ACTC1 Variants Result in Isolated and Syndromic Cardiac Phenotypes.

Individuals carrying pathogenic variants in ACTC1 present with several cardiac phenotypes, including hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular noncompaction cardiomyopathy. In the current work, we expand the clinical and genetic spectrum of phenotypes caused by ACTC1 genetic variants by describing two individuals with heterozygous variants involving residues Gly57 or Glu101. These individuals presented with facial dysmorphism, short stature, and skeletal anomalies in addition to hypertrophic and left ventricular noncompaction cardiomyopathies.

Familial complete pachydermoperiostosis presenting with vertebral hypertrophy and myelopathy.

Pachydermoperiostosis (PDP) is a rare, male-predominant (9:1) primary hypertrophic osteoarthropathy of the skin and bone, commonly called the acromegaly mimic. Clinical diagnosis of PDP is based on a triad of digital clubbing, pachydermia with coarse facial features, and radiographic evidence of long bone periostosis. It can manifest in a complete or incomplete form, with skin involvement distinguishing the complete subtype.

Artificial intelligence-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics.

Background: Decisions to split two or more phenotypic manifestations related to genetic variations within the same gene can be challenging, especially during the early stages of syndrome discovery. Genotype-based diagnostics with artificial intelligence (AI)-driven approaches using next-generation phenotyping (NGP) and DNA methylation (DNAm) can be utilized to expedite syndrome delineation within a single gene.

Methods: We utilized an expanded cohort of 56 patients (22 previously unpublished individuals) with truncating variants in the MN1 gene and attempted different methods to assess plausible strategies to objectively delineate phenotypic differences between the C-Terminal Truncation (CTT) and N-Terminal Truncation (NTT) groups.

Individuals with SATB2-associated syndrome have impaired vitamin and energy metabolism pathways.

Special AT-rich sequence-binding protein 2 (SATB2) is a master regulator of gene expression. Mutations of the SATB2 gene results in the SATB2-associated syndrome (SAS), a genetic disorder characterized by neurodevelopmental disabilities and autism-related phenotype. The importance of plasma as an indicator of SAS phenotypes is unknown.

Pathogenic missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes.

-associated syndrome (SAS) is caused by pathogenic variants in , which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with variants that affect p.

Abnormalities in pharyngeal arch-derived structures in SATB2-associated syndrome.

SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches.

NR3C2 microdeletions-an underrecognized cause of pseudohypoaldosteronism type 1A: a case report and literature review.

Objectives: Pseudohypoaldosteronism type 1A (PHA1A) is caused by haploinsufficiency of the mineralocorticoid receptor (MR). Heterozygous small insertions/deletions, transitions, and/or transversions within NR3C2 comprise the majority (85%-90%) of pathogenic copy number variants. Structural chromosomal abnormalities, contiguous gene deletion syndromes, and microdeletions are infrequent.

Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.

Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.

Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial.

Bone health in SATB2-associated syndrome: Results from a large prospective cohort and recommendations for surveillance.

Alterations in SATB2 result in SATB2-associated syndrome (SAS; Glass syndrome, OMIM 612313), an autosomal dominant multisystemic disorder predominantly characterized by developmental delay, craniofacial anomalies, and growth retardation. The bone phenotype of SAS has been less explored until recently and includes a variety of skeletal deformities, increased risk of low bone mineral density (BMD) with a propensity to fractures, and other biochemical abnormalities that suggest elevated bone turnover. We present the results of ongoing surveillance of bone health from 32 individuals (47% females, 3-18 years) with molecularly-confirmed SAS evaluated at a multidisciplinary clinic.

Quantitative Phenotype Morbidity Description of -Associated Syndrome.

Characterized by developmental delay with severe speech delay, dental anomalies, cleft palate, skeletal abnormalities, and behavioral difficulties, -associated syndrome (SAS) is caused by pathogenic variants in . The SAS phenotype range of severity has been documented previously in large series. Using data from the SAS registry, we present the SAS severity score, a comprehensive scoring rubric that encompasses 15 different individual neurodevelopmental and systemic features.

Bi-allelic variants in INTS11 are associated with a complex neurological disorder.

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.

Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.

Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes.

Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features.

Growth in individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is an autosomal dominant multisystemic disorder caused by alterations in the SATB2 gene. In addition to a predominant neurodevelopmental phenotype, individuals with SAS often present with feeding difficulties and growth retardation that persist past infancy. In this study, we present growth and measurement data from 211 individuals (53.

A clinical scoring system for early onset (neonatal) Marfan syndrome.

Purpose: This study aimed to develop objective diagnostic criteria for early onset Marfan syndrome (eoMFS) to facilitate early diagnosis and timely interventions.

Methods: On the basis of an extensive literature review and the responses from a survey distributed among providers with expertise in the diagnosis and management of eoMFS, we developed an age-based, diagnostic scoring system encompassing 10 features common to eoMFS (9 clinical + 1 laboratory) and divided them into cardiac, systemic, and FBN1 (on the basis of the location of the pathogenic FBN1 variant) scores.

Results: In total, 77 individuals with eoMFS (13 newly reported) and 49 individuals diagnosed with classical Marfan syndrome during early childhood were used to validate the criteria.

Craniosynostosis is a feature of Costello syndrome.

Costello syndrome (CS) is an autosomal dominant disorder caused by pathogenic variants in HRAS. Craniosynostosis is a known feature of other RASopathies (Noonan and cardiofaciocutaneous syndromes) but not CS. We describe four individuals with CS and craniosynostosis and present a summary of all previously reported individuals with craniosynostosis and RASopathy.

Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.

Primary ciliopathies are heterogenous disorders resulting from perturbations in primary cilia form and/or function. Primary cilia are cellular organelles which mediate key signaling pathways during development, such as the sonic hedgehog (SHH) pathway which is required for neuroepithelium and central nervous system development. Joubert syndrome is a primary ciliopathy characterized by cerebellar/brain stem malformation, hypotonia, and developmental delays.