De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms.

The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1-5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands and monozygotic twins.

GATA6 regulates WNT and BMP programs to pattern precardiac mesoderm during the earliest stages of human cardiogenesis.

Haploinsufficiency for is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages.

Distinct Clinical Phenotypes in KIF1A-Associated Neurological Disorders Result from Different Amino Acid Substitutions at the Same Residue in KIF1A.

KIF1A is a neuron-specific kinesin motor responsible for intracellular transport along axons. Pathogenic mutations cause KIF1A-associated neurological disorders (KAND), a spectrum of severe neurodevelopmental and neurodegenerative conditions. While individual mutations have been studied, how different substitutions at the same residue affect motor function and disease progression remains unclear.

Recessive genetic contribution to congenital heart disease in 5,424 probands.

Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands.

Modeling Mutations in Induced Pluripotent Stem Cells Provides Insights Into Cardiovascular Disease Pathogenesis.

Background: SMAD2 is a coregulator that binds a variety of transcription factors in human development. Heterozygous loss-of-function and missense variants are identified in patients with congenital heart disease (CHD) or arterial aneurysms. Mechanisms that cause distinct cardiovascular phenotypes remain unknown.

MYRF is Essential in Mesothelial Cells to Promote Lung Development and Maturation.

The mesothelium is a squamous monolayer that ensheathes internal organs, lines the body cavity, and the diaphragm. It serves as a protective barrier, coated in glycocalyx, and secretes lubricants to facilitate tissue movement. How the mesothelium forms is poorly understood.

Deciphering the digenic architecture of congenital heart disease using trio exome sequencing data.

Congenital heart disease (CHD) is the most common congenital anomaly and a leading cause of infant morbidity and mortality. Despite extensive exploration of the monogenic causes of CHD over the last decades, ∼55% of cases still lack a molecular diagnosis. Investigating digenic interactions, the simplest form of oligogenic interactions, using high-throughput sequencing data can elucidate additional genetic factors contributing to the disease.

Proprioceptive synaptic dysfunction is a key feature in mice and humans with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology.

Paving the way toward treatment solutions for CTNNB1 syndrome: a patient organization perspective.

The CTNNB1 Connect & Cure and CTNNB1 Foundation, alongside Asociación CTNNB1, CTNNB1 Italia, Association CTNNB1 France, and researchers and clinicians globally are dedicated to finding effective treatments and cures for CTNNB1 syndrome. The syndrome is also characterized by progressive spasticity, which can in some cases cause loss of already achieved motor milestones. Since 2019, they have brought together researchers from different fields and invested in various research efforts to advance the search for treatment solutions for patients with CTNNB1 syndrome.

Impact of Setmelanotide on Metabolic Syndrome Risk in Patients With Bardet-Biedl Syndrome.

Context: Bardet-Biedl syndrome (BBS) is a rare genetic disease associated with disruptions in melanocortin-4 receptor pathway signaling that can contribute to increased risk for metabolic syndrome and obesity-related comorbidities.

Objective: Here, MetS-Z-BMI scores, a continuous measure based on body mass index, were calculated to determine metabolic syndrome severity and response to treatment with the melanocortin-4 receptor agonist setmelanotide in BBS.

Methods: All patients from a Phase 3 study (NCT03746522) of setmelanotide with data required for the calculation of MetS-Z-BMI scores were included.

Comparison of autism domains across thirty rare variant genotypes.

Background: A number of Neurodevelopmental risk Copy Number Variants (ND-CNVs) and Single Gene Variants (SGVs) are strongly linked to elevated likelihood of autism. However, few studies have examined the impact on autism phenotypes across a wide range of rare variant genotypes.

Methods: This study compared Social Communication Questionnaire (SCQ) scores (total and subdomains: social, communication, repetitive behaviour) in 1314 young people with one of thirty rare variant genotypes (15 ND-CNVs; n = 1005, 9.

De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies.

Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.

Noncoding variants and sulcal patterns in congenital heart disease: Machine learning to predict functional impact.

Neurodevelopmental impairments associated with congenital heart disease (CHD) may arise from perturbations in brain developmental pathways, including the formation of sulcal patterns. While genetic factors contribute to sulcal features, the association of noncoding variants (ncDNVs) with sulcal patterns in people with CHD remains poorly understood. Leveraging deep learning models, we examined the predicted impact of ncDNVs on gene regulatory signals.

Rare variants in cause Van der Woude syndrome and other features of peridermopathy.

Van der Woude syndrome (VWS) is an autosomal dominant disorder characterized by lower lip pits and orofacial clefts (OFCs). With a prevalence of approximately 1 in 35,000 live births, it is the most common form of syndromic clefting and may account for ~2% of all OFCs. The majority of VWS is attributed to genetic variants in (~70%) or (~5%), leaving up to 25% of individuals with VWS without a molecular diagnosis.

Risk factors affecting polygenic score performance across diverse cohorts.

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed the effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS) across four cohorts of European (N = 491,111) and African (N = 21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R differences among strata.

Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.

The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, a fundamental adaptation with an elusive physiological role. Its significance is underscored by the discovery of neonatal patients suffering from often fatal heart failure caused by severe dilated cardiomyopathy when both copies of the gene are mutated. RPL3L is a muscle-specific paralog of the ubiquitous ribosomal protein L3 (RPL3), which makes the closest contact of any protein to the ribosome's RNA-based catalytic center.

DNA Sequencing in Newborn Screening: Opportunities, Challenges, and Future Directions.

Background: Newborn screening is a public health system designed to identify infants at risk for conditions early in life to facilitate timely intervention and treatment to prevent or mitigate adverse health outcomes. Newborn screening programs use tandem mass spectrometry as a platform to detect several treatable inborn errors of metabolism, and the T-cell receptor excision circle assay to detect some inborn errors of the immune system. Recent advancements in DNA sequencing have decreased the cost of sequencing and allow us to consider DNA sequencing as an additional platform to complement other newborn screening methods.

Designing and implementing the IDEAL Study: A randomized clinical trial of genotype disclosure for late-onset Alzheimer's disease in an urban Latino population.

Introduction: The (IDEAL) Study is a randomized clinical trial investigating the psychosocial, behavioral, and cognitive impacts of apolipoprotein E () genotype disclosure for late-onset Alzheimer's disease (AD) among Latinos.

Methods: We used address-based sampling to recruit English- and Spanish-speaking Latinos aged 40-64 living in northern Manhattan for a community-based Baseline Survey about their knowledge and opinions about AD. Participants eligible for the clinical trial were invited to complete an Introductory Session, including AD and genetics education and informed consent, before undergoing genotyping for .

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants.

Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse.

Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA.