Further evidence of biallelic NAV3 variants associated with recessive neurodevelopmental disorder with dysmorphism, developmental delay, intellectual disability, and behavioral abnormalities.

Neuron navigators (NAVs) are cytoskeleton-associated proteins well known for their role in axonal guidance, neuronal migration, and neurite growth necessary for neurodevelopment. Neuron navigator 3 (NAV3) is one of the three NAV proteins highly expressed in the embryonic and adult brain. However, the role of the NAV3 gene in human disease is not well-studied.

LINE1-mediated epigenetic repression of androgen receptor transcription causes androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is a difference of sex development (DSD) characterized by different degrees of undervirilization in individuals with a 46,XY karyotype despite normal to high gonadal testosterone production. Classically, AIS is explained by hemizygous mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, the majority of individuals with clinically diagnosed AIS do not carry an AR gene mutation.

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.

Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees.

STIGMA: Single-cell tissue-specific gene prioritization using machine learning.

Clinical exome and genome sequencing have revolutionized the understanding of human disease genetics. Yet many genes remain functionally uncharacterized, complicating the establishment of causal disease links for genetic variants. While several scoring methods have been devised to prioritize these candidate genes, these methods fall short of capturing the expression heterogeneity across cell subpopulations within tissues.

Single-Cell Sequencing in Neurodegenerative Disorders.

Neurodegenerative disorders are typically characterized by late onset progressive damage to specific (sub)populations of cells of the nervous system that are essential for mobility, coordination, strength, sensation, and cognition. Addressing this selective cellular vulnerability has become feasible with the emergence of single-cell-omics technologies, which now represent the state-of-the-art approach to profile heterogeneity of complex tissues including human post-mortem brain at unprecedented resolution. In this review, we briefly recapitulate the experimental workflow of single-cell RNA sequencing and summarize the recent knowledge acquired with it in the most common neurodegenerative diseases: Parkinson's, Alzheimer's, Huntington's disease, and multiple sclerosis.

Comparative single-cell analysis of the adult heart and coronary vasculature.

The structure and function of the circulatory system, including the heart, have undergone substantial changes with the vertebrate evolution. Although the basic function of the heart is to pump blood through the body, its size, shape, speed, regeneration capacity, etc. vary considerably across species.

Transcriptional Alterations in X-Linked Dystonia-Parkinsonism Caused by the SVA Retrotransposon.

X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the intron retention transcript can be found in XDP cells as compared to healthy controls.

Elucidating Hexanucleotide Repeat Number and Methylation within the X-Linked Dystonia-Parkinsonism (XDP)-Related SVA Retrotransposon in with Nanopore Sequencing.

Background: X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by progressive dystonia and parkinsonism. It is caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion in the gene with a polymorphic () domain that acts as a genetic modifier of disease onset and expressivity.

Methods: Herein, we used Nanopore sequencing to investigate SVA genetic variability and methylation.

X-linked dystonia-parkinsonism: over and above a repeat disorder.

X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative movement disorder, caused by a founder retrotransposon insertion in an intron of the gene. This insertion contains a polymorphic hexanucleotide repeat (CCCTCT), the length of which inversely correlates with the age at disease onset (AAO) and other clinical parameters, aligning XDP with repeat expansion disorders. Nevertheless, many other pathogenic mechanisms are conceivably at play in XDP, indicating that in contrast to other repeat disorders, the (CCCTCT) repeat may not be the actual (or only) disease cause.

Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism.

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10). The lead single nucleotide polymorphisms collectively account for 25.

The importance of genetic testing for dystonia patients and translational research.

Genetic testing through a variety of methods is a fundamental but underutilized approach for establishing the precise genetic diagnosis in patients with heritable forms of dystonia. Our knowledge of numerous dystonia-related genes, variants that they may contain, associated clinical presentations, and molecular disease mechanism may have significant translational potential for patients with genetically confirmed dystonia or their family members. Importantly, genetic testing permits the assembly of patient cohorts pertinent for dystonia-related research and developing therapeutics.

DNA Methylation as a Potential Molecular Mechanism in X-linked Dystonia-Parkinsonism.

Background: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation of TAF1 expression. In X-linked dystonia-parkinsonism, 3 disease-specific single-nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation.

A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism.

Objective: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT) repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP.

Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: Detailed phenotyping of 10 new cases.

Objective: The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome.

Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed "transcriptomopathies" that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex.

Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous disorder with a high phenotypic variability including mental retardation, developmental delay, and limb malformations. The genetic causes in about 30% of patients with CdLS are still unknown. We report on the functional characterization of two intronic NIPBL mutations in two patients with CdLS that do not affect a conserved splice-donor or acceptor site.

Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin-Siris and Nicolaides-Baraitser syndromes.

Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified.

De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.

Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published.