Ciliary phenotyping in renal epithelial cells in a cranioectodermal dysplasia patient with variants.

Cranioectodermal dysplasia (CED) is a skeletal autosomal recessive ciliopathy. The characteristic clinical features of CED are facial dysmorphisms, short limbs, narrow thorax, brachydactyly, ectodermal abnormalities, and renal insufficiency. Thus far, variants in six genes are known to be associated with this disorder: , , , , , and .

Surveillance of multiple congenital anomalies; searching for new associations.

Many human teratogens are associated with a spectrum of congenital anomalies rather than a single defect, and therefore the identification of congenital anomalies occurring together more frequently than expected may improve the detection of teratogens. Thirty-two EUROCAT congenital anomaly registries covering 6,599,765 births provided 123,566 cases with one or more major congenital anomalies (excluding chromosomal and genetic syndromes) for the birth years 2008-2016. The EUROCAT multiple congenital anomaly algorithm identified 8804 cases with two or more major congenital anomalies in different organ systems, that were not recognized as part of a syndrome or sequence.

A genotype-phenotype correlation in split-hand/foot malformation type 1: further refinement of the phenotypic subregions within the 7q21.3 locus.

Split-hand/foot malformation type 1 (SHFM1) refers to the group of rare congenital limb disorders defined by the absence or hypoplasia of the central rays of the autopods with or without accompanying anomalies, such as hearing loss, craniofacial malformation, and ectodermal dysplasia. Consequently, the condition is characterized by clinical variability that hinders diagnostic and counseling procedures. SHFM1 is caused by pathogenic variants affecting the genes and/or their tissue-specific enhancers at the 7q21.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

Significance Statement: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects.

Craniosynostosis (CS) represents a highly heterogeneous genetic condition whose genetic background has not been yet revealed. The abnormality occurs either in isolated form or syndromic, as an element of hundreds of different inborn syndromes. Consequently, CS may often represent a challenging diagnostic issue.

Case Report: Autoimmune Lymphoproliferative Syndrome vs. Chronic Active Epstein-Barr Virus Infection in Children: A Diagnostic Challenge.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder characterized by a disruption of the lymphocyte apoptosis pathway, self-tolerance, and immune system homeostasis. Defects in genes within the first apoptosis signal (FAS)-mediated pathway cause an expansion of autoreactive double-negative T cells leading to non-malignant lymphoproliferation, autoimmune disorders, and an increased risk of lymphoma. The aim of the study was to show the diagnostic dilemmas and difficulties in the process of recognizing ALPS in the light of chronic active Epstein-Barr virus (CAEBV) infection.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly.

Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly.

Signal Detection in EUROmediCAT: Identification and Evaluation of Medication-Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference.

Introduction: Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications.

Aims: This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals.

Maternal Risk Factors Associated with Limb Reduction Defects: Data from the Polish Registry of Congenital Malformations (PRCM).

Data from the Polish Registry of Congenital Malformations (PRCM) suggest that the prevalence of limb reduction defects (LRDs) in some Polish regions is significantly higher in comparison to that reported in the European Surveillance of Congenital Anomalies (EUROCAT) registry, but specific risk factors are still unknown. The objectives of this study were two-fold: to detect risk factors linked to isolated LRDs among Polish natives and to search for geospatial clusters of isolated LRDs to identify high-risk areas across the country. Among the 2,939,001 births accounted for in the PRCM, we determined that there were 852 children with distinct LRDs.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood.

Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR.

Mosaic IL6ST variant inducing constitutive GP130 cytokine receptor signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy.

Interleukin-6 signal transducer (IL6ST) encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through Janus kinase signal transducers and activators of transcription pathway (JAK/STAT) activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of the Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular, small monoallelic in-frame deletions of which the most prevalent is the IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been described.

Macrolide and lincosamide antibiotic exposure in the first trimester of pregnancy and risk of congenital anomaly: A European case-control study.

This study investigated the risk of congenital heart defects (CHD) and other congenital anomalies (CA) associated with first trimester use of macrolide antibiotics (mainly erythromycin, spiramycin, clarithromycin and azithromycin) and lincosamides (clindamycin) using a case-malformed control design. Data included 145,936 babies with a CA diagnosis (livebirths, stillbirths and terminations of pregnancy for CA) from 15 population-based EUROCAT registries in 13 European countries, covering 9 million births 1995-2012. Cases were babies with CHD, anencephaly, orofacial clefts, genital and limb reduction anomalies associated with antibiotic exposure in the literature.

Targeted Next-Generation Sequencing in the Diagnosis of Facial Dysostoses.

Background: Defects in the development of the first and second pharyngeal arches and their derivatives result in abnormal formation of the craniofacial complex, consequently giving rise to facial dysostoses (FDs). FDs represent a group of rare and highly heterogeneous disease entities that encompass mandibulofacial dysostoses (MFDs) with normal extremities and acrofacial dysostoses (AFDs) with limb anomalies in addition to craniofacial defects.

Methods: We examined 11 families with variable clinical symptoms of FDs, in most of which only one member was affected.

Genetic and Environmental Risk Factors for Isolated Hemangiomas in Infants.

The goal of this analysis is to identify risk factors for infantile hemangiomas (IH) to better delineate hemangioma predisposition. We analyzed live birth children with isolated cutaneous hemangioma that were reported to the Polish Registry of Congenital Malformations from across Poland between the years 1998 and 2016. Lower birthweight and gestational age were the most significant risk factors associated with IH.

Breakpoint Mapping of Symptomatic Balanced Translocations Links the , and Genes to Novel Disease Phenotype.

De novo balanced chromosomal aberrations (BCAs), such as reciprocal translocations and inversions, are genomic aberrations that, in approximately 25% of cases, affect the human phenotype. Delineation of the exact structure of BCAs may provide a precise diagnosis and/or point to new disease loci. We report on six patients with de novo balanced chromosomal translocations (BCTs) and one patient with a de novo inversion, in whom we mapped breakpoints to a resolution of 1 bp, using shallow whole-genome mate pair sequencing.

Author Correction: The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

In the version of this article initially published, affiliation 38 incorrectly read "ICNU-Nephrology and Urology Department, Barcelona, Spain"; "Renal Division, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain" is the correct affiliation. The error has been corrected in the HTML and PDF versions of the article.

The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD).

Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and risk of congenital anomaly: a retrospective population-based cohort study.

Objectives: To evaluate the risk of major congenital anomaly associated with first-trimester exposure to insulin analogues compared with human insulin in offspring of women with pregestational diabetes.

Design And Setting: A population-based cohort of women with pregestational diabetes (n=1661) who delivered between 1996 and 2012 was established retrospectively from seven European regions covered bythe European Surveillance of Congenital Anomalies (EUROCAT) congenital anomaly registries.

Primary Outcome Measures: The risk of non-chromosomal major congenital anomaly in live births, fetal deaths and terminations for a fetal anomaly exposed to insulin analogues in the first trimester of pregnancy was compared with the risk in those exposed to human insulin only.