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. These maps are continually updated with the most recent and relevant data regarding chromosome 18. Over the course of the past decade, there have also been advances in our understanding of the molecular mechanisms underpinning genetic disease. Therefore, we have updated the maps to more accurately reflect this knowledge. Our Gene Dosage Map 2.0 has expanded from the gene and phenotype maps to also include a pair of maps specific to hemizygosity and suprazygosity. Moreover, we have revamped our classification from mechanistic definitions (e.g., haplosufficient, haploinsufficient) to clinically oriented classifications (e.g., risk factor, conditional, low penetrance, causal). This creates a map with gradient of classifications that more accurately represents the spectrum between the two poles of pathogenic and benign. While the data included in this manuscript are specific to chromosome 18, they may serve as a clinically relevant model that can be applied to the rest of the genome.

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. It is problematic for practicing physicians to obtain and use the emerging data on specific genes because this information is derived from diverse sources (e.g., animal studies, case reports, in vitro explorations) and is often published in sources that are not easily accessible in the clinical setting. METHODS: The Chromosome 18 Clinical Resource Center remedies this challenging problem by curating and synthesizing the data with clinical implications. The data are collected from our database of over 26 years of natural history and medical data from over 650 individuals with chromosome 18 abnormalities. RESULTS: The resulting management guides and video presentations are a first edition of this collated data specifically oriented to guide clinicians toward the optimization of care for each child. CONCLUSION: The chromosome 18 data and guides also serve as models for an approach to the management of any individual with a rare chromosome abnormality of which there are over 1,300 born every year in the US alone.

Genetic counseling in industry settings: Opportunities in the era of precision health.

The skill sets of genetic counselors are strongly utilized in industry, as evidenced by 20% of genetic counselors reporting employment within industry in 2016. In addition, industry genetic counselors are expanding their roles, taking on new responsibilities, and creating new opportunities. These advances have impacted the profession as a whole including, but not limited to, genetic counseling training curricula, a shift back to genetic counseling directly to patients, and a growing influence of genetic counselors on industry test offerings. Industry genetic counselors and training programs are working together to address the challenges and opportunities presented by workforce changes and novel interpretations of how genetic counselors' core competencies can be utilized. Counseling of patients by industry genetic counselors has become more commonplace and addresses a need for alternate service delivery models. Industry genetic counselors often provide significant contributions to test development, education, marketing, and interpretation. Beyond these broad examples, individual industry genetic counselors have created unique niches for themselves, using their genetic counseling training combined with unique opportunities offered through industry, as illustrated by genetic counselors' various roles and responsibilities highlighted here.

HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study.

BACKGROUND: X linked intellectual disability (XLID) syndromes account for a substantial number of males with ID. Much progress has been made in identifying the genetic cause in many of the syndromes described 20-40 years ago. Next generation sequencing (NGS) has contributed to the rapid discovery of XLID genes and identifying novel mutations in known XLID genes for many of these syndromes. METHODS: 2 NGS approaches were employed to identify mutations in X linked genes in families with XLID disorders. 1 involved exome sequencing of genes on the X chromosome using the Agilent SureSelect Human X Chromosome Kit. The second approach was to conduct targeted NGS sequencing of 90 known XLID genes. RESULTS: We identified the same mutation, a c.12928 G>C transversion in the HUWE1 gene, which gives rise to a p.G4310R missense mutation in 2 XLID disorders: Juberg-Marsidi syndrome (JMS) and Brooks syndrome. Although the original families with these disorders were considered separate entities, they indeed overlap clinically. A third family was also found to have a novel HUWE1 mutation. CONCLUSIONS: As we identified a HUWE1 mutation in an affected male from the original family reported by Juberg and Marsidi, it is evident the syndrome does not result from a mutation in ATRX as reported in the literature. Additionally, our data indicate that JMS and Brooks syndromes are allelic having the same HUWE1 mutation.

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. Because of this heterogeneity, we take a gene by gene approach to understanding the clinical consequences. There are 196 genes on 18q. We classified 133 of them as dosage insensitive, 15 (8%) as dosage sensitive leading to haploinsufficiency while another 10 (5%) have effects that are conditionally haploinsufficient and are dependent on another factor, genetic or environmental in order to cause an abnormal phenotype. Thirty-seven genes (19%) have insufficient information to classify their dosage effect. Phenotypes attributed to single genes include: congenital heart disease, minor bone morphology changes, central nervous system dysmyelination, expressive speech delay, vesicouretreral reflux, polyposis, Pitt-Hopkins syndrome, intellectual disability, executive function impairment, male infertility, aural atresia, and high frequency sensorineural hearing loss. Additionally, identified critical regions for other phenotypes include: adolescent idiopathic scoliosis and pectus excavatum, Virchow-Robin perivascular spaces, small corpus callosum, strabismus, atopic disorders, mood disorder, IgA deficiency, nystagmus, congenital heart disease, kidney malformation, vertical talus, CNS dysmyelination growth hormone deficiency and cleft palate. Together these findings make it increasingly feasible to compile an individualized syndrome description based on each person's individuated genotype. Future work will focus on understanding molecular mechanisms leading to treatment.

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. In addition, establishing the molecular underpinnings of the condition will potentially suggest targets for molecular treatments. Thus, the next step is to establish the precise effects of specific gene deletions. As we look forward to deepening our understanding of 18p-, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our 18p- cohort closely as they age to determine the presence or absence of some of these diagnoses, including spinocerebellar ataxia (SCA), facioscapulohumeral muscular dystrophy (FSHD), and dystonia. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. Mouse models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development.

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. Intellectual abilities ranged from mild impairment/borderline normal to severe/profound impairment calling into question the assumption that severe cognitive limitation is always a feature of tetrasomy 18p. For persons with tetrasomy 18p with mild cognitive deficits, the main barriers to successful functioning stems from limited social and metacognitive skill development and behavior regulation problems rather than being solely determined by cognitive deficits alone.

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. In addition, the developmental profile of 18p- has not been well-delineated. We undertook a thorough review of the medical histories of 31 individuals with 18p- and a breakpoint in the centromeric region. We collected developmental data using mailed surveys and questionnaires. The most common findings included neonatal complications; cardiac anomalies; hypotonia; MRI abnormalities; endocrine dysfunction; strabismus; ptosis; and refractive errors. Less common features included holoprosencephaly and its microforms; hearing loss; and orthopedic anomalies. The developmental effects of the deletion appear to be less severe than reported in the literature, as average IQ scores were in the range of borderline intellectual functioning. Based on responses to standardized questionnaires, it appears this population has marked difficulty with activities of daily living, though several young adults were able to live independent of their parents. This manuscript represents the most comprehensive description of a cohort of 18p- individuals with identical breakpoints. Despite identical breakpoints, a great deal of phenotype variability remained among this population, suggesting that many of the genes on 18p- cause low-penetrance phenotypes when present in a hemizygous state. Future efforts will focus on the clinical description of individuals with more distal breakpoints and the identification of critical regions and candidate genes.

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. Four ring chromosomes had no detectable deletion of one of the chromosome arms using aCGH. However, two of these ring chromosomes had telomeric sequences detected using FISH. These data confirm the importance of molecular and cytogenetic analysis to determine both chromosome content and morphology. We failed to find dramatic changes in mosaicism percentage between cytogenetic measurements made at the time of diagnosis and those made years later at the time of this study, demonstrating that dynamic ring mosaicism is unlikely to be a major cause of phenotypic variability in the ring 18 population. Lastly, we present data on the clinical features present in our cohort, though the extreme genotypic variability makes it impossible to draw direct genotype-phenotype correlations. Future work will focus on determining the role of specific hemizygous genes in order to create individualized projections of the effect of each person's specific ring 18 compliment.

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. The objective of this study is to describe the lifespan, educational attainment, living situation, and behavioral phenotype of adults with chromosome 18 abnormalities. The Chromosome 18 Clinical Research Center has enrolled 483 individuals with one of the following conditions: 18q-, 18p-, Tetrasomy 18p, and Ring 18. As a part of the ongoing longitudinal study, we collect data on living arrangements, educational level attained, and employment status as well as data on executive functioning and behavioral skills on an annual basis. Within our cohort, 28 of the 483 participants have died, the majority of whom have deletions encompassing the TCF4 gene or who have unbalanced rearrangement involving other chromosomes. Data regarding the cause of and age at death are presented. We also report on the living situation, educational attainment, and behavioral phenotype of the 151 participants over the age of 18. In general, educational level is higher for people with all these conditions than implied by the early literature, including some that received post-high school education. In addition, some individuals are able to live independently, though at this point they represent a minority of patients. Data on executive function and behavioral phenotype are also presented. Taken together, these data provide insight into the long-term outcome for individuals with a chromosome 18 condition. This information is critical in counseling families on the range of potential outcomes for their child.

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. SETTING: The study was conducted as a component of the ongoing research protocols at the Chromosome 18 Clinical Research Center at the University of Texas Health Science Center at San Antonio. PATIENTS: Thirty-eight participants with a deletion of the distal portion of the long arm of chromosome 18 were recruited to this study. INTERVENTIONS: The participants underwent an otologic examination as well as a basic audiometry evaluation. Blood samples were obtained, and high-resolution chromosome microarray analysis was performed. MAIN OUTCOMES MEASURES: Pure tone averages and speech discrimination scores were determined for each participant. The region of hemizygosity for each participant was determined to within 2 Kb each of their breakpoints. RESULTS: Twenty-four participants (63%) had high-frequency hearing loss, similar to the pattern seen in presbycusis. Comparison of microarray results allowed identification of eight genes, including the candidate gene for dysmyelination (MBP). CONCLUSION: Individuals with a deletion of a 2.8 Mb region of 18q23 have a high probability (83%) of high-frequency sensorineural hearing loss.

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 17.6-Mb region. This group represents the most genotypically similar group yet identified with distal 18q deletions. As the deletion is of average size when compared with other 18q deletions, this group can serve as a reference point for the clinical and molecular description of this condition. We performed a thorough medical record review as well as a series of clinical evaluations on 14 of the 16 individuals. Common functional findings included developmental delays, hypotonia, growth hormone deficiency, and hearing loss. Structural anomalies included foot anomalies, ear canal atresia/stenosis, and hypospadias. The majority of individuals performed within the low normal range of cognitive ability but had more serious deficits in adaptive abilities. Of interest, the hemizygous region contains 38 known genes, 26 of which are sufficiently understood to tentatively determine dosage sensitivity. Published data suggest that 20 are unlikely to cause an abnormal phenotype in the hemizygous state and five are likely to be dosage sensitive: TNX3, NETO1, ZNF407, TSHZ1, and NFATC. A sixth gene, ATP9B, may be conditionally dosage sensitive. Not all distal 18q- phenotypes can be attributed to these six genes; however, this is an important advance in the molecular characterization of 18q deletions.

Ophthalmic manifestations of tetrasomy 18p.

PURPOSE: To characterize ophthalmic findings in patients with tetrasomy 18p, a rare chromosomal anomaly that has been previously associated with strabismus. METHODS: All subjects underwent a complete eye examination to screen for ocular pathology. RESULTS: A total of 25 subjects (13 female) were examined after they were diagnosed with tetrasomy 18p. The average age of subjects was 8.2 years (range, 13 months to 22 years). Of the 25 subjects, 18 (72% of examined subjects, 42% of the cohort) showed evidence of strabismus; 16 had esotropia (8 uncategorized, 5 infantile, and 3 accommodative), 1 had esophoria, and 1 was diagnosed with intermittent exotropia. CONCLUSIONS: The coincidence of esotropia with tetrasomy 18p indicates the need to routinely screen these patients for strabismus at the time of diagnosis.

The role of the TCF4 gene in the phenotype of individuals with 18q segmental deletions.

The goal of this study is to define the effects of TCF4 hemizygosity in the context of a larger segmental deletion of chromosome 18q. Our cohort included 37 individuals with deletions of 18q. Twenty-seven had deletions including TCF4 (TCF4 (+/-)); nine had deletions that did not include TCF4 (TCF4 (+/+)); and one individual had a microdeletion that included only the TCF4 gene. We compared phenotypic data from the participants' medical records, survey responses, and in-person evaluations. Features unique to the TCF4 (+/-) individuals included abnormal corpus callosum, short neck, small penis, accessory and wide-spaced nipples, broad or clubbed fingers, and sacral dimple. The developmental data revealed that TCF4 (+/+) individuals were only moderately developmentally delayed while TCF4 (+/-) individuals failed to reach developmental milestones beyond those typically acquired by 12 months of age. TCF4 hemizygosity also conferred an increased risk of early death principally due to aspiration-related complications. Hemizygosity for TCF4 confers a significant impact primarily with regard to cognitive and motor development, resulting in a very different prognosis for individuals hemizygous for TCF4 when compared to individuals hemizygous for other regions of distal 18q.

Tetrasomy 18p: report of the molecular and clinical findings of 43 individuals.

Thus far, the phenotype of tetrasomy 18p has been primarily delineated by published case series and reports. Findings reported in more than 25% of these cases include neonatal feeding problems, growth retardation, microcephaly, strabismus, muscle tone abnormalities, scoliosis/kyphosis, and variants on brain MRI. Developmental delays and cognitive impairment are universally present. The purpose of this study was to more fully describe tetrasomy 18p at both the genotypic and the phenotypic levels. Array CGH was performed on 43 samples from individuals with tetrasomy 18p diagnosed via routine karyotype. The medical records of 42 of these 43 individuals were reviewed. In order to gain additional phenotypic data, 31 individuals with tetrasomy 18p underwent a series of clinical evaluations at the Chromosome 18 Clinical Research Center. Results from the molecular analysis indicated that 42 of 43 samples analyzed had 4 copies of the entire p arm of chromosome 18; one individual was also trisomic for a section of proximal 18q. The results of the medical records review and clinical evaluations expand the phenotypic description of tetrasomy 18p to include neonatal jaundice and respiratory distress; recurrent otitis media; hearing loss; seizures; refractive errors; constipation and gastroesophageal reflux; cryptorchidism; heart defects; and foot anomalies. Additional findings identified in a small number of individuals include hernias, myelomeningocele, kidney defects, short stature, and failure to respond to growth hormone stimulation testing. Additionally, a profile of dysmorphic features is described. Lastly, a series of clinical evaluations to be considered for individuals with tetrasomy 18p is suggested.

Genetic determinants of autism in individuals with deletions of 18q.

Previous research has suggested that individuals with constitutional hemizygosity of 18q have a higher risk of autistic-like behaviors. We sought to identify genomic factors located on chromosome 18 as well as other loci that correlate with autistic behaviors. One hundred and five individuals with 18q- were assessed by high-resolution oligo aCGH and by parental ratings of behavior on the Gilliam Autism Rating Scale. Forty-five individuals (43%) had scores within the "possibly" or "very likely" categories of risk for an autism diagnosis. We searched for genetic determinants of autism by (1) identifying additional chromosome copy number changes (2) Identifying common regions of hemizygosity on 18q, and (3) evaluating four regions containing candidate genes located on 18q (MBD1, TCF4, NETO1, FBXO15). Three individuals with a "very likely" probability of autism had a captured 17p telomere in addition to the 18q deletion suggesting a possible synergy between hemizygosity of 18q and trigosity of 17p. In addition, two of the individuals with an 18q deletion and a "very likely" probability of autism rating had a duplication of the entire short arm of chromosome 18. Although no common region of hemizygosity on 18q was identified, analysis of four regions containing candidate genes suggested that individuals were significantly more likely to exhibit autistic-like behaviors if their region of hemizygosity included TCF4, NETO1, and FBXO15 than if they had any other combination of hemizygosity of the candidate genes. Taken together, these findings identify several new potential candidate genes or regions for autistic behaviors.

A gene dosage map of Chromosome 18: a map with clinical utility.

PURPOSE: Microarray technology has revolutionized the field of clinical genetics with the ability to detect very small copy number changes. However, challenges remain in linking genotype with phenotype. Our goal is to enable a clinical geneticist to align the molecular karyotype information from an individual patient with the annotated genomic content, so as to provide a clinical prognosis. METHODS: We have combined data regarding copy number variations, microdeletion syndromes, and classical chromosome abnormalities, with the sparse but growing knowledge about the biological role of specific genes to create a genomic map of Chromosome 18 with clinical utility. RESULTS: We have created a draft model of such a map, drawing from our long-standing interest in and data regarding the abnormalities of Chromosome 18. CONCLUSION: We have taken the first step toward creating a genomic map that can be used by the clinician in counseling and directing preventive or symptomatic care of individuals with Chromosome 18 abnormalities.

Narrowing critical regions and determining penetrance for selected 18q- phenotypes.

One of our primary goals is to help families who have a child with an 18q deletion anticipate medical issues in order to optimize their child's medical care. To this end we have narrowed the critical regions for four phenotypic features and determined the penetrance for each of those phenotypes when the critical region for that feature is hemizygous. We completed molecular analysis using oligo-array CGH and clinical assessments on 151 individuals with deletions of 18q and made genotype-phenotype correlations defining or narrowing critical regions. These nested regions, all within 18q22.3 to q23, were for kidney malformations, dysmyelination of the brain, growth hormone stimulation response failure, and aural atresia. The region for dysmyelination and growth hormone stimulation response failure were identical and was narrowed to 1.62 Mb, a region containing five known genes. The region for aural atresia was 2.3 Mb and includes an additional three genes. The region for kidney malformations was 3.21 Mb and includes an additional four genes. Penetrance rates were calculated by comparing the number of individuals hemizygous for a critical region with the phenotype to those without the phenotype. The kidney malformations region was 25% penetrant, the dysmyelination region was 100% penetrant, the growth hormone stimulant response failure region was 90% penetrant with variable expressivity, and the aural atresia region was 78% penetrant. Identification of these critical regions suggest possible candidate genes, while penetrance calculations begin to create a predictive phenotypic description based on genotype.

High resolution genomic analysis of 18q- using oligo-microarray comparative genomic hybridization (aCGH).

The advent of oligonucleotide array comparative genomic hybridization (aCGH) has revolutionized diagnosis of chromosome abnormalities in the genetics clinic. This new technology also has valuable potential as a research tool to investigate larger genomic rearrangements that are typically diagnosed via routine karyotype. aCGH was used as a tool for the high-resolution analysis of chromosome content in individuals with known deletions of chromosome 18. The aim of this study was to clarify the precise location of the breakpoints as well as to determine the presence of occult translocations creating additional deletions and duplications. One hundred eighty-nine DNA samples from individuals with 18q deletions were analyzed. No breakpoint clusters were identified, as no more than two individuals had breakpoints within 2 kb of each other. Only two regions of 18q were never found to be haploid, suggesting the existence of haplolethal genes in those regions. Of the individuals with only a chromosome 18 abnormality, 17% (n = 29) had interstitial deletions. Six percent (n = 11) had a region of duplication immediately proximal to the deletion. Eight percent (n = 15) had more complex rearrangements with captured (non-18q) telomeres thus creating a trisomic region. The 15 captured telomeres originated from a limited number of other telomeres (4q, 10q, 17p, 18p, 20q, and Xq). These data were converted into a format for ease of viewing and analysis by creating custom tracks for the UCSC Genome Browser. Taken together, these findings confirm a higher level of variability and genomic complexity surrounding deletions of 18q than has previously been appreciated.