Nurse Prac**oner Educa*on in Developmental Disabili*es Webinar Series Genetics and Genomics Bonnie R. Lanternier, ARNP
In order for Nurse Practitioners to provide optimum care for individuals with developmental disabilities, they must be able to understand the underlying causes. This is where the roles of genetics and genomics come into play.
Genetics is the study of heredity and the variation of inherited characteristics. Genomics is the study of the human genome. By having a good foundation in basic genetic concepts, providers will be able to understand which tests, therapies and interventions would be the most appropriate to order.
Gene*c Causes of Developmental Disabili*es I. Chromosomal abnormalities ~ 2-4% Down syndrome II. Single Gene Disorders ~ 5-10% Fragile X syndrome III. Microarray abnormalities ~ 10-20% DiGeorge syndrome and Prader-Willi syndrome IV. Multifactorial and Idiopathic ~ 40-50% Spina Bifida and Cerebral Palsy V. Exome/Genome abnormalities ~? Neurology 2011; 77 (17):1629-1635
I. Chromosome Problems
Human chromosomes have been systematically described using a variety of laboratory techniques.
Normal Male: 46, XY
Normal Female 46, XX
Incidence of chromosome abnormali*es at birth Down Syndrome 1/800 (~250,000 people) Edwards Syndrome 1/8,000 Patau Syndrome 1/10,000 Turner Syndrome 1/5,000 females Klinefelter Syndrome 1/1,000 males 47,XYY 1/1,000 males 47,XXX 1/1,000 females Balanced translocations 1/500
3 Types of Down Syndrome Nondisjunction: 95% of cases. Not inherited. Recurrence risk of 0.75-1%. Mosaic: Two or more cell lines with at least one having Trisomy 21. 2-3% of cases. Translocation: 1-2% of cases. Can be inherited. If parent has 21q:21q translocation, risk for child with DS is 100%!
Down Syndrome: 14/21 Transloca.on (46,XY,-14,+t(14q21q))
Diagnosing Down Syndrome 1 in 600 to 1 in 800 Nondisjunction Trisomy 21 (95%) Brushfeld spots (50%) Mid face hypoplasia Heart defects 40 % (A- V canal most common) Chromosome analysis
Common Health Problems Seen with Down Syndrome Hirschsprungs disease: associated with severe constipation or bowel obstruction in some cases (~ 10-20% children) Hypothyroidism ~ 30-50% lifetime risk Leukemia Hearing impairment (~10%) * No one gets every associated symptom
REMOVE THIS SLIDE? Concerns for Adults with DS Alzheimer's/Dementia ~ 25% by age 35 (normally 5-10% over age 65) Depression Estate Planning Sexuality (Fertility/ Infertility) Sleep Apnea
Alzheimer s in Down syndrome Many persons with DS have features of Alzheimer s disease in the central nervous system by age 35 70% of people with DS live to 40 or over 85% of people with DS over 35 years had one or more signs of dementia Deposition of amyloid A4 in brain of DS as much as 50 years earlier than general population.
RESOURCES ON ID/DOWN SYNDROME Pueschel, Siegfried M. (Ed.). (2001). A Parent's Guide to Down Syndrome: Toward a Brighter Future. Brookes Publishing Co., Box 10624, Baltimore, MD 21285. (800)638-3775 Healthcare Supervision Guidelines from the AAP: http://aappolicy.aappublications.org/cgi/content/ full/pediatrics;107/2/442 National Down Syndrome Society: www.ndss.org National Down Syndrome Congress: http://www.ndsccenter.org
Internet Resources For Down Syndrome Global Down Syndrome Foundation http://www.globaldownsyndrome.org/ National Association for Down syndrome http://www.nads.org/ National Down Syndrome Congress http://www.ndsccenter.org/ National Down Syndrome Society http://www.ndss.org/ Down Syndrome Information Network http://www.down-syndrome.info/
II. Single Gene Disorders
Fragile X syndrome History 1943 - Martin and Bell s description of a family with X-linked Intellectual Disability (ID) 1969 - Lubs identified the fragile site on the X chromosome 1977 - Fragile site at band q27.3 on the long arm of the X chromosome. Fragile X syndrome. 1991 - The FMR1 gene was identified. Discovery of the CGG trinucleotide repeat expansion.
Fragile X Prevalence 1:4000 Affected Males 1:8000 Affected Females 1:259 Carrier Females 1:755 Carrier Males 30% of individuals with Fragile X syndrome have an Autism Spectrum Disorder (ASD) 2-6% of individuals with an ASD have FXS National Fragile X Foundation
Genetics: Fragile X Emotional & Neurocognitive Features Mild to profound ID Fragile X Syndrome Hyperactivity, impulsivity and/or short attention span Executive function deficits: Organizational issues, shifting set, planning, inhibition, tangential speech, perseveration Over reactivity to stimuli: Anxiety excessive outbursts, tantrums Autism or ASD Mood instability
Fragile X Facial Features
Fragile X Syndrome Therapeutic Interventions Medical Director/Clinical Geneticist Genetic Counselor and Coordinator Assistive Technology and Educational Specialist Child Psychologist Developmental and Behavioral Pediatrician Audiologist Speech and Language Pathologist Occupational Therapist Physical therapist Social worker Research coordinators Occupational Therapist Social Worker
Fragile X Genotype Xq27.3 CGG trinucleotide expansion repeat Typical CGG<45 Premutation CGG 55-200 Full mutation >200 CGG mrna FMRP Clinical Normal Primary ovarian insufficiency (POI) Fragile X-associated tremor ataxia syndrome (FXTAS) Depression, Anxiety, ADHD and ASD Fragile X syndrome
Regional Support http://www.fragilex.org/community/links-supportnetwork/ http://www.floridafragilexfamilies.org http://www.thexfamily.org Fragile X Syndrome
III. Microarray Abnormali*es
What is an Array? Utilizes hybridization between two DNA strands (patient and lab probes) A microarray experiment can accomplish many genetic tests in parallel. Oligo (CGH), BAC (CGH) & targeted vs whole genome SNP arrays! (not all arrays are equal!)
What is a SNP? Single Nucleotide Polymorphism A SNP is a single base pair substitution of one nucleotide for another. Substitution usually not considered a mutation (polymorphism) The substitution must be found in the population at a frequency greater than 1.0%. E.g., one individual has a CAACCT sequence and a CAGCCT sequence (heterozygous)
Advantages of SNP Array Analysis High density coverage throughout entire genome Both known and unknown regions of potential clinical significance targeted Known regions targeted in high density Ability to review archival data as new syndromes and genes are identified Ability to detect deletions/duplications in balanced rearrangements Detection of uniparental disomy (UPD) Detection of Consanguinity if present
SNP Arrays - limita*ons Not necessary for patients with suspected recognizable aneuploidy (Trisomy 21, Turners, Trisomy 18 or 13?). Clinical discretion should be used to avoid unnecessary cost. Not for single gene disorders (CF, SMA, Sickle cell, etc ). It is NOT a form of gene sequencing!
Prader-Willi Syndrome 1:12,000-15,000 Chromosome 15 deletion ~ 60-80% Hyperphagia (<12mo s) Almond shaped eyes Hypogonadism Variable ID Frequently require behavior modification
PWS Resources Prader-Willi Syndrome Association (PWSA): http://www.pwsausa.org/. Genetics Home Reference: http://ghr.nlm.nih.gov/condition/prader-willisyndrome. Foundation for Prader Willi Research: http://www.fpwr.org/.
IV. Exome tes*ng
Whole Exome Sequencing The coding region of the genome = ~ 180,000 exons 1-2% of the genome (30Mb) ~20,500 genes 85% of known mutations are in exons Capture of the exons using array-based or liquid-phase hybridization (using DNA or RNA biotinylated bate) Sequence using Next Generation Sequencing technology Generates a massive amount of data which needs to be filtered (through computer software) to generate smoking guns (candidate genes)
Whole Exome Sequencing Trio testing (affected individual and both parents) Current costs - $5,000-10,000, but falling $1,500 2,500 Microarray $350 800 Karyotype Takes 6-8 weeks to get results Requires informed consent (ideally genetics should be involved to coordinate?)
V. Mul*factorial & Idiopathic
Mul*factorial Inheritance Threshold model for multifactorial inheritance. There is a liability toward the trait that consists of a combination of genetic and nongenetic factors and is normally distributed in the population. The trait is expressed only in individuals whose liability exceeds a threshold.
40 Neural Tube Defects-Spina Bifida 1-2/1000 births 80-90% of Spina Bifida cystica cases develop hydrocephaly Morbidity and mortality is influenced by location, size and associated abnormalities Variable degrees of paralysis, bladder and bowel dysfunction Significant intellectual disabilities are uncommon
From March of Dimes Genetics and Your Practice 41
42 NTD s Con*nued 90 % occur without a family history More common in offspring of diabetic women and women on valproic acid or tegretol 2-3 % recurrence risk for subsequent pregnancies if isolated 80% of cases are in the lumbar-sacral region
Resources Related to Spina Bifida SBAA (Spina Bifida Association of America): www.spinabifidaassociation.org/. Spina Bifida fact Sheet (National Institute of Neurological Disorders & Stroke): http://www.ninds.nih.gov/disorders/spina_bifida/ detail_spina_bifida.htm.l.
Au*sm Epidemic: What is the role of Gene*cs? Incidence: 1 in 68 individuals* Recurrence risk (1 st degree relatives): 6 % Sex ratio - Male:Female 4.3:1 Increased risk with Advanced Paternal Age Genetic etiology frequency: 6-30 % Majority are idiopathic *CDC 2014
Au*sm Resources National Institute for Neurologic Diseases & Stroke: http://www.ninds.nih.gov/disorders/autism/ detail_autism.htm. Autism Speaks: https://www.autismspeaks.org/. Autism Society: http://www.autism-society.org/. Autism Research Institute: http://www.autism.com/.
Gene*cs and Genomics Online Resources National Coalition for Health professionals in Genetics (NCHPEG): http://www.nchpeg.org/index.php? option=com_content&view=article&id=26&itemid=64. Genetics Is Relevant Now: Nurses' views and patients' stories Classroom version Online Mendelian Inheritance in Man (OMIM): http://www.omim.org/ Genetic Testing Registry (GTR): https://www.ncbi.nlm.nih.gov/gtr/
Conclusions Reviewed Genetic Causes of Developmental Disabilities Chromosomal Single gene Microarray NGS/Whole Exome Sequencing Multifactorial Whole Exome Sequencing the future?