Understanding type and quality of relationships between individuals with chromosome 18 syndromes and their siblings.

Siblings of individuals with disabilities hold a pivotal and sometimes unappreciated position in the lives of their brother or sister. We sought to understand the unique challenges and opportunities in relationships between children with chromosome 18 conditions and their siblings and to identify the ways to support this relationship. Participants were recruited through the lay advocacy organization, the Chromosome 18 Registry & Research Society.

Causes of death in individuals with trisomy 18 after the first year of life.

Mortality in individuals with trisomy 18 has significantly decreased over the past 20 years, but there is scant literature addressing the prognosis and cause of death in individuals with trisomy 18 and survival past the first year of life (YOL). This study analyzed factors associated with mortality and cause of death in a retrospective cohort of 174 individuals with trisomy 18 and survival past the first YOL, the largest such series to date. Data were collected via retrospective survey of parents of affected individuals.

The Consequences of Abnormal Gene Dosage: Lessons from Chromosome 18.

Accurate interpretation of genomic copy number variation (CNV) remains a challenge and has important consequences for both congenital and late-onset disease. Hemizygosity dosage characterization of the genes on chromosome 18 reveals a spectrum of outcomes ranging from no clinical effect, to risk factors for disease, to both low- and high-penetrance disease. These data are important for accurate and predictive clinical management.

Abnormal bone mineral content and density in people with tetrasomy 18p.

Tetrasomy 18p is a rare chromosomal abnormality, resulting from an additional iso-chromosome composed of two copies of the short arm. It is characterized by craniofacial abnormalities, neuromuscular dysfunction, and developmental delay. The Chromosome 18 Clinical Research Center has established the largest cohort of individuals with this rare genetic condition.

Chromosome 18 gene dosage map 2.0.

In 2009, we described the first generation of the chromosome 18 gene dosage maps. This tool included the annotation of each gene as well as each phenotype associated region. The goal of these annotated genetic maps is to provide clinicians with a tool to appreciate the potential clinical impact of a chromosome 18 deletion or duplication.

The Chromosome 18 Clinical Resource Center.

Background: The Chromosome 18 Clinical Research Center has created a pediatrician-friendly virtual resource center for managing patients with chromosome 18 abnormalities. To date, children with rare chromosome abnormalities have been cared for either symptomatically or palliatively as a reaction to the presenting medical problems. As we enter an era of genomic-informed medicine, we can provide children, even those with individually unique chromosome abnormalities, with proactive medical care and management based on the most contemporary data on their specific genomic change.

Monosomy 18p is a risk factor for facioscapulohumeral dystrophy.

Background: 18p deletion syndrome is a rare disorder caused by partial or full monosomy of the short arm of chromosome 18. Clinical symptoms caused by 18p hemizygosity include cognitive impairment, mild facial dysmorphism, strabismus and ptosis. Among other genes, structural maintenance of chromosomes flexible hinge domain containing 1 () is hemizygous in most patients with 18p deletions.

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene .

Genetic variation within the transcription factor locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts.

Making chromosome abnormalities treatable conditions.

Individuals affected by the classic chromosome deletion syndromes which were first identified at the beginning of the genetic age, are now positioned to benefit from genomic advances. This issue highlights five of these conditions (4p-, 5p-, 11q-, 18p-, and 18q-). It focuses on the increased in understanding of the molecular underpinnings and envisions how these can be transformed into effective treatments.

A review of 18p deletions.

Since 18p- was first described in 1963, much progress has been made in our understanding of this classic deletion condition. We have been able to establish a fairly complete picture of the phenotype when the deletion breakpoint occurs at the centromere, and we are working to establish the phenotypic effects when each gene on 18p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families with an 18p- diagnosis.

Consequences of chromsome18q deletions.

Providing clinically relevant prognoses and treatment information for people with a chromsome18q deletion is particularly challenging because every unrelated person has a unique region of hemizygosity. The hemizygous region can involve almost any region of 18q including between 1 and 101 genes (30 Mb of DNA). Most individuals have terminal deletions, but in our cohort of over 350 individuals 23% have interstitial deletions.

Tetrasomy 18p: report of cognitive and behavioral characteristics.

Our purpose was to describe intellectual and behavioral characteristics of persons with tetrasomy 18p. This is a more detailed investigation into the cognitive and behavioral characteristics of our previously reported tetrasomy 18p cohort of 43 plus six additional participants. We evaluated the intellectual functioning using standard measures of cognitive ability, measures of executive functioning, adaptive and maladaptive behaviors.

Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome.

Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p.

Whole arm deletions of 18p: medical and developmental effects.

Deletions of the short arm of chromosome 18 have been well-described in case reports. However, the utility of these descriptions in clinical practice is limited by varied and imprecise breakpoints. As we work to establish genotype-phenotype correlations for 18p-, it is critical to have accurate and complete clinical descriptions of individuals with differing breakpoints.

Adults with Chromosome 18 Abnormalities.

The identification of an underlying chromosome abnormality frequently marks the endpoint of a diagnostic odyssey. However, families are frequently left with more questions than answers as they consider their child's future. In the case of rare chromosome conditions, a lack of longitudinal data often makes it difficult to provide anticipatory guidance to these families.

Ring 18 molecular assessment and clinical consequences.

Ring chromosome 18 is a rare condition which has predominantly been described by case reports and small case series. We assessed a cohort of 30 individuals with ring 18 using both microarray comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). We determined that each participant had a unique combination of hemizygosity for the p and q arms.

Otologic characteristics of individuals with deletions of distal 18q.

Objectives/hypothesis: To fully describe the otologic features seen in individuals with deletions of the distal long arm of chromosome 18 (distal 18q-).

Study Design: Cross-sectional/observational.

Methods: More than 200 individuals with deletions of the long arm of chromosome 18 underwent a complete otologic and audiologic examination.

Sensorineural hearing loss in people with deletions of 18q: hearing in 18q-.

Objective: The objective of this study was to characterize hearing loss in individuals with deletions of distal chromsome18q and to identify the smallest region of overlap of their deletions, thereby identifying potential causative genes.

Study Design: The clinical data were collected via a retrospective case study. Molecular data were obtained via high-resolution chromosome microarray analysis.

Large inverted duplications in the human genome form via a fold-back mechanism.

Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown.

Establishing a reference group for distal 18q-: clinical description and molecular basis.

Although constitutional chromosome abnormalities have been recognized since the 1960s, clinical characterization and development of treatment options have been hampered by their obvious genetic complexity and relative rarity. Additionally, deletions of 18q are particularly heterogeneous, with no two people having the same breakpoints. We identified 16 individuals with deletions that, despite unique breakpoints, encompass the same set of genes within a 17.

Mood disorders in individuals with distal 18q deletions.

We examined 36 participants at least 4 years old with hemizygous distal deletions of the long arm of Chromosome 18 (18q-) for histories of mood disorders and to characterize these disorders clinically. Since each participant had a different region of 18q hemizygosity, our goal was also to identify their common region of hemizygosity associated with mood disorders; thereby identifying candidate causal genes in that region. Lifetime mood and other psychiatric disorders were determined by semi-structured interviews of patients and parents, supplemented by reviews of medical and psychiatric records, and norm-referenced psychological assessment instruments, for psychiatric symptoms, cognitive problems, and adaptive functioning.

Differential expression analysis with global network adjustment.

Background: Large-scale chromosomal deletions or other non-specific perturbations of the transcriptome can alter the expression of hundreds or thousands of genes, and it is of biological interest to understand which genes are most profoundly affected. We present a method for predicting a gene's expression as a function of other genes thereby accounting for the effect of transcriptional regulation that confounds the identification of genes differentially expressed relative to a regulatory network. The challenge in constructing such models is that the number of possible regulator transcripts within a global network is on the order of thousands, and the number of biological samples is typically on the order of 10.

An evaluation tool for collaborative clinical research centers.

There is a need for metrics that describe the full range of services provided by a clinical research unit; given that services have expanded to include such things as investigator training, regulatory compliance monitoring, and budget negotiations. We developed a tool and methodology that allows tracking of these expanded services. This not only allowed us to more accurately describe the work of the research unit staff, but to monitor the status of a study across the entire study lifespan from the idea to the publication.

A recurrent translocation is mediated by homologous recombination between HERV-H elements.

Background: Chromosome rearrangements are caused by many mutational mechanisms; of these, recurrent rearrangements can be particularly informative for teasing apart DNA sequence-specific factors. Some recurrent translocations are mediated by homologous recombination between large blocks of segmental duplications on different chromosomes. Here we describe a recurrent unbalanced translocation casued by recombination between shorter homologous regions on chromosomes 4 and 18 in two unrelated children with intellectual disability.