High-Throughput Genomics Identify Novel Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by and , respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families.

Large-Scale Whole Genome Sequence Analysis of >22,000 Subjects Provides no Evidence of Premutation Allele Involvement in Autism Spectrum Disorder.

Expansion of a CGG repeat in the Fragile X Messenger Ribonucleoprotein 1 ( gene on the X chromosome is the cause of Fragile X Syndrome (FXS). The repeat length of unaffected individuals varies between 5-40 repeats, whereas >200 repeats are observed in cases of FXS. The intermediate range between 55-200 repeats is considered the premutation range and is observed in roughly 1:300 females and 1:900 males in the general population.

A Primer on Gene Editing.

Context—: Gene editing-based therapies are currently in development in the areas of oncology, inherited disease, and infectious disease. These potentially life-altering therapies are derived from decades of research in both academic and industry settings that developed technologies rooted in principles and products of nature. However, with such technologic developments come many important considerations, including adverse risks, high cost, and ethical questions.

Synonymous Variants of Uncertain Silence.

Synonymous variants, traditionally regarded as silent mutations due to their lack of impact on protein sequence, structure and function, have been the subject of increasing scrutiny. This commentary explores the emerging evidence challenging the notion of synonymous variants as functionally inert. Analysis of the activity of 70 synonymous variants in the HIV Tat transcription factor revealed that 50% of the variants exhibited significant deviations from wild-type activity.

Recessive ciliopathy mutations in primary endocardial fibroelastosis: a rare neonatal cardiomyopathy in a case of Alstrom syndrome.

Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function.

Central 22q11.2 deletion (LCR22 B-D) in a fetus with severe fetal growth restriction and a mother with severe systemic lupus erythematosus: Further evidence of CRKL haploinsufficiency in the pathogenesis of 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2 DS, MIM #188400) is the most common chromosomal microdeletion with an incidence of 1 in 4000 live births.

Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition.

Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition.

CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods.

Genetic characterization and long-term management of severely affected siblings with intellectual developmental disorder with cardiac arrhythmia syndrome.

We report two brothers with severe global cognitive and motor delay, cortical visual impairment and sick sinus syndrome who were born to consanguineous parents. Standard genetic evaluations did not reveal the cause of their mental retardation. As expected, chromosomal microarray (CMA) revealed extensive regions of homozygosity.

International perspectives on the implementation of reproductive carrier screening.

Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay-Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X-linked recessive disorders, to allow for informed decision making about reproductive options.

Confidential genetic testing and electronic health records: A survey of current practices among Huntington disease testing centers.

Background: Clinical care teams providing presymptomatic genetic testing often employ advanced confidentiality practices for documentation and result storage. However, patient requests for increased confidentiality may be in conflict with the legal obligations of medical providers to document patient care activities in the electronic health record (EHR). Huntington disease presents a representative case study for investigating the ways centers currently balance the requirements of EHRs with the privacy demands of patients seeking presymptomatic genetic testing.

The transformation of medical genetics by clinical genomics: hubris meets humility.

There is no question that the advent of massively parallel ("next-generation") DNA sequencing has thrust Medical Genetics and Molecular Diagnostics into a new era, availing practitioners and patients of a form of genetic testing unprecedented in its scope and comprehensiveness. It has produced impressive diagnostic yield, ended the "diagnostic odyssey" for many patients and families, expanded the known phenotypes of countless disorders, and led to almost weekly new disease gene discoveries. Nevertheless, it still fails to identify the molecular cause of many patients who clearly exhibit genetic/syndromic conditions, while at the same time unmasking other sequence changes of uncertain significance or unexpected consequences.

Generalized Cytokine Increase in the Setting of a Multisystem Clinical Disorder and Carcinoid Syndrome Associated with a Novel NLRP12 Variant.

Background: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a group of cytoplasmic sensors that survey danger signals released by invading pathogens or damaged tissue. Mutations in the NLRP subfamily affect pro-inflammatory mediators and cause nonspecific systemic symptoms.

Aims: We sought to identify a potential genetic etiology of an inflammatory syndrome in a patient that presented with an atypical multisystem illness with carcinoid syndrome as well as atopic and autoimmune features.

Home use of a compact, 12‑lead ECG recording system for newborns.

Background: An easy-to-operate ECG recorder should be useful for newborn screening for heart conditions, by health care workers - or parents. We developed a one-piece electrode strip and a compact, 12‑lead ECG recorder for newborns.

Method: We enrolled 2582 newborns in a trial to assess abilities of parents to record a 12‑lead ECG on their infants (2-4 weeks-old).

Electric Field-Induced Release and Measurement Liquid Biopsy for Noninvasive Early Lung Cancer Assessment.

Previously, we detected circulating tumor DNA that contained two EGFR mutations (p.L858R and exon19 del) in plasma of patients with late-stage non-small-cell lung carcinoma (NSCLC) using the electric field-induced release and measurement (EFIRM) platform. Our aim was to determine whether EFIRM technology can detect these mutations in patients with early-stage NSCLC.

Identification of novel PIEZO1 variants using prenatal exome sequencing and correlation to ultrasound and autopsy findings of recurrent hydrops fetalis.

Nonimmune hydrops fetalis (NIHF) is a rare disorder with a high perinatal mortality of at least 50%. One cause of NIHF is generalized lymphatic dysplasia (GLD), a rare form of primary lymphedema of the extremities and systemic involvement including chylothoraces and pericardial effusions. An autosomal recessive form of GLD has been described, caused by variants in the PIEZO1 gene.