Blood Module Flashcards

Question

Wolf-Hirschhorn Syndrome What causes it? What specific rearrangement can lead to WH phenotype? What are the clinical features?

Answer 1

It is a deletion of 4p. - Deletions are often cytogenetically visible, but may need array, - the 4p region is unstable due to high amount of repetitive sequence, - Critical region is at 4p16.3 and contains WHSCR - the size of the deletion correlates with the phenotypic severity, - can be terminal, interstitial or caused by a balanced rearrangement in a parent, - could also be due to a ring chromosome, - could be caused by the t(4;8) in a parent (2nd most common recurrent trans). Clinical features: - Greek warrior helmet facial appearance: widely spaced protruding eyes; broad, flat nasal bridge and high forehead. - delayed growth and development, - FTT and feeding problems, - weak muscle tone, - mild to severe I.D, - good socialisation skills in comparison to their I.D, - seizures in 90-100%.

Answer 2

17p11. 2 deletion is Smith-Magenis Syndrome (SMS) 17p11. 2 reciprocal duplication is Potocki-Lupski Syndrome (PTLS) A series of repeat elements at 17p11.2 cause non-allelic homologous recombination and produce reciprocal deletion-duplication events. 17p is one of the most recombination prone regions in the genome. The most common deleted/duplicated region is ~3.7Mb in size and is between the distal and proximal repeat. 90% of the deletions are the classic size. Other repeats produce other deletion sizes but are rarer (~1.5Mb to 9Mb). A key gene affected is RAI1. Clinical features of Smith-Magenis Syndrome: - distinctive dysmorpholgy, - mental defect (mild-moderate) - fractious behaviour - sleep disturbance is characteristic. Sleepy in the day and struggle to sleep with frequent awakenings. Reversal of circadian pattern of melatonin secretion. - self injury and self mutilation. Diminished pain sensitivity. Clinical features of Potocki-Lupski Syndrome: - features are milder - normal facies - mild MR/borderline normal cognitive function. - ADHD common - autistic features - most have short stature.

Answer 3

Key clinical feature is overgrowth of tissues and organs. Tissues with greater fraction of UPD11p15 show greater degree of overgrowth and give classic hemi-hyperplasia (big clinical indicator).

Answer 4

This region harbours 5 'breakpoints' which are involved in various deletion/duplications. - the 16p11.2 microdeletion between BP4-BP5 of ~600kb is one of the most frequent single locus causes of neurodevelopmental disorders and ASD. - clinical manifestations vary due to incomplete penetrance and variable expressivity but include the following: Developmental delay and language delay Mild I.D Social impairment Seizures Variable dysmorphism Predisposition to obesity - the reciprocal duplication of above is also ~600kb and again has very variable features and asymptomatic carriers. Common features include: Developmental delay, speech and language delay, learning difficulties etc Opposite to those with the deletion they can be thin and struggle to gain weight. BP2-BP3 of 16p11.2 harbours a distinct ~200kb microdeletion which includes the gene SH2B1. This gene has been reported in association with developmental delay and severe early onset obesity. There are many other dels/dups which involve this region including large rearrangements of up to 8Mb.

Answer 5

The 1q21.1 region contains extensive low copy repeats making it susceptible to rearrangement. There are 2 distinct regions: - the TAR region - the distal 1q21.1 region. There is a region at 1q21.1 of ~1.3Mb which can harbour a deletion or its reciprocal duplication. This occurs between BP3-BP4 and is referred to by 'Unique' as a Class-I del/dup. Class-I deletion at 1q21.1: Highly variable phenotype, mild to severe developmental delay, dysmorphic features, microcephaly. Asymptomatic and mildly affected parents have been noted. (Variable expressivity and reduced penetrance) Class-I microduplications at 1q21.1: Enriched in neurodevelopmental disorders Vs controls......? Predisposes to neuro and autism? Deletion occurs more commonly, dup may just be a susceptibility locus. Patients display features such as macrocephaly (opposite to deletion!), developmental delay and dysmorphic features. 1q21.1 region and TAR: Thrombocytopenia - Absent Radius. BP2-BP3 encase the TAR region - the minimal region is ~200kb. Characterised by reduction in number of platelets and by absence of the radius (in this Syndrome the thumb is preserved). In other similar syndromes the thumb is missing such as Fanconi . Class-II dels and dups: When the deletion or duplication is larger and encompasses both the distal BP3-BP4 region as described above and the BP2-BP3 TAR region it tends to be larger at ~2Mb. Unique refer to these as Class-II dels/dups. The Class-II deletion has a much broader phenotype.

Answer 6

Fetal haemoglobin is resistant to alkali denaturation, whereas adult haemoglobin is susceptible. Exposing the blood spot to sodium hydroxide will turn an adult blood sample a yellow/brown whereas a fetal blood sample will stay red/pink.

Answer 7

It is determined by the parent of origin. | Genomic imprinting.

Answer 8

75% is caused by a deletion of paternal chr 15 including SNRPN.

Answer 9

Loss of activity of a segment of chr15. | This occurs either by a physical loss of the region e.g. a deletion or by uniparental disomy.

Answer 10

25% caused by maternal UPD | 1% result of imprinting centre issue e.g. a functional defect or microdeletion of the imprinting centre

Answer 11

70% caused by a deletion of maternal chr 15q11-q13 (UBE3A gene).

Answer 12

10-15% UBE3A mutation (UBE3A shows biparental expression except in the brain where only the maternal copy is expressed) 2-4% imprinting centre issue such as point mutation or deletion of imprinting centre 1-5% paternal UPD of chr15 (much rarer as paternal meiotic errors are rarer)

Answer 13

- Low copy repeats present in the 15q11-q13 region mediate deletions by non-homologous recombination. - Deletion can be larger class 1 (5.9Mb) or smaller class 2 (5Mb) dependant on the breakpoint. - BP1 and BP3 produce class 1 deletions. - BP2 and BP3 produce class 2 deletions. - Behavioural phenotype is slightly worse with class 1. - Larger deletions can be seen and exhibit are more severe phenotype.

Answer 14

The imprinting centre. It controls expression of genes in this region, switching them on or off depending on parent of origin. (Imprinting is reset at each generation to reflect the sex of the donor parent.)

Answer 15

- Infantile hypotonia - insatiable appetite and hyperphagia (over eating) - overweight/obesity - mild to moderate mental retardation - behavioural difficulties e.g. Temper tantrums, stubbornness - skin picking - facial dysmorphism - hypogonadism - sleep abnormalities.

Answer 16

- AS primarily affects the nervous system - Severe mental retardation - Seizures - Sleep difficulties - Difficulty with balance and walking - Characteristic behaviour and movements e.g. laughing, smiling, hand flapping - Happy demeanour and excitable.

Answer 17

Low for UPD and typical de novo deletions, 50% for an imprinting centre defect 50% for an UBE3A mutation Unknown? Up to 50%

Answer 18

Risk factor! Often associated with developmental delay, ID, autism, epilepsy, psychiatric disorders etc. but are associated with being reduced penetrance and variable expression and seen in normal individuals.

Blood Module Flashcards

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