Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating Börjeson-Forssman-Lehmann (BFLS) and White-Kernohan (WHIKERS) Syndromes.

: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead to ambiguity and further delay in diagnosis and medical management. Phenotyping, additional genetic testing, and functional studies can all add valuable information to help reclassify these variants.

Intravenous allogeneic mesenchymal stromal cell therapy in 13 Pugs with presumptive early necrotizing meningoencephalitis.

Objective: To describe the tolerability and activity of IV allogeneic mesenchymal stromal cell (MSC) therapy in 13 Pugs with presumptive early necrotizing meningoencephalitis (NME).

Methods: 255 Pugs were screened from 2021 to 2024 for neurological examination (NE) abnormalities suggestive of early NME. All dogs received a minimum of 2 NEs spaced 2 to 4 weeks apart.

Impact of APOE4-related dementia risk in underrepresented groups from the All of Us research program.

Introduction: Longitudinal electronic health records (EHRs), "dementia" diagnostic codes, and genetic data from All of Us were used to see if there is a higher risk of dementia and an attenuated impact of apolipoprotein ε4 (APOE4) on Alzheimer's disease (AD) risk in Black and Hispanic/Latino groups.

Methods: Participants included 9,784 Hispanic/Latinos, 14,937 Non-Hispanic Blacks (NHB), and 60,388 Non-Hispanic Whites (NHWs) ≥age 60 without an initial dementia diagnosis.

Results: There was a significantly higher risk of developing a dementia diagnosis in Hispanic/Latino and NHB participants than NHW participants and comparably increased dementia hazard ratios in the Hispanic/Latino, NHB, and NHW APOE4 carriers than non-carriers (hazard ratio [HR] [95% confidence interval {CI}] 1.

Phenome-wide association of APOE alleles in the All of Us Research Program.

Background: Apolipoprotein E (APOE) variation is associated with altered lipid metabolism, as well as cardiovascular and neurodegenerative disease. Prior studies are largely limited to European ancestry populations and differential risk by sex and ancestry has not been widely evaluated.

Methods: We utilised a phenome-wide association study (PheWAS) to explore APOE-associated phenotypes in the All of Us Research Program.

The genetics of TDP43-Type-C neurodegeneration: a whole genome sequencing study.

Frontotemporal lobar degeneration-TDP Type C (TDP-C) is a unique neurodegenerative disease that starts by attacking the anterior temporal lobe leading to language and/or behavioral syndromes. Current literature on the genetic associations of TDP-C, which we have reviewed here, is uneven and lacks a discernible corpus of robust findings. In our study, we completed genome wide hypothesis-free analyses utilizing artificial Intelligence (AI) to identify rare and common variants associated with TDP-C.

Duchenne Muscular Dystrophy in Two Half-Brothers Due to Inherited 306 Kb Inverted Insertion of 10p15.1 into Intron 44 of the Dp427m Transcript of the Gene.

Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by the absence of a fully functional dystrophin protein in myocytes. In skeletal muscle, the lack of dystrophin ultimately results in muscle wasting and the replacement of myocytes with fatty or fibrous tissues. In the heart, cardiomyocytes eventually fail and cause fatal cardiomyopathy.

Snyder-Robinson syndrome presenting with learning disability, epilepsy, and osteoporosis: a novel gene variant.

Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder characterized by a collection of clinical features including mild to severe intellectual disability, hypertonia, marfanoid habitus, facial asymmetry, osteoporosis, developmental delay and seizures. Whole genome sequencing (WGS) identified a mutation in the spermine synthase () gene (c.746 A>G, p.

FGF12 copy number variant associated with epileptic encephalopathy.

FGF12 related epilepsy presents with variable phenotypes. We report another patient with a duplication involving the FGF12 gene who presented similar to other published cases having normal early development and responded to phenytoin.

Parent-reported child appetite moderates relationships between child genetic obesity risk and parental feeding practices.

Background: Food parenting practices are associated with child weight. Such associations may reflect the effects of parents' practices on children's food intake and weight. However, longitudinal, qualitative, and behavioral genetic evidence suggests these associations could, in some cases, reflect parents' response to children's genetic risk for obesity, an instance of gene-environment correlation.

Leukocyte and cytokine variables in asymptomatic Pugs at genetic risk of necrotizing meningoencephalitis.

Background: Necrotizing meningoencephalitis (NME, aka Pug dog encephalitis) is an inflammatory brain condition associated with advanced disease at initial presentation, rapid progression, and poor response to conventional immunomodulatory therapy.

Hypothesis/objectives: That genetic risk for NME, defined by a common germline DNA haplotype located on chromosome 12, is associated with altered blood cytokine concentrations and leukocyte subsets in asymptomatic Pugs.

Animals: Forty Pug dogs asymptomatic for NME from a hospital sample.

Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases.

Background: Clinical interpretation of genetic variants in the context of the patient's phenotype is becoming the largest component of cost and time expenditure for genome-based diagnosis of rare genetic diseases. Artificial intelligence (AI) holds promise to greatly simplify and speed genome interpretation by integrating predictive methods with the growing knowledge of genetic disease. Here we assess the diagnostic performance of Fabric GEM, a new, AI-based, clinical decision support tool for expediting genome interpretation.

Family SES Is Associated with the Gut Microbiome in Infants and Children.

Background: While early life exposures such as mode of birth, breastfeeding, and antibiotic use are established regulators of microbiome composition in early childhood, recent research suggests that the social environment may also exert influence. Two recent studies in adults demonstrated associations between socioeconomic factors and microbiome composition. This study expands on this prior work by examining the association between family socioeconomic status (SES) and host genetics with microbiome composition in infants and children.

DNA Methylation and Expression Profiles of Whole Blood in Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. It is presently only accurately diagnosed at an advanced stage by a series of motor deficits, which are predated by a litany of non-motor symptoms manifesting over years or decades. Aberrant epigenetic modifications exist across a range of diseases and are non-invasively detectable in blood as potential markers of disease.

() overexpression reduces APP processing and increases alpha- versus beta-secretase activity, .

The organic anion transporter (), also known as , has been demonstrated in murine models of Alzheimer's disease (AD) to export amyloid beta (Abeta) from the endothelial cells of the blood-brain barrier to the periphery, and that pharmaceutical activation of can reduce amyloid plaque deposition in the brain. Here, we show that ABCC1 is not only capable of exporting Abeta from the cytoplasm of human cells, but also that its overexpression significantly reduces Abeta production and increases the ratio of alpha- versus beta-secretase mediated cleavage of the amyloid precursor protein (APP), likely via indirect modulation of alpha-, beta- and gamma-secretase activity.

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease.

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66).

Genes Implicated in Rare Congenital Inner Ear and Cochleovestibular Nerve Malformations.

Objective: A small subset of children with congenital hearing loss have abnormal cochleovestibular nerves (i.e., absent, aplastic, or deficient cochlear nerves), with largely unknown etiology.

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

A de novo SIX1 variant in a patient with a rare nonsyndromic cochleovestibular nerve abnormality, cochlear hypoplasia, and bilateral sensorineural hearing loss.

Background: Childhood hearing impairment affects language and cognitive development. Profound congenital sensorineural hearing impairment can be due to an abnormal cochleovestibular nerve (CVN) and cochleovestibular malformations, however, the etiology of these conditions remains unclear.

Methods: We used a trio-based exome sequencing approach to unravel the underlying molecular etiology of a child with a rare nonsyndromic CVN abnormality and cochlear hypoplasia.