Treatment with 5-MTHF to support the one-carbon cycle can overcome the deleterious impact of a triple SNP mutation in the male partner's MTHFR gene for a couple with a history of repeated miscarriage.

A couple presenting with more than 3 years' history of infertility and three miscarriages was tested for serum homocysteine levels and for the two principal MTHFR SNPs: 677C < T and 1298A < C, as per our general policy for patients with infertility of long duration. The woman was found to be wild type for both MTHFR SNPs with a serum homocysteine 10.5 µM, slightly higher than our accepted normal value of 8.

Can some metabolic one-carbon cycle linked diseases be prevented? The impact of treating hypo-fertile couples carrying MTHFR SNPs with folic acid and 5-MTHF on outcomes in the offspring: a case retrospective series.

Purpose: In our practice, testing hypo-fertile patients for circulating homocysteine (Hcy) and the two principal MTHFR SNPs (677C > T and 1298A > C) has been routine for the past 7 years. Couples carrying a genetic background known to be associated with the disease were proposed treatment regimens consisting of 5-methyl tetrahydrofolate (5-MTHF) together with nutritional support of the one-carbon cycle (1-CC). Some patients preferred to continue with folic acid (FA) as prescribed by their referring gynecologist/obstetrician: this gave us the opportunity to compare outcomes between the two groups of patients.

The importance of preconception Hcy testing: identification of a folate trap syndrome in a woman attending an assisted reproduction program.

Methylation is a ubiquitous and permanent key biochemical process playing a major role in gametogenesis and embryogenesis in relation to epigenetics and imprinting. Methylation relies on a unique cofactor S-Adenosyl Methionine: SAM. Release of the methyl group onto target molecules is followed by liberation of S-Adenosyl Homocysteine (SAH), and then homocysteine (Hcy), both potent inhibitors of the methylation process.

Fetal growth disorders following medically assisted reproduction: due to maternal context or techniques? A national French cohort study.

Research Question: What part do maternal context and medically assisted reproduction (MAR) techniques play in the risk of fetal growth disorders?

Design: This retrospective nationwide cohort study uses data available in the French National Health System database and focuses on the period from 2013 to 2017. Fetal growth disorders were divided into four groups according to the origin of pregnancy: fresh embryo transfer (n = 45,201), frozen embryo transfer (FET, n = 18,845), intrauterine insemination (IUI, n = 20,179) and natural conceptions (n = 3,412,868). Fetal growth disorders were defined from the percentiles of the weight distribution according to gestational age and sex: small and large for gestational age (SGA and LGA) if <10th and >90th percentiles, respectively.

Risk factors associated with preterm birth in singletons born after IVF: a national cohort study.

Research Question: What are the risk factors for prematurity other than intrauterine growth restriction in singletons after IVF?

Design: Data were collected from a national registry, based on an observational prospective cohort of 30,737 live births after assisted reproductive technology (fresh embryo transfers: n = 20,932 and frozen embryo transfer [FET] n = 9805) between 2014 and 2015. A population of not-small for gestational age singletons conceived after fresh embryo transfers and FET, and their parents, was selected. Data on a number of variables were collected, including type of infertility, number of oocytes retrieved and vanishing twins.

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility.

Purpose: MTHFR, one of the major enzymes in the folate cycle, is known to acquire single-nucleotide polymorphisms that significantly reduce its activity, resulting in an increase in circulating homocysteine. Methylation processes are of crucial importance in gametogenesis, involved in the regulation of imprinting and epigenetic tags on DNA and histones. We have retrospectively assessed the prevalence of MTHFR SNPs in a population consulting for infertility according to gender and studied the impact of the mutations on circulating homocysteine levels.

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

Background: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.

Do in vitro fertilization, intrauterine insemination or female infertility impact the risk of congenital anomalies in singletons? A longitudinal national French study.

Study Question: Do IVF, IUI or female infertility (i.e. endometriosis, polycystic ovary syndrome [PCOS] and primary ovarian insufficiency [POI]) lead to an increased risk of congenital anomalies in singletons?

Summary Answer: After multivariable adjustments, the increased risks of congenital defects associated with IUI were no longer significant, but the underlying maternal infertility presented a potential emental risk, in addition to the risk associated with IVF.

Reproductive technologies, female infertility, and the risk of imprinting-related disorders.

Background: Epidemiological studies suggest that singletons born from assisted reproductive technologies (ART) have a high risk of adverse perinatal outcomes, specifically for imprinting disorders. Because ART processes take place at times when epigenetic reprogramming/imprinting are occurring, there is concern that ART can affect genomic imprints. However, little is currently known about the risk of imprinting defects according to the type of ART or the type of underlying female infertility.

A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report.

Background: Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene.

Case Presentation: Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype.

Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.

Background: Cerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub.

MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay.

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD.

Non-invasive prenatal diagnosis of paternally inherited disorders from maternal plasma: detection of NF1 and CFTR mutations using droplet digital PCR.

Background: To limit risks of miscarriages associated with invasive procedures of current prenatal diagnosis practice, we aim to develop a personalized medicine-based protocol for non-invasive prenatal diagnosis (NIPD) of monogenic disorders relying on the detection of paternally inherited mutations in maternal blood using droplet digital PCR (ddPCR).

Methods: This study included four couples at risk of transmitting paternal neurofibromatosis type 1 (NF1) mutations and four couples at risk of transmitting compound heterozygous CFTR mutations. NIPD was performed between 8 and 15 weeks of gestation, in parallel to conventional invasive diagnosis.

Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature.

Background: Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism.

Objectives: To better characterise the natural history of PMM2-CDG.

Methods: Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed.

CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy.

De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants.

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome.

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects.

Loss of Function of KCNC1 is associated with intellectual disability without seizures.

p.(Arg320His) mutation in the KCNC1 gene in human 11p15.1 has recently been identified in patients with progressive myoclonus epilepsies, a group of rare inherited disorders manifesting with action myoclonus, myoclonic epilepsy, and ataxia.

Adverse health effects in children of women exposed in utero to diethylstilbestrol (DES).

Objective: Exposure to diethylstilbestrol (DES) in utero is associated with adverse health effects, including genital anomalies in women and men, and cancers in women. Animal studies showed birth defects and tumors in the offspring of DES exposed mice, revealing transgenerational transmission of DES effects. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women.

A de novo 10p11.23-p12.1 deletion recapitulates the phenotype observed in WAC mutations and strengthens the role of WAC in intellectual disability and behavior disorders.

Chromosomal microarray analysis has become a powerful diagnostic tool in the investigation of patients with intellectual disability leading to the discovery of dosage sensitive genes implicated in the manifestation of various genomic disorders. Interstitial deletions of the short arm of chromosome 10 represent rare genetic abnormalities, especially those encompassing the chromosomal region 10p11-p12. To date, only 10 postnatal cases with microdeletion of this region have been described, and all patients shared a common phenotype, including intellectual disability, abnormal behavior, distinct dysmorphic features, visual impairment, and cardiac malformations.

Identification of a new DPY19L2 mutation and a better definition of DPY19L2 deletion breakpoints leading to globozoospermia.

Study Hypothesis: The purpose of this study was to analyze DPY19L2 sequence variants to investigate the mechanism leading to the entire DPY19L2 deletion in a large cohort of infertile globozoospermic patients.

Study Finding: An improved analysis of the DPY19L2 deletion breakpoints (BPs) allowed us to identify two BPs located in a small 1 kb region and to more precisely localize the BPs reported previously.

What Is Known Already: Three genes [spermatogenesis associated 16 (SPATA16), protein interacting with PRKCA (PICK1) and DPY19L2] were previously correlated with globozoospermia, but a homozygous deletion of the entire DPY19L2 was identified as the most frequent alteration causing this phenotype.

Neonatal Silver-Russell syndrome with maternal uniparental heterodisomy, trisomy 7 mosaicism, and dysplasia of the cerebellum.

Objectives: We report here the unusual association of Silver-Russell syndrome (SRS) and cerebellar dysplasia with trisomy 7 mosaicism and maternal uniparental disomy of chromosome 7 [UPD(7)m].

Methods: Low-level trisomy 7 mosaicism was diagnosed prenatally on amniocytes, and UPD(7)m was confirmed after birth.

Results: Medical examination at birth showed dysmorphic facial features of SRS.

New insights into genotype-phenotype correlation for GLI3 mutations.

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features.