplasmosis, 50 developed ocular disease, and 17 had recurrent retinochoroiditis during a median follow-up of 4.1 years. Prenatal treatment had no significant effect on the age at first or subsequent lesions. Delayed start of postnatal treatment did not increase retinochoroiditis, but the analysis lacked power. Older gestational age at maternal seroconversion was weakly associated with a reduced risk of retinochoroiditis. The presence of nonocular clinical manifestations of congenital toxoplasmosis at birth strongly predicted retinochoroiditis. For 92% (230 of 249) of children with no retinochoroiditis detected before 4 months of age, the probability of retinochoroiditis by 4 years was low, whether clinical manifestations were present or not 8.0%. CONCLUSIONS. Prenatal treatment did not significantly reduce the risk of retinochoroiditis in this European cohort. If children have no retinochoroiditis in early infancy, the low risk of subsequent ocular disease may not justify postnatal treatment and repeated ophthalmic assessments during childhood. Controlled trials are needed to address the lack of evidence for the effectiveness of postnatal treatment

Fetal organ weight estimation by postmortem high-field magnetic resonance imaging before 20 weeks' gestation

Objective To ascertain whether high-field magnetic resonance imaging (MRI) allows accurate estimation of the weight of various fetal organs at postmortem before 20 weeks' gestation. Methods From 23 fetuses at 9-20 weeks, following termination of pregnancy or in-utero fetal death (IUFD), 207 assorted fetal organs were evaluated by high-field MRI at 9.4 T prior to conventional autopsy. Fetal organ density was calculated by correlating volume and weight at autopsy using linear regression analysis, and this was used to estimate fetal organ weight by MRI. The relative error in MRI estimation of organ weight was calculated as follows: (SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Minimally invasive fetal autopsy using ultrasound: a feasibility study

We aim to evaluate a new technique for minimally invasive autopsy: the Post-Mortem Ultrasound (PM-US). Our purpose is to demonstrate its feasibility and sensitivity in detecting major congenital abnormalities as compared to conventional autopsy