Lecture 19 Flashcards
Spectrum of Clinical Geneticist
Diagnosis and clinical management of genetic disease
Identification of preventable complications by early surveillance e.g. cancer in familial cancer predisposition syndromes, aortic dissection in Marfan Syndrome
Consultation regarding reproductive implications of genetic disorders and reproductive options
Advice about inheritance of genetic conditions
Information and genetic testing for those affected by of perceived to be at risk of genetic disorders in extended families
Genetics eduction for professional and lay groups
Types of Genetic conditions
Chromosomal:
-individually rare, typically sporadic e.g. Down syndrome
Single Gene (Mendelian)
-individually rare but collectively numerous with clear patterns of inheritance e.g. cystic fibrosis, Huntingtons Disease
Multifactorial
-common conditions with no clear pattern of inheritance genetic predisposition with environmental threshold e.g. T2DM
Burden of genetic disease
2004 study: admission to children’s hospital in Ohio in 1996 (McCandless et al. AJHG 2004)
71% of children admitted had an underlying disorder with significant genetic component
Increasing knowledge about genetic component of common diseases e.g. cancer, heart disease, psychiatric illness
Personalised genomics - risk treatment
Genetic Counseling
Genetic counselling is a communication process, which aims to help individuals, couples and families understand and adapt to the medical, psychological, familial and reproductive implications of the genetic contribution to specific conditions
Methods of providing genetic counselling
Provide information in plain language
Explain individual genetic risk in a way the patient clearly understands
Discuss current testing procedures and research
Explore potential impact the condition/decision/testing may have on the patient and their famaily
Identify issues and negative psychological outcomes and provide support and strategies to help them adjust
Facilitate decision-making to promote informed choices
Advocate for parents and their fmaily
Liason with laboratory
Work closely with cytogenetics and molecular genetic laboratory located at LabPLUS at ACH
NZ Herald Google
Stag’s Hoani MacDonald in induced coma after collapsing on rugby pitch
Tourist dies of natural causes during dolphin swim. Found floating face down in the water after 10 minutes
The Rotorua cycling community are in chock following the sudden death of the 21 year old last night. He fell of his bike towards the end of the race, there is a possibility he had a heart attack but dont know the cause
Christmas 2005 was fun for AJ. 2 days later their fit sun collapsed and died regardless of paramedic help.
Unravelling the cases of SUDY
SUDY= Sudden Unexpected Death in Young
Incidence - 20/1mil /year (80 in NZ)
In NZ they are Coronal cases
Postmortem performed:
-Positive in 2/3 of cases, many cardiac related deaths (dilated cardio myopathy- not pumping, muscle saggy, hypertrophic (thicker), arythmagenic rV cardiomyopathy-muscle replace by fat, ion channel disorders-effects electrical signals)
-negative in 1/3 of cases
All post mortem negative cases of sudden unexplained death under the age of 40 referred to CIDG team in Auckland Hospital
Case study SUDY: 13 yr old child with clinical diagnosis of epilepsy has a community VF arrest (Hawkes Bay)
Doesn’t survive
Post mortem negative. DNA stored
referred to CIDG
Family very concerned about their relatives risks (engagement is variable)
-cardiologists look at family history. ECG looking at heart rhythm and electrical activity (not normal + abnormal repolorisation)
Case history SUDY Long QT syndrome
(part of ECG)- abnormal repolorisation Ion channel disorder Multiple genes Autosomal Dominant Variable expressivity --KCNH2 Deletion of exons 6-14
Genetic Testing
Cost $2000 for 7 gene panel
pick up rate
Management of gene positive living relatives
Risk stratification on which gene, sex, age, history of symptoms, FHx
-avoid LQT prolonging drugs
-Beta blockade
-Sympathectomy
-Implanted defibrillators
All of this is sorted out in joint cardiac genetics outpatient clinics
NICU and Pediatric referrals
Reasons for referral:
- Risk of future recurrent cases in family
- Concerns over unusual appearance
- Collection of structural problems with no obvious cause
- Developmentally delayed
- Autism or FHx autism
- Abnormal genetic test result … microarray
- Brain abnormalities on MRI and Abnormal neurology/seizures
Dysmorphology
Looking at faces and other subtle clues, and whether or not theyre in a pattern which suggests a particular diagnosis
-trying to figure out is it different from normal and down it Nose
Remarkable variability, profile, frontal plane and undersurface
Soft tissue and boney landmarks
Roof, bridge, tip (pronesion), Base, Nares, Columella, ala nasi
Syndrome
Collection of unusual features
22 cudalesion
present congenital heart diseaes
schizoprenia
Faces common: Nose: long midface/tubular nose, as wide at top as at bottom (Bulbus)
-some unusual ears
Picked up routinely in karyotype analysis (dont need geneticist now) - more diagnosis by test than by clinical acumun)
Crude test
chromosome analysis
-genetic material, missing/extra bits almost always disase causeing
-big things
-often people with deletions or duplications seen on a karyotype, will have quite obvious abnormalities
5%
More specific than crude test
Molecular Karyotype -millions of probes -higher detail -karyotype wont pick it ups long arm Chromsome 22q11.2 Deletion (common)
Then Individual genes. (gene panels) decreasing cost
Marfans Syndrome result
looking at single gene:
Fibrillin -C.7376G>T -P Cys2459Phe
Changes conserved cysteine in EGF like domain
Higher Resolution techniques
Gene panels
Exomes
Whole genomes
-potential to cause harm/be detrimental to family
-sometimes testing is so broad, you discover condition B
Incidental findings
- 5 yr old has developmental delay. Detailed chromosome analysis performed. Patient found to have MLH1 deletion (hereditary bowel cancer)
- 11 yr old has epilepsy. Epilepsy gene panel finds one mutation in fumarate hydratase. At risk for renal cancer
- Patient has family history of late onset esophageal cancer. has exoma. P53 variant identified in5’ UTR?? Overseas child calls it pathogenic. P53 is tumour suppressor
- carriage of mutation significantly increases lifetime risk of a whole variety of cancers
- we are not sure if this variant is disease causing
Predicitve Testing
Breast cancer. 1/9 develop. often environmental. 5% strongly familial. (dominant)
Sisters refered to GHSNZ for predicitve testing
Mother known to have BRCA1 mutation and had prophylactic masectomy and oophorectomy
MAt grandmother was diagnosed with ovarian cancer at 48 years and was found to carry BRCA1 mutation. Passed away at 56 years from breast cancer. MAt great aunt died from breast cancer 60 years
-explore her perception of her own risk and her experience of cancer
-fully informed re inheritance, cancer risk, management options, insurance implications
-psychosocial issues- timing of test, life planning, relationship/dating, support available
-adjusting to results - anticipate how results may affect her and how she may cope
-some woman decide not to proceed with testing
Prenatal genetics
29 year old woman Past medical history -cleft palate -hearing loss -Type 1 diabetes -Mild learning difficulties
Obstetric history
One healthy son aged 2 years
One termination of pregnancy at 14 weeks for fetal anomalies? Underlying cause
Currently 18 weeks pregnant
Referred in current pregnancy at 19 weeks gestation
Abnormal fetal anatomy on ultrasound (reasons for referral)
-micrognathia (small lower jaw)
-mild cerebral ventriculomegaly (dilatations of cerebral ventricles)
-abnormal ossification/absence of fibulae
Diagnosis in fetus?
Does mother have underlying diagnosis?
-Take detailed family history
Clinical diagnosis of Osteopathia Striata with Cranial sclerosis
Genetic testing confirmed diagnosis in mother
Prenatal testing done and diagnosis confirmed in fetus. X-linked condition (males likely to have sever form )
Post-mortem- cleft palate, intestinal malrotation, aplasia of the fibulae
OSCS
X-linked condition Females: -Sclerotic striations long bones -Cranial sclerosis -Craniofacial dysmorphism Males: -likely to have severe form -die in utero/survive only a short time -Cranial sclerosis -Congenital abnormalities (heart, GI, GUT) -Pre and postnatal lethality -Neurodevelopmental Disbaility
Mutations in the WTX gene on Xq11.1
Issues in this case?
Diagnosis of an adult (never heard before impacting her/first time she had known, also affecting her child)
Late diagnosis in pregnancy
Implications for future pregnancies
What is so important about a diagnosis
Explanation (even if no treatment)
Prognosis
Guides management
Beneficial when applying to educational support
Avoids other investigations
Recurrence risk (siblings, relatives, offspring)
Take home message
Forget about the condition, rare, less than 100 described in literature
Refer to Genetics (tie conditions together earlier, could have helped and provided her with more choices/more informed, rather than finding out late in the piece with limited choices as to what to do)
(Paedeatrics, ORL, opthamology, Plastics, endocrinologists, obstectrians, GP)
Prenatal diagnosis
Genetic testing of the fetus
-both early second Trimester
Chorionic Villus Sampling (CVS) 11-13 weeks
Amniocentesis (from 15 weeks)
Benefits and Disadvantages of Prenatal diagnosis
Benefits:
- Planning - manage pregnancy, labour or early postnatal care differently
- Choice- parents can make decision about continuing pregnancy
Disadvantages:
- Termination of pregnancy only option
- Invasive: risk of miscarriage with procedure
PGD
Preimplantation Genetic Diagnosis
IVF –> Embryo –> Biopsy (1 or more cells (blastocyts) –> genetic Screening –> Unaffected embryos transferred
-8 cell embyro stage remove cell/pipete biposy. Most cells survive
after 3 days
Cell free fetal DNA (NRPT)
Analysis of cell free fetal DNA in maternal blood
Detectable from 7 weeks and cleared from maternal circulation within hours after birth
Sequencing lots (millions) of fetal DNA molecules simultaneously using NGS
Identify chromosome of interest
Calculate difference between numbers of chr 21 chromosome from fetus compared to control or use SNPs from fetal DNA to determine copy number
Advantage of Cell Free DNA testing (NRPT)
Higher sensitivity and specificity than current available screening tests
Low false positive rate will lead to fewer invasive tests
Can be done earlier than current available screening
Disadvantages of Cell Free DNA testing (NRPT)
Test failure - fetal fraction cfDNA too low (gestation, maternal weight) 1-4%
Cost ($800-$1500)
Only detects limited number of chromosome abnormalities
-30% of abnormal results found after 1st trimester screening involve other abnormalities
Serum analysis and ultrasound at 12 weeks gives additional information about pregnancy
Where are we heading?
Direct to consumer genetic testing (23 and me)-ancestory
Precision making - “treat the individual”(better response to medicine eg)
Preconceptual medicine: one potential development from this type of testing could be he eventual reduction or elimination of certain genetic conditions, he said “the eradication of certain diseases is possible if parents in sufficient numbers decide not to have a child with the condition” he said - forced? community support?
Direct to consumer prenatal testing (send to company to find if your baby is a boy or girl early)
Prenatal testing: Non-invasive (fetal microarray, whole exome/genome sequencing)
