Clinical Aspects of Common Chromosomal Disorders

What is the first line analysis?

QF-PCR, array CGH and genome sequencing  

What are the features of QF-PCR?

Can count the loci in the genome, used to detect trisomy but not triploidy as it uses relative levels

What are the features of array CGH?

Looks at the quantity of the genomic content  

What are the features of genome sequencing?

Provides more locational information  

What are the follow-up lines of analysis?

FISH and karyotypingWhat

What are the features of FISH?

Shows which part is missing or additional and where  

What is the feature of karyotyping?

Important for detecting large balanced arrangements  

What are the features of chromosome abnormalities?

• Numerical – copy number  

• Structural  

• Size -> 1 gene (blur with structural re-arrangements)  

How are there large differences in the genome between people?

• Copy number variants – structural variants are the easiest type to measure  

• DNA segment of 1kb or larger that is present at a variable copy number in comparison with a reference genome  

What are the features of CNVs in general population?

• As important a component of genomic diversity as a single nucleotide polymorphism  

• In a healthy individual 99% CNVs inherited  

• Every human has ~250 CNVs > 10kb in size  

What did mapping the CNVs show?

• Some regions are enriched in CNVs due to genomic architecture  

• Repetitive sequences are subject to variation  

What are the features of different loci?

• Genes have different locations throughout the genome  

• The gene density also varies  

• Some genes have a degree of redundancy 

When do miscarriages happen?

• Miscarriages is a spontaneous loss of pregnancy before 24 weeks ‘viability' 

• After 24 weeks it is considered a still birth 

How common are miscarriages?

• 20-24 years have 11%  

• 40-44 years have 51%  

What are the features of many miscarriages?

• Three or more miscarriages affect around 1% of couples 

• Balanced and unbalanced could produce a recurrence risk  

• Others are most likely sporadic  

What causes miscarriages?

• Many non-genetic reasons  

• Estimated that 50% will have chromosomal abnormalities  

• In contrast about 0.6% liveborn have a chromosome abnormality  

What happens after 3 or more miscarriages?

Cytogenetic analysis should be performed on products on conception of the third and subsequent consecutive miscarriages and any second trimester miscarriage  

What are the features of cytogenetic analysis?

• R464 parental karyotype – 5 or more miscarriages  

• Looks at the parental risk  

• 2-5% of couples with recurrent miscarriages, one of the partners carries a balanced structural chromosomal abnormality  

• Reciprocal or Robertsonian translocation  

What are the features of trisomy tests?

• Scan to measure the nuchal translucency and CLR performed from 11+2 – 14+1 gestation  

• Serum sample from 10+0 – 14+1 weeks gestation (BhCG and PAPP-A) 

• Other methods for later gestation  

What is a high risk in trisomy testing and how common are they?

• A high risk is classified as > 1 in 150  

• 3.4% of all pregnancy women have a higher risk result  

• Depends on age of population and agreed cut offs  

What are the features of the NIPT?

• Screens for trisomy 13,18 and 21 foetal sex not assessed  

• Also used in NHS to identify Y chromosome markers  

• Doesn't look at sex chromosome aneuploidy  

• Many other things looked for commercially  

• Different to NIPD (diagnosis) 

• Uses next generation sequencing and counts chromosomes relative to others  

• Has a high specificity and sensitivity 

What are the features of trisomy?

• 3 copies of a chromosome  

• All autosomal trisomies have been recorded  

• Some are viable to term – 13,18 and 21  

• Others are survivable in mosaic forms  

What are the features of monosomy?

• 1 copy of a chromosome  

• Few develop past early pregnancy (autosome)  

What are the features of sex aneuploidies?

• 45, XO 47, XXY 47, XXX 47, XYY  

• Much more tolerated  

• Significantly viability at term  

What is the incidence rate of trisomy 21?

• 1 in 800 medical impact of TOP debate, 3% mosaic  

• Incidence rate is impacted by medical input  

• About 60% spontaneously miscarry  

What are some common traits of trisomy 21?

• Learning disability  

• 40% have cardiac abnormalities  

• Average life expectancy 55-68 years  

• Alzheimer's (APP) 

• Hypothyroidism  

• Obesity  

What are other features of trisomy 21?

• Coeliac disease, arthritis, atlantoaxial substitution, DM, obstructive sleep apnoea, seizures, hearing loss, meatal health problems and valve prolapse  

• Upslanding palpebral fissures, epicanthic folds, single palmar crease, brush field spots, sandal gap  

What is the most common cause of trisomy 21?

About 95% affected have three separate copies of chromosome 21 due to non-disjunction during meiosis  

What is the middle cause of trisomy 21?

• 4% have the extra chromosome 21 because of a Robertsonian translocation  

• Important as this produces a recurrence risk and there could be issues with other chromosomes  

What is the rarest form of trisomy 21?

1-3% have mosaicism with normal and trisomy 21 lines – occurs post-zygotically non-disjunction  

What is the incidence rate of trisomy 13?

• 1 in 5,000 liveborn  

• >90% die in the first year of life Wha

What are the features of trisomy 13?

• IUGR 

• Microcephaly  

• Holoprosencephaly  

• Polydactyl  

• Clenched hands  

• Heart defects  

• Cleft lip and palate  

• Omphalocele  

• Cutis aplasia  

What is the incidence rate of trisomy 18?

• 1 in 5,000 liveborn  

• >80% die in first year of life 

What are the features of trisomy 18?

• IUGR  

• Cleft palate  

• Structural heart defects  

• Other structural abnormalities  

• Microencephaly  

• Low set ears  

What is the assumption of invasive testing?

• Generally offered on the assumption may terminate an affected pregnancy – but can be used for information 

• Is used less for information due to the increased miscarriage risk  

• Is done using sequencing rather than microarrays  

What are the ethical considerations of trisomy testing?

• All the screening comes with complication ethical issues  

• There is a high uptake of the screening, but individuals don’t know what to do with the information  

What were the features of Lily at birth?

• Weight 2.8kg  

• Concerns regarding colour, oxygen saturation and puffy feet  

• Admitted to neonatal unit  

• Echocardiogram showed a bicuspid aortic valve and ‘mild coarctation’ of the aorta  

What did Lily’s test show?

• Genetic test results  

• First line – postnatal microarray 

• Result – Arr (X)x1  

• Pathogenic profile consistent with Turner syndrome  

What did the karyotype show?

• Result 45, X  

• Conventional cytogenetics analysis of the blood from sample from the patient has shown 45 chromosomes with only one X chromosome  

• There was no evidence of mosaicism in the 30 cells examined  

• There are a number of different variants of Turner syndrome due to structural rearrangements of the X Y chromosome mosaicism is a concern 

What is the incidence rate for Turner synrome?

Affects 1 in 2000 liveborn females  

What are the prenatal Turner features?

Prenatal antenatal nuchal cystic hygroma can be featured in pregnancy  

What are the other features of Turner syndrome?

• Webbed neck, ptosis low hairline, shield chest  

• Bicuspid aorta / coarctation of the aorta  

• Small stature  

• Streak gonads  

• Delayed puberty/infertility 

• Hearing loss  

• High blood pressure  

• Kidney and urinary tract problems  

• Autoimmune conditions  

• Thyroid, diabetes, coeliac  

• Generally normal intellect but often specific difficulties such as visuospatial organisation problems  

What is Klinefelter syndrome and incidence rate?

• 47, XXY  

• Additional X’s are inactivated reducing phenotypic affect  

• Frequently found as apparently incidental findings  

• Found in 1 in 500-1000 liveborn males  

What are the features of Klinefelter?

• Tall stature 

• Gynaecomastia  

• Hypogonadism  

• Intention tremors  

• Mildly reduced IQ 

• Very subtle  

• Expressive language problems  

What are the features of Charlotte?

• Seen by paediatricians and recently came to the UK 

• Global development delay  

• Walked at 2 years old  

• Speech delay  

• Dysmorphic features  

• A developmental screen was arranged 

• First line microarray -> genome sequencing  

• Showed a duplication of approx 8Mb from 7q36.1 to qter  

• Additional part of chromosome 7 but doesn’t show the location  

What are considered with reciprocal translocations?

• Need to look at what the genotypes of the potential offspring are  

• Are they survivable  

• Predict the phenotype of the liveborn affected  

What are the features of the translocations?

• Generally, monosomy is less survivable than trisomy  

• Based on the percentage of the genome involved  

• Search for examples in the literature  

• Look for the monosomic and trisomic regions separately  

• Survivability important when thinking about utility of PGT  

What are the features of Jacob?

• Mild global developmental delay  

• Moderate learning difficulties 

• Severe talipes  

• Myopia  

• Has genome sequencing  

What questions should be asked about genetic test results?

• Does this fully explain the phenotype  

• What are the implications for management  

• What are the implications for the family  

• Segregation studies found de novo  

• Are there environmental considerations  

What does DECIPHER do?

• Looked on DECIPHER to look at the gene content, morbid genes and overlapping cases  

• Can find what genes are in the deleted area  

• Can see other cases that have the same genetic change  

What were the implications of management for Jacob?

• Proportion of patients with congenital cardiac disease  

• Refer for echo  

• Monitor due to increased risk for polyps  

What are the features of common microdeletions/duplications?

• Large repeat sequences – segmental duplications  

• Mediated by repetitive regions of genomes causing misalignment  

• Susceptible to non-allelic homologous recombination usually during meiosis  `

What are the features of non-reccurent deletions/duplications?

• Non-recurrent due to unique genomic errors  

• Are familial or individual duplications and are harder to predict the impact or if they are causing the problem  

What is the incidence rate of DiGeorge syndrome?

• 1 in 2000-4000 livebirths  

• Most frequent cause of syndromic palatal defects  

• 1 in 68 children born have a heart defect  

• Most common sub-microscopic deletion 

• 10% inherited 

• Can have mildly affected parents  

• Speech difficulties and unrecognised issue with palat 

What is confusing about DiGeorge syndrome?

Has a large variability in the expression of the condition  

What are other aspects of common chromosomal disorders?

• Translocations and inversions  

• Neurosuceptability loci  

• Other structural differences such as ring chromosomes, marker chromosomes, isodicentric chromosomes  

• Imprinting related  

• Mosaicism