Model matchmaking via the Solve-RD Rare Disease Models & Mechanisms Network (RDMM-Europe).

In biomedical research, particularly for rare diseases (RDs), there is a critical need for model organisms to unravel the mechanistic basis of diseases, perform biomarker studies and develop potential therapeutic interventions. Within Solve-RD, an EU-funded research project with the aim of solving large numbers of previously unsolved RDs, the European Rare Disease Models & Mechanisms Network (RDMM-Europe) has been established.

Gastroschisis prevalence patterns in 27 surveillance programs from 24 countries, International Clearinghouse for Birth Defects Surveillance and Research, 1980-2017.

Background: Gastroschisis is a serious birth defect with midgut prolapse into the amniotic cavity. The objectives of this study were to evaluate the prevalence and time trends of gastroschisis among programs in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), focusing on regional variations and maternal age changes in the population.

Methods: We analyzed data on births from 1980 to 2017 from 27 ICBDSR member programs, representing 24 countries and three regions (Europe , Latin America, North America).

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

Objective: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals.

Using a health observance event to raise awareness: An assessment of World Birth Defects Day.

World Birth Defects Day (WorldBDDay), observed annually on March 3, was launched in 2015 to advocate for public health surveillance, research, and prevention of birth defects, along with improved care and treatment for affected individuals. Following its fifth observance in 2019, we assessed WorldBDDay by analyzing: (a) engagement and content of over 2000 WorldBDDay posts on Facebook, Twitter, and Instagram; (b) interview responses from 9 WorldBDDay charter (founding) organizations on their perceptions of strengths and areas for improvement for WorldBDDay; (c) survey responses from 61 WorldBDDay 2019 partner (participating) organizations on their WorldBDDay 2019 activities; and (d) post-2019 social media engagement. Most social media posts (60%) occurred from organizations using Twitter (80% vs.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1.

Differences in Expression of Transcript Isoforms in Male and Female Cases with Loss of Function Variants and Neurodevelopmental Disorder.

Pathogenic hemizygous or heterozygous mutations in the IQSEC2 gene cause X-linked intellectual developmental disorder-1 (XLID1), characterized by a variable phenotype including developmental delay, intellectual disability, epilepsy, hypotonia, autism, microcephaly and stereotypies. It affects both males and females typically through loss of function in males and haploinsufficiency in heterozygous females. Females are generally less affected than males.

A Multicountry Analysis of Prevalence and Mortality among Neonates and Children with Bladder Exstrophy.

Objective: Bladder exstrophy (BE) is a rare but severe birth defect affecting the lower abdominal wall and genitourinary system. The objective of the study is to examine the total prevalence, trends in prevalence, and age-specific mortality among individuals with BE.

Study Design: We conducted a retrospective cohort study.

Prevention of Neural Tube Defects in Europe: A Public Health Failure.

Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA.

Survival of infants born with esophageal atresia among 24 international birth defects surveillance programs.

Background: Esophageal atresia (EA) affects around 2.3-2.6 per 10,000 births world-wide.

Smoking during pregnancy: changes and associated risk factors in Spain, 1980-2016.

Background: Trends for maternal smoking rates have varied substantially across industrialized countries. The objective was to describe how the prevalence of maternal smoking evolved in Spain during 1980-2016.

Methods: Data came from the Spanish Collaborative Study of Congenital Malformations.

De novo small deletion affecting transcription start site of short isoform of AUTS2 gene in a patient with syndromic neurodevelopmental defects.

Disruption of the autism susceptibility candidate 2 (AUTS2) gene through genomic rearrangements, copy number variations (CNVs), and intragenic deletions and mutations, has been recurrently involved in syndromic forms of developmental delay and intellectual disability, known as AUTS2 syndrome. The AUTS2 gene plays an important role in regulation of neuronal migration, and when altered, associates with a variable phenotype from severely to mildly affected patients. The more severe phenotypes significantly correlate with the presence of defects affecting the C-terminus part of the gene.

Prevalence and mortality in children with congenital diaphragmatic hernia: a multicountry study.

Purpose: This study determined the prevalence, mortality, and time trends of children with congenital diaphragmatic hernia (CDH).

Methods: Twenty-five hospital- and population-based surveillance programs in 19 International Clearinghouse for Birth Defects Surveillance and Research member countries provided birth defects mortality data between 1974 and 2015. CDH cases included live births, stillbirths, or elective termination of pregnancy for fetal anomalies.

A multi-country study of prevalence and early childhood mortality among children with omphalocele.

Background: Omphalocele is the second most common abdominal birth defect and often occurs with other structural and genetic defects. The objective of this study was to determine omphalocele prevalence, time trends, and mortality during early childhood, by geographical region, and the presence of associated anomalies.

Methods: We conducted a retrospective study with 23 birth defect surveillance systems in 18 countries who are members of the International Clearinghouse for Birth Defects Surveillance and Research that submitted data on cases ascertained from 2000 through 2012, approximately 16 million pregnancies were surveyed that resulted in live births, stillbirths, or elective terminations of pregnancy for fetal anomalies (ETOPFA) and cases with omphalocele were included.

Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.

Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu-Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre- or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders.

Five new cases of syndromic intellectual disability due to KAT6A mutations: widening the molecular and clinical spectrum.

Background: Pathogenic variants of the lysine acetyltransferase 6A or KAT6A gene are associated with a newly identified neurodevelopmental disorder characterized mainly by intellectual disability of variable severity and speech delay, hypotonia, and heart and eye malformations. Although loss of function (LoF) mutations were initially reported as causing this disorder, missense mutations, to date always involving serine residues, have recently been associated with a form of the disorder without cardiac involvement.

Results: In this study we present five new patients, four with truncating mutations and one with a missense change and the only one not presenting with cardiac anomalies.

Analysis of Mortality among Neonates and Children with Spina Bifida: An International Registry-Based Study, 2001-2012.

Background: Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida remains.

Objectives: To examine stillbirth and infant and child mortality among those affected by spina bifida using data from multiple countries.

Methods: We conducted an observational study, using data from 24 population- and hospital-based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR).

Primary prevention as an essential factor ensuring sustainability of health systems: the example of congenital anomalies.

Protection of early development contributes to health of next generations. Congenital anomalies (and other adverse reproductive outcomes) are an important public health issue and early indicator of public health risks, as early development is influenced by many risk factors (e.g.

Heterozygous pathogenic variants in GLI1 are a common finding in isolated postaxial polydactyly A/B.

Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with PAP-B corresponding to a more rudimentary extra-digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP-A, may include syndromic features.

Changes in Alcohol Intake During Pregnancy in Spain, 1980 to 2014.

Background: Even small amounts of alcohol consumed during pregnancy can have adverse effects on the embryo and the fetus. We estimated how alcohol intake among pregnant women in Spain changed between 1980 and 2014, and identified factors associated with alcohol use.

Methods: Data came from the Spanish Collaborative Study of Congenital Malformations (ECEMC).

Hypospadias Prevalence and Trends in International Birth Defect Surveillance Systems, 1980-2010.

Background: Hypospadias is a common male birth defect that has shown widespread variation in reported prevalence estimates. Many countries have reported increasing trends over recent decades.

Objective: To analyze the prevalence and trends of hypospadias for 27 international programs over a 31-yr period.

Tetralogy of Fallot in Spain: a nationwide registry-based mortality study across 36 years.

Background: Tetralogy of Fallot (TOF) is the most frequent cyanotic congenital heart defect. TOF mortality has fallen remarkably in recent years due to therapeutic advances. Accordingly, the aim of this study was to assess temporal and spatial variability in TOF-related mortality in Spain across the period 1981-2016, using data drawn from the nationwide population-based registry.

Value of sharing and networking among birth defects surveillance programs: an ICBDSR perspective.

Birth defects (BD), also known as congenital anomalies, are structural or functional abnormalities present at birth as a result of abnormal prenatal development. Their cause can be broadly categorized as genetic, environmental, or a combination of both. It is estimated that approximately 3-6% of newborn infants worldwide are affected by BD, many of which are associated with serious morbidity, mortality, and lifelong disabilities.