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Genetics Flashcards

1
Q

What is the significance of long contiguous stretches of homozygosity (LCOH)?

A

Likely parental consanguinity (8% LCOH indicates first cousins)

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2
Q

What condition is associated with heterochromic iridis (different coloured eyes)?

A

Waardenburg syndrome:

  • sensorineural hearing loss
  • heterochromia iridis
  • hair hypopigmentation (white)
  • telecanthus (lateral displacement of inner canthi)
  • first‐degree relative with Waardenburg syndrome
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3
Q

Hearing loss, thyroid problems, goitre, vestibular issues?

A

Pendred syndrome

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4
Q

Sturge Weber Syndrome features?

A

Facial capillary malformation (port-wine stain)
Leptomeningeal angioma (abnormal brain blood vessels)
Abnormal eye vessels - glaucoma
Patients present with seizures, hemiparesis, strokelike episodes, headaches and developmental delay
Not all PWS are associated with SWS

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5
Q

McCune-Albright Syndrome features?

A

Endocrine dysfunction (precocious puberty in females initially noted, pituitary, thyroid and adrenal abnormalities, ovarian cysts)
Patchy cutaneous pigmentation - coast of Maine
Fibrous dysplasia of the skeletal system

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6
Q

Retinitis pigmentosa with polydactyly, obesity, mental retardation

A

Bardet-Biedl syndrome

  • polydactyly, obesity, renal abnormalities, and mental retardation
  • micro-orchidism, polyuria and polydipsia
  • autosomal recessive disorder
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7
Q

Gene associated with Hirschprungs

A

RET gene

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8
Q

CHARGE syndrome features and gene

A

CHARGE = Coloboma, Heart defects, choanal Atresia, Retarded growth, GU defects, Ear anomalies – caused by mutations of CHD7 on chromosome 8q12

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9
Q

Renal-coloboma syndrome feaures and gene

A

Renal-coloboma syndrome is associated with mutations in the PAX2 gene. It is an autosomal disorder associated with coloboma, renal abnormalities, SNHL, seizures and joint laxity.

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10
Q

Gene for Beckwith-Wiedemann Syndrome?

A
  • 11p15.5, leads to overactivity of IGF-2, lack of maternal copy (paternally imprinted)
  • Associated with IVF conception
  • Loss of methylation (50%), paternal UPD (20%), gain of methylation (5%), CDKN1C mutations (5-10%)
  • 85% sporadic, 15% inherited
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11
Q

Features of Beckwith-Wiedemann?

A
  • Macrosomia, macroglossia, abdominal wall defect in 50% (omphalocele)
  • Anterior ear lobe creases or posterior helix pits, facial naevus flammmeus, hypoglycaemia (due to hyperinsulinism), organomegaly, hemihypertrophy.
  • Increased risk malignancy (5%): Wilm’s tumour, adrenocortical carcinoma, hepatoblastoma, neuroblastoma
  • Abdo USS every 3m until age 8
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12
Q

What are the diagnostic criteria for NF1?

A

2 or more of:

  • Six or more café-au-lait spots or hyperpigmented macules >5mm in diameter in pre-pubertal children and 15mm post-pubertal
  • Axillary or inguinal freckles (>2 freckles)
  • Two or more typical neurofibromas or one plexiform neurofibroma (benign tumour of peripheral nerves)
  • Optic nerve glioma
  • Two or more iris hamartomas (Lisch nodules)
  • Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis
  • First-degree relative with NF1
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13
Q

What genetic test would you use to look for SMA?

A

Multiplex ligand-dependent probe amplification (MLPA)

  • SMA caused by homozygous deletions of exon 7 in the SMN1 gene
  • Test is for deletion/duplication analysis of SMN1 (done via MLPA)
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14
Q

Describe Smith-Lemli-Opitz syndrome

A
  • AR, inborn error of cholesterol synthesis
  • Varied phenotype mild-severe
  • Syndactyly 2+3rd toes most common finding, polydactyly, microcephaly, ptosis, epicanthic folds, capillary haemangioma nose, low set ears, cleft lip/palate, CHD, hypoplasia corpus callosum
  • Growth failure, intellectual disability, behavioural problems, autistic features
  • Mutations of 7-DHC reductase (DHCR7) result in decreased cholesterol and increased dehydrocholesterol levels
  • Elevated 7DHC in blood
  • Require dietary cholesterol supplementation
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15
Q

Infants with Prader-Willi exhibit which features?

A
  • Hypotonia, poor suck and feeding, weak cry, genital hypoplasia (eg, cryptorchidism, scrotal hypoplasia, clitoral hypoplasia)
  • Facial features include narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, and down-turned mouth.
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16
Q

Mutation of the CHD7 gene

A

CHARGE syndrome. Mutation of CHD7 on Ch 8q12

  • Coloboma
  • Heart defects
  • Choanal Atresia
  • Retarded growth
  • GU defects
  • Ear anomalies
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17
Q

An infant with joint laxity, ocular abnormality and renal hypoplasia is found to have mutations in the PAX2 gene

A
  • Renal-coloboma syndrome
  • Mutations in the PAX2 gene
  • AD
  • Associated with coloboma, renal abnormalities, SNHL, seizures and joint laxity
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18
Q

Trichorrhexis invaginata of hair is also known as “bamboo hair” and is pathognomonic of?

A
  • Netherton syndrome
  • Severe disorder of cornification caused by (SPINK5) mutations
  • Seizures and development delay due to genetic disorder leading to severe copper deficiency
  • Eczema, recurrent infections, raised IgE
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19
Q

What is the gene for tuberous sclerosis?

A

TBSC1 or TBSC2 mutation

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20
Q

Describe Loeys-Dietz syndrome

A

Similar to Marfans but get hypertelorism, bifid uvula, aortic root aneurysm, cleft palate

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21
Q

Describe Noonan’s syndrome

A
  • Short stature, webbed neck, ptosis
  • Fetal hydrops, pulmonary stenosis, HOCM, superior axis
  • Hypertelorism, posteriorly rotated ears, redundant nuchal skin, chest wall deformity, cryptorchidism
  • Juvenile myelomonocytic leukaemia, risk bleeding disorders (check coags), Wilms, NHL
  • Mild ID
  • PTPN11 mutation most common (RASMAPK pathway) but many other genes, AD. Test via Noonan gene panel or clinical exome
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22
Q

Describe Cockayne Syndrome

A
  • Photosensitivity, growth failure, premature aging

- AR, associated with leukodystrophy

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23
Q

Thymic and parathyroid abnormalities in 22q11 deletion are due to defective development of which embryological structure?

A

Pharyngeal pouches

Failure of development of 3rd and 4th branchial arches

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24
Q

What base is different on mRNA than DNA?

A

T is replaced with U (uracil) on mRNA

Also has ribose instead of deoxyribose

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25
Q

Exons vs introns

A

Exons code for protein

Introns don’t code for protein

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26
Q

Describe the process of transcription

A
  • Replication of a segment of DNA that forms a gene into mRNA (protein blueprint)
  • RNA polymerase binds to the promoter region and assembles mRNA
  • Copy of the DNA is made, except for T bases are replaced with U bases, and introns are cut out
  • The mRNA then goes to the ribosome in the cytoplasm to make a new protein
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27
Q

What are the processes called by which genes becomes proteins?

A
  • Transcription = DNA -> mRNA

- Translation = mRNA -> protein

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28
Q

Describe the process of translation

A
  • Ribosomes assemble proteins from amino acids
  • transfer RNA brings amino acids to the ribosome and has an anticodon that complements mRNA
  • As ribosome moves down the mRNA, it leaves a polypeptide tail which is the growing protein
  • Ribosome takes fresh protein to endoplasmic reticulum
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29
Q

What are the start and stop codons?

A 
AUG = start
UGA = stop
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30
Q

What are the roles of codons?

A

Provide start or stop codons, or code for a particular amino acid

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31
Q

What happens in the S phase of the cell cycle?

A

DNA replication, 46 chromosomes are duplicated

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32
Q

Describe the DNA base pair bonds

A

A to T, 2 hydrogen bonds

C to G, 3 hydrogen bonds

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33
Q

What is the role of DNA helicase?

A

Unwinds the DNA into single strands, ready for replication

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34
Q

What is the role of DNA polymerase?

A
  • In DNA replication
  • Binds to area of single stranded DNA that has an RNA patch on it, then goes on to synthesise second strand of DNA by adding complementary nucleotides to the template strand of DNA
  • Moves from 3’ to 5’
  • Leading strand and lagging strand
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35
Q

What are some examples of trinucleotide repeat disorders?

A
  • Fragile X (X-linked dominant)
  • Huntington’s disease (AD)
  • Myotonic dystrophy (AD)
  • Friedreich’s ataxia (AR)
  • Juvenile myoclonic epilepsy
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36
Q

Describe what interphase is

A
  • Longest part of the cell cycle where the cell prepares to divide
  • G1 phase: growth 1 phase, longest phase, cell grows, organelles synthesise proteins
  • G1 checkpoint for DNA damage and to ensure correct proteins synthesised. If errors then enter G0 (cell repair) or apoptosis
  • S phase: synthesis phase where DNA replicates (still have 46 Ch).
  • G2 phase: growth 2 phase, duplication of organelles
  • G2 checkpoint: if no damage found, then cell enters mitosis
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37
Q

What is the role of G0 in the cell cycle?

A
  • DNA repair or non-dividing phase, outside cell cycle
  • e.g. hepatocytes rest in G0 until there is liver damage, at which point they enter G1 again
  • e.g. neurons, spend entire life in G0
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38
Q

Describe the processes of mitosis

A
  • When one cell divides into two daughter cells “please make another two cells”
  • Prophase: chromatids condense into chromosomes, nucleolus disappears
  • Metaphase: nuclear membrane disintegrate, chromosomes line up along middle of cell, spindle fibres from centrosomes attach to centromere of each chromosome
  • Anaphase: centrosomes pull on spindle fibres to pull sister chromatids apart
  • Telophase: nuclear membrane reforms around each set of chromatids
  • Cytokinesis: cell membrane pinches in until 2 daughter cells separate
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39
Q

What is the difference between a chromatid and a chromosome?

A
  • Chromosome is made up of 2 chromatids joined by a centromere i.e. double the DNA
  • The 2 chromatids are exact copies of each other
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40
Q

Describe the process of meiosis 1

A
  • Formation of 4 haploid gametes from 1 diploid cell
  • Meiosis 1 + 2, each made up of prophase, metaphase, anaphase, telophase
  • Prophase 1 makes up 90% of meiosis: membrane disintegrates, tetrads form between homologue chromosomes and crossover events occur (so maternal and paternal DNA mixed), chromosomes start to pull away but still connected at chiasmata/crossover region
  • Metaphase 1: tetrads line up along metaphase plate
  • Anaphase 1: tetrads pulled to opposite sides of cell
  • Telophase 1: nuclear membrane reforms, cell pinches, 2 haploid daughter cells formed
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41
Q

Describe meiosis 2

A
  • At the end of meiosis 1, cell enters interphase. However, no duplication of chromosomes at S phase
  • Prophase 2, metaphase 2, anaphase 2, telophase 2 occur in the same way
  • Resulting 2 cells contain 23 chromatids, rather than 23 chromosomes
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42
Q

What is the purpose of PCR?

A

To double the amount of DNA in each cycle, so there is more DNA available to analyse

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43
Q

What is the purpose of gel electrophoresis?

A
  • Allows us to look for DNA mutations and DNA repeats
  • Smaller pieces of DNA can move across gel faster, allowing separation of segments along the gel
  • Uses markers to follow alleles through crossover events in meiosis (SNPs and STRPs)
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44
Q

What is the inheritance of vWD?

A

Autosomal dominant

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45
Q

What is the significance of long continuous stretches of homozygosity (LCOH)?

A
  • As an SNP array compares the polymorphisms found in individual patients, it can detect contiguous LCOH (long stretches where the same SNP is found on both alleles)
  • They are not in themselves disease-causing, but may be significant if an AR condition is suspected
  • > 8% LCOH is suggestive of parents who are first cousins
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46
Q

Describe the genetics of Prader-Willi

A
  • Maternally imprinted
  • Prader-Willi syndrome is caused by loss/abnormal methylation of the paternal allele of chromosome 15q11.2q13.
  • Paternal deletion 65-75%, maternal UPD 20-30%, imprinting defever 5%, gene mutation 0.1% and balanced translocation 0.1%.
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47
Q

What is the gene mutation associated with Noonan’s syndrome?

A
  • There are currently over 14 genes that have been associated with Noonan syndrome and conditions on the Ras-Mpk pathway
  • PTPN11 is the most commonly associated gene, but only accounts for approximately 50% of cases
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48
Q

What are the features of CHARGE syndrome?

A
  • Coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies
  • 15-20% also have tracheoesophageal fistula
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49
Q

What are the features of VACTERL association?

A
  • Vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities
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50
Q

What is a missense mutation?

A
  • Altered codon produces amino acid substitution (single base pair substitution might not change AA)
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51
Q

What is a nonsense mutation?

A
  • Altered codon becomes a stop codon and produces a truncated protein (mRNA terminates at that point)
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52
Q

Describe the genetics of Prader-Willi and Angelman syndrome

A
  • Prader-Willi = absent paternal expression = microdeletion of paternally derived gene or maternal uniparental disomy
  • Angelman = absent maternal expression = microdeletion of maternally derived gene or paternal uniparental disomy
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53
Q

What is the genetic mutation found in William’s syndrome/

A

Microdeletion on 7q11.23

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54
Q

Describe Simpson-Golabi-Behmel syndrome

A
  • X-linked
  • Overgrowth, organomegaly
  • Coarse facial appearance, hypertelorism, large mouth and tongue
  • Congenital heart disease
  • Polydactyly
  • Wilms tumour (7.5%)
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55
Q

What is Sotos syndrome?

A
  • Overgrowth syndrome, associate cognitive abnormalities
  • Known as cerebral gigantism
  • 2-3% risk of WIlms tumour
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56
Q

What is Perlman syndrome?

A
  • Overgrowth syndrome
  • Fetal gigantism, visceromegaly, unusual facies
  • Renal issues including WIlms
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57
Q

What does a southern blot look for?

A

Amplified DNA

RNA is northern plot, protein is Western plot

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58
Q

What is a strong indicator for AD inheritance?

A

Male to male transmission

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59
Q

What is the FMR1 gene related to?

A

Fragile-X

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60
Q

Mutations in the FBN1 gene cause?

A

Marfans

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61
Q

DMD vs BMD genetics

A
  • DMD caused by deletion or mutation

- BMD caused by in-frame mutation which leads to a short protein with some preservation of function

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62
Q

If a disease is only inherited from females then it suggests?

A
  • Mitochondrial disorder

- Autosomal dominant with paternal imprinting

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63
Q

How do you work out the carrier frequency of an autosomal recessive condition?

A

Divide the frequency by 4, then take the square root.

E.g. if frequency is 1 in 1,000,000. Then carrier frequency = 500

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64
Q

Does non-coding RNA influence gene expression?

A

Yes

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65
Q

Bilateral cataracts can be found in?

A

NF 2, often present earlier than schwannomas

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66
Q

Discuss the repeat sizes found in Fragile X

A

< 50 - normal
55-200 - carrier/pre-mutation
>200 - Fragile X (ID in males, females variably affected)

Pre-mutations:

  • Premature ovarian failure, shy personality (females)
  • Cerebellar tremor/ataxia syndrome (males>females)
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67
Q

Undescended testes and short stature can be seen in?

A

Noonan’s syndrome

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68
Q

How many genes do humans have?

A

22,000 genes, separated by non-coding DNA

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69
Q

How many genes are in the mitochondrial genome?

A

37 genes, no introns, 93% of mitochondrial genome is coding DNA (c.f. nuclear = ~2%)

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70
Q

Microcephaly, seizures, spontaneous laughter, ataxic gait

A

Angelman’s syndrome

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71
Q

Superior vs inferior lens dislocation

A
  • Superior = Marfan’s

- Inferior = homocystinuria

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72
Q

What does an SNP microarray detect?

A

Microduplications and deletions

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73
Q

What is the risk of consanguineous first cousins have a child born with a major congenital problem?

A

6% (normal population = 3%) (note incest = 50%)

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74
Q

What are the keys of X-linked recessive karyotypes?

A
  • Fathers can’t pass on to sons, all daughters are carriers

- Mothers pass on to 50% sons (affected), 50% daughters (carriers)

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75
Q

What are the keys of X-linked dominant karyotypes?

A
  • Fathers can’t pass on to sons, all daughter are affected

- Mothers pass on to 50% sons and 50% daughters (affected)

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76
Q

Most common cause of sensorineural hearing loss?

A

Homozygous Connexin 26 mutation

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77
Q

What is chromatin?

A

Double-stranded DNA macromolecule wrapped around histone proteins

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78
Q

What is the exome?

A

Protein-coding genes, only make up 1-2% of genome. Rest is non-coding DNA

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79
Q

What does chromosome non-disjunction lead to?

A

Aneuploidy

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80
Q

When the lagging strand of DNA is being replicated, what molecule helps to seal the gaps?

A

Ligase

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81
Q

How many codon combinations are there?

A

64 combinations = 61 specify 20 amino acids + 3 specify stop signals

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82
Q

What is the outcome of deletions and insertions?

A
  • Alter the reading frame, leading to a completely different set of amino acids
  • Can result in a premature stop codon
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83
Q

What is haploinsufficiency?

A
  • Reduction by about half in amount of protein
  • Usually due to a whole gene deletion
  • Can occur secondary to a frameshift mutation or nonsense mutation
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84
Q

What does polymorphism describe?

A

Where there are at least two, or more, relatively common alleles of a gene in the population (>1%) e.g. different alleles in ABO blood groups. These are not mutations, just variations

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85
Q

What are allelic conditions?

A

Different mutations in the same gene causing different conditions

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86
Q

What is genetic heterogeneity?

A

Mutations in different genes can cause the same condition e.g hearing loss, ID, epilepsy

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87
Q

What is a Robertsonian translocation?

A

Translocation between two acrocentric chromosomes (short-arm chromosomes) = 13, 14, 15, 21, 22

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88
Q

Discuss Klinefelter syndrome

A
  • 47, XXY, nondisjunction during mitotic division
  • Testing: karyotype, microarray, FISH
  • Most common cause of primary male hypogonadism
  • Low testosterone - hypogonadotropic hypogonadism
  • Infertility, incomplete virilisation, small testes, gynaecomastia
  • Euchnoid body habitus, tall stature, truncal obesity
  • Mild learning difficulties, emotionally immature, shy
  • Increased rates ASD, depression, anxiety
  • Inc rates diabetes, hypothyroidism, osteoporosis, breast cancer, mediastinal germ cell tumour
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89
Q

What genetic test do you use to look for copy number variants?

A
  • Molecular karyotype = microarray
  • Look for microduplications or deletions
  • Below the resolution of a conventional karyotype
  • Increasing number of human diseases recognised to be due to copy number variants in non-coding DNA
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90
Q

Incomplete penetrance

A

Still have the genotype, but don’t express the phenotype. Black and white.

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91
Q

Variable expressivity

A

Still have the genotype and the phenotype, but have varied spectrum of disease e.g. NF1, may just have some cafe au lait, or may have all the features. Shades of grey.

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92
Q

What is the chance that the sibling of an individual affected by an early-onset autosomal recessive condition is a carrier?

A

2/3rds/ 66%

93
Q

What are some examples of X-linked dominant disorders?

A
  • X-linked hypophosphatemic rickets (Vit-D resistant rickets), incontinentia pigmenti, Rett syndrome, most cases of Alport syndrome, Fragile X
  • X-linked dominant disorders are often lethal in males (survivors are mosaic)
94
Q

Discuss triplet repeats

A
  • Increased instability with larger repeat sizes
  • Milder symptoms may be noted in those with intermediate range expansions
  • Gender of transmitting parents may affect stability .e.g myotonic dystrophy, HD, Fragile-X maternal copy more likely to be unstable, Huntington’s paternal copy
  • Anticipation: phenotype worsens in subsequent generations
  • e.g. Fragile X, myotonic dystrophy, HD, spinocerebellar ataxia
95
Q

What is epigenetics and what is it affected by?

A
  • “above the gene”
  • Alterations in the way a gene is expressed
  • Gene regulation is affected by: DNA methylation, histone modification/conformation of chromatin (how open/closed chromatin is), non-coding RNA
96
Q

Prader-Willi vs. Angelman syndrome

A
  • Prader-Willi - loss of paternal allele (paternal deletion 70% or maternal UPD 25% or imprinting defect <1%)
  • Angelman - loss of maternal allele (maternal deletion 70%, or paternal UPD 5%, UBE3A mutation 5-10%, imprinting defects 3%, unknown 10-20%)
97
Q

How does uniparental disomy occur?

A
  • Arises from non-disjunction

- Either fertilisation with a nullisomic gamete, or trisomic rescue (kick out wrong copy)

98
Q

Discuss karyotype testing

A
  • Visually analyses whole chromosomes
  • Detects aneuploidy, large chromosomal imbalances, balanced and unbalanced translocations
  • Cells arrested in metaphase (chromosomes maximally condensed and visible)
  • Google maps: looking at world from outer space
  • Takes up to 10 days
  • Cannot detect: microdeletions/duplications, DNA sequence changes
99
Q

Discuss FISH testing

A
  • Fluorescent labelled DNA probes for specific target
  • Need to know what you are looking for
  • Detect presence/absence of specific DNA sequences on chromosomes
  • E.g. 22q11, Williams, trisomies/monosomies
  • Replaced by chromosomal microarray but still used for localisation and looking for balanced rearrangements, and rapid testing (24-48hrs)
  • Google maps: satellite image highlighting specific cities
100
Q

Discuss CGH microarray testing

A
  • Test of dosage - too much or too little
  • Test DNA (red) compared to control DNA (green). More green = deletion, more red = duplication
  • Can detect: microdeletions/duplications, monosomies and trisomies e.g. T21, 22q11, Williams
  • Cannot detect: balanced chromosomal changes/rearrangements
  • Google maps: world is a jigsaw puzzle, looking for missing/duplicated bits
101
Q

Discuss SNP microarray

A
  • Can detect variation in a single nucleotide at a specific locus (copy number variation) and allelic imbalance (are 2 copies of allele the same or different e.g. UPD)
  • Genome-wide test of chromosomal dosage, or SNP at specific locus
  • Can go to submicroscopic level
  • Cannot detect: balanced rearrangements, triple repeats, sequence changes, methylation changes, whole/partial gene deletions
  • Good for T21, 22qq11, UPD
  • Google maps: individual houses on both sides of the street, microarray = every street on the map
102
Q

What can an SNP microarray detect that a CGH microarray cannot?

A
  • Chimerism
  • UPD (as can detect allelic imbalance)
  • Long continuous stretches of homozygosity
  • Mosaicism to approx 7%
103
Q

What can CGH and SNP microarray detect?

A
  • Microdeletions and microduplications
  • Trisomy
  • Some single gene disorders
  • CGH mosaicism to approx 15%
104
Q

What can SNP microarray not detect?

A
  • Balanced rearrangements (as looks for copy number variation)
  • Methylation changes
  • Sequence changes
  • Triplet repeat expansion disorders
105
Q

What are the negatives of a microarray?

A
  • Copy number variances of unknown significance
  • LCSH - not related to reason you did test, risk of unmasking recessive disease
  • Unable to detected balanced rearrangements
  • Incidental findings e.g. BRACA1 gene in a child
106
Q

Discuss Sanger sequencing

A
  • Used to determine the exact sequence of bases “spelling of DNA”
  • e.g, sequencing the Marfan gene (FBN1) or NF1 gene (NF1), Noonans gene (PTPN11)
  • Can detect single gene mutations
  • Need to know what you are looking for
  • Cannot detect exonic deletions or duplications
  • Struggles with larger than 100 triple repeats (which is usually a pre-mutation size)
  • Google maps: down the street we are labelling houses 4 diff colours (A, T, C, G)
107
Q

What is linkage analysis?

A
  • Indirect method of looking at genes
  • Genes that are close together are inherited together, therefore looking at markers around a gene of interest
  • e.g. if you know the parent have a genetic mutation and want to find out if offspring have it but direct mutation analysis not possible
  • Google maps: if you see a McDonalds, you know there will be a Burger King close by
108
Q

Discuss triplet repeat studies

A
  • PCR to look at number of triplet repeats
  • PCR can only detect up to certain number of repeats, then need Southern Blot (which can size the full range of expansion)
  • Southern blot: large pieces move slowly through the gel, small pieces move quickly
  • Southern blot: DNA, Western blot: protein (e.g. dystrophin in DMD/BMD)
109
Q

Discuss MLPA (multiplex ligand-dependent probe amplification) studies

A
  • Tests for deletions and duplications below the resolution of a microarray
  • Separates each amplification product by its unique length, therefore know if any are missing or duplicated
  • Similar to FISH but looking at a much smaller level
  • Looks for microdeletion/microduplication in a specific gene (c.f. microarray is in the whole genome)
  • e.g. DMD, SMA (SMN1 gene)
  • Cannot detect sequence changes, or large copy number changes
  • Need to know exactly which gene to look at
  • Google maps: in each town on the map the streets have different lengths
110
Q

Discuss Methylation Sensitive-MLPA

A
  • Used for imprinting disorders
  • Prader Willi, Angelman, Beckwith Wiedemann, Russell Silver
  • MLPA probes only identify methylated targets, then looks at whether pattern is normal or abnormal
  • Google map: there is an ASB ATM located on only some streets
111
Q

What is Next Generation Sequencing?

A
  • DNA sequencing of a whole genome/exome
  • Analyse multiple genes simultaneously
  • Used for genetically heterogeneous conditions
  • Cannot detect triplet repeats or methylation defects
  • Need to give lab lots of information so they know what you are looking for
  • High diagnostic yield, fast and accurate, allows re-analysis, good for ultra-rare diagnoses, but get unexpected diagnoses
112
Q

Discuss targeted gene panels

A
  • Looks for mutations (spelling changes) within a set number of genes at once
  • Good for genetically heterogeneous conditions e.g. arrhythmias, cardiomyopathy, Noonan’s
  • Only good for single-system diseases
  • Serial panel testing is not cost effective - do exome sequencing instead
  • Cannot detect: copy number changes, methylation abnormalities, changes in genes not included in panel
113
Q

Which disorder is due to mutations in one of the fibroblast growth factor receptor (FGFR) genes?

A

FGFR3 mutations = achondroplasia group = thanatophoric dysplasia, achondroplasia, hypochondroplasia

114
Q

What does hemizygous mean?

A

Mutation on the X-chromosome in a male (or a female with Turner’s)

115
Q

What are examples of AD diseases?

A

Marfans, osteogenesis imperfecta, Noonans, vWD, NF1, tuberous sclerosis, myotonic dystrophy, Huntingtons, ADPKD, hereditary spherocytosis, familial hypercholesterolaemia

116
Q

What are the exceptions in AD diseases?

A
  • De novo mutations
  • Incomplete penetrance
  • Variable expressivity
  • Gonadal mosaicism
117
Q

Discuss mosaicism

A
  • More than one genotype in different cells
  • Can be a point mutation or chromosomal abnormality
  • Constitutional (somatic) vs germline (gonadal)
118
Q

De novo mutations are common in… and rare in…

A
  • Common: AD and X-linked
  • Rare: AR
  • The more severe the disorder, the more common de novo mutation is (severe disorders are less likely to procereate - low/zero fecundity)
119
Q

Examples of AR disorders

A

Deafness (some), albinism, Wilson disease, sickle cell, thalassaemia, CF, Friedreich ataxia, haemochromatosis, PKU, a1aT deficiency, homocystinuria

120
Q

What is the Hardy Weinberg principle?

A
  • The allele and genotype frequencies in the population will remain constant in the absence of other evolutionary influences (mate choice, new mutations, selection etc)
  • p2 + 2pq + q2 = 1
121
Q

What percentage of genes are shared with your relative?

A

100% identical twin
50% parents/sibling
25% 2nd degree relative = uncle/aunt/niece/grandparent
12.5% 3rd degree relative = cousin
Number of unbroken lines = degree of relative

122
Q

What is pseudo-dominant inheritance

A

Recessive conditions in more than one generation by bad luck. Pedigree looks dominant but is in fact recessive

123
Q

What are examples of X-linked disorders?

A

Fragile X, haemophilia, G6PD, ocular albinism, testicular feminisation, CGD, Rett syndrome (X-linked dom, males die at birth), colour blindness, DMD, hypophosphatemic rickets

124
Q

Describe the features of Prader-Willi

A
  • Loss of paternal genes 15q12

- Floppy baby (hypotonia), large appetite (hyperphagia), obesity, short stature, moderate ID, hypogonadism

125
Q

Describe the features of Angelman

A
  • Loss of maternal genes (UBE3A) 15q11-13
  • Severe intellectual disability, lack speech, spontaneous laughter, happy puppets with hand flapping, love water, poor sleep, ataxia
  • Unsteady gait, epilepsy
  • Microcephaly, large mouth and chin
  • Monitor for obesity
126
Q

Describe Beckwith Wiedemann syndrome

A
  • Loss of maternal genes 11p15
  • Overgrowth disorder
  • Macrosomia, neonatal hypoglycaemia
  • Hemihypertrophy
  • Macroglossia, visceromegaly
  • Inc risk Wilms, hepatoblastoma
127
Q

Describe Russell Silver syndrome

A
  • Loss of paternal genes 11p15 (or Chr 7) - methylation defect in 60%, maternal UPD7 10%, rest unknown
  • Short stature, IUGR, macrocephaly, asymmetry, cafe au lait, clinodactyly
  • Triangular face
  • Test: methylation studies, if normal then UPD7 studies (can do SNP) and DNA from parents
  • Usually normal IQ, can use growth hormone, risk fasting hypoglycaemia in infancy
128
Q

Where is the IGF-2 gene located?

A

11p15
Excess expression = BWS (loss of maternal allele)
Lack of expression = RSS (loss of paternal allele)

129
Q

Discuss imprinting pedigrees

A
  • Maternal imprinting - no affected children from females (mothers with mutation silence it when passed on). All affected persons inherit mutated gene from father
  • Paternal imprinting - no affected children from males (fathers with mutation silence it when passed on). All affected persons inherit mutated gene from their mother.
  • If pedigree shows affected offspring from both males and females then can’t be imprinted
130
Q

What is heteroplasmy?

A
  • Some mitochondria have the mutation and others don’t, and not all mitochondria are replicated to daughter cells during oogenesis
  • Therefore not all children of a mother with mitochondrial disorder will be affected, and mother can be asymptomatic but have profoundly affected child
131
Q

Describe linkage disequilibrium

A

The closer together two genes or genetic markers, the higher the linkage disequilibrium i.e. the tendency for alleles of genes to be inherited together in a non-random fashion

132
Q

Discuss chorion villous sampling

A
  • 11-15 weeks
  • Needle into placenta
  • 1:500 miscarriage risk
133
Q

Discuss amniocentesis

A
  • 15-20 weeks
  • Needle into uterus
  • 1:1000 miscarriage risk
134
Q

What mutations are seen in HD, Fragile-X and myotonic dystrophy?

A
  • Huntington CAG
  • Fragile-X CGG
  • Myotonic dystrophy CTG
135
Q

Describe the genetics of NF1

A
  • AD
  • 30-50% are new mutations
  • Mutation in NF1 gene (tumour suppressor gene, codes for neurofibromin)
  • Virtually 100% penetrant by 5 years
  • Large gene, many possible mutations, therefore diagnosis is clinical
136
Q

Lisch nodules vs Brushfield spots

A
  • Lisch - brown, NF1

- Brushfield - grey-brown, T21

137
Q

What are other complications of NF1?

A
  • Unidentified bright objects on T2 MRI - inc in size until age 10 then often disappear, benign
    Optic glioma - 15%, only 5% symptomatic ; majority present <7 (most <2)
  • Seizures 5%
  • Learning difficult approx 50%, ID approx 5%
  • CNS tumours - optic nerve glioma + meningiomas, astrocytomas (5 x more common than average)
  • Malignant peripheral nerve sheath tumours - neurofibrosarcoma, highly malignant
  • Spinal neurofibromas - in spinal canal, can be extensive and cause pain
  • Scoliosis 5%
  • Short stature 10-15%
  • Macrocephaly
  • Hypertension 6% (essential HTN, renal artery stenosis, pheochromocytoma)
  • Leukaemia
  • Glaucoma
  • Moyamoya
  • Mortality - mean M 54y, F 59y
138
Q

Follow up in NF1?

A
  • Children - yearly follow up
  • Learning evaluation, psychometric testing occ.
  • Neuro assessment
  • BP
  • Scoliosis, growth
  • Yearly ophthalmology until age 8 (optic glioma more common when younger)

Asses neurofibromas; if concern over MPNST consider PET and tumour resection +/- MEK inhib

139
Q

Discuss the genetics of NF2

A
  • AD, up to 50% are new mutations (lower fecundity)
  • Mutation in NF2 gene
  • Tumour suppressor gene that codes for merlin (links membrane proteins/cell cytoskeleton)
  • Nonsense/frameshift leads to severe disease
  • Missense often milder
140
Q

What are the diagnostic criteria for NF2?

A

One of:

  • Bilateral vestibular schwannoma - almost all will have by 30 years
  • 1st degree relative with NF2 AND unilateral VS or any two of meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
  • Multiple meningiomas AND unilateral VS and any two of schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
141
Q

Other features of NF2?

A
  • Eye lesions - cataracts 60-80%, retinal hamartomas
  • Multiple CNS tumours
  • Unilateral hearing loss 35%
  • Focal weakness 12%
  • Tinnitus, bilateral hearing loss 10%
  • Balance dysfunction
  • Seizures 8%
  • Diagnosis due to family history
  • Focal sensory deficit
  • Visual loss
142
Q

Prognosis/management of NF2?

A
  • Nastier than NF1
  • Death ~36y (15y from onset first symptoms)
  • Annual MRI scans and early surgical treatment of VS to preserve hearing
  • Monitor vision and treat cataracts
  • New med: avastin (bevacizuman) shrinks VS
143
Q

Genetics of tuberous sclerosis

A
  • AD, 2/3rds have new mutations
  • TSC1 - hamartin (9q34) - 20%
  • TSC2 - tuberin (16p13.3) - 50%
  • Highly variable expression, broad phenotypic changes
  • Assess parents: skin exam, MRI brain, RUSS, opthal
144
Q

Diagnosis of tuberous sclerosis?

A
  • Pathogenic mutation in TSC1 or TSC2 genes
  • Clinical: 2 major or 1 major + 2 minor = definite, 1 major + 1 minor = probable, 1 major or 2 minor = possible
  • Major:
  • Skin: facial angiomas/adenoma sabaceum or forehead plaque, periungal fibroma, >3 ash-leaf (Woods lamp), shagreen patch, retinal nodular hamartomas
  • Brain: cortical tubers, subependymal nodules, SEGA
  • Other: renal angiomyolipoma (often bilateral, 80%), cardiac rhabdomyoma (benign, regress spont), lymphangioleiomyomatosis
  • Minor:
  • Skin: confetti skin lesions, dental enamel pits, gingival fibromas, retinal achromic patch
  • Brain: cerebral white matter migration lines
  • Other: non-renal hamartomas, bone cysts, hamartomatous rectal polyps, multiple renal cysts
145
Q

What are the complications of tuberous sclerosis?

A
  • 85% have CNS complications
  • Seizures 75% including infantile spasms, myoclonic, partial, GTCS
  • Intellectual disability 50%, 30% profound
  • Behaviour - ADHD, autistic-like, sleep issues
  • CNS changes and tumours - tubers, cortical dysplasia, subependymal glial nodules,
    SEGA (highest risk adolescence ; 10-25% TS ; need MRI surveillance every 1-3 yrs until 25)
  • Renal - Angiomyolipomas >2 ; multiple renal cysts, risk renal cell ca
  • Opthal: mulberry lesions, retinal hamartoma
  • Resp (LAM): dilated lymphatics, cystic lung disease, pneumothorax
146
Q

Treatment in tuberous sclerosis?

Follow up

A
  • mTOR inhibitors (mTOR pathway activated by mutations in TSC1 and 2)
  • Sirolimus- des angiomyolipomas, improved PFTs
  • Everolimus - decr size SEGA, decr seizure frequency
  • Topical rapamycin - facial angiofibromas

Follow up

  • SEGA monitoring, MRI every 1-3yrs if asymptomatic
  • Screen for neuropsych disorders
  • MRI abdomen every 1-3 yrs for angiomyolipomas/cysts - embolisation if haemorrhage, avoid nephrectomy, consider MTOR inhib if >3cmyrs
  • Skin examine annually
  • Teeth - every 6/12 dental check
  • Heart - echo every 1-3yrs, ECG every 3-5yrs
  • Eyes - Annual exam, periodic exam if on vigabatrin
  • Screen for LAM (lung) with lung function/6min walk test >18yrs and HRCT every 5-10
147
Q

Discuss Friedreich Ataxia

A
  • AR hereditary ataxia
  • GAA repeat expansion in intron 1 of FXN, affected if >56 reepats
  • Onset 10-15 years, death 37 years
  • Progressive neurological dysfunction: cerebellum and dorsal root ganglia
  • Gait and limb ataxia
  • Absent LL reflexes but upgoing plantars
  • Posterior column dysfunction (vibration/proprioception_
  • HCOM, diabetes mellitus
148
Q

Features of Fragile-X

A
  • Often asymptomatic until puberty
  • Intellectual disability
  • Elongated face, large protruding ears, high arched palate, double-jointed thumbs
  • Large testes, flat feet, low muscle tone
  • Flapping hand movements, shyness, poor eye contact, may meet criteria for ASD
  • ADHD
  • Seizures up to 20%
  • Strabismus, refractory errors 30%
  • Mitral valve prolapse, aortic root dilation
149
Q

Discuss Huntington’s Disease

A
  • Inherited progressive neurodegenerative disorder
  • Chorea, dementia, psychiatric symptoms
  • Onset until death 18yrs
  • Usual onset age 40, can present in childhood <20 years with dystonia
  • Due to CAG repeat in HTT Huntington gene exon 1
  • AD with anticipation, fully penetrant if >40 repeats
150
Q

Describe the genetics of DMD/BMD

A
  • X-linked, 1:4000 (1:30,000 BMD)
  • Due to mutation in dystrophin gene which codes for dystrophin protein
  • 60% deletion, 8% duplications, others point mutations
  • DMD: disrupts the reading frame and therefore no functioning protein
  • BMD: “in frame” mutation, resulting in a shortened and semi-functional protein/milder phenotype
  • High gonadal mosaicism rate, therefore always need prenatal genetic counselling
151
Q

What are the clinical features of DMD?

A
  • Proximal muscle weakness, onset ~age 3
  • Delayed motor milestones
  • Broad, waddling gait, falls
  • Gower sign, trouble with stairs
  • Calf pseudohypertrophy (muscle replaced with fat and connective tissue)
  • Wheelchair age 12, loss of UL muscles age 16, death 20y
  • Mild IQ impairment
  • Cardiomyopathy
152
Q

Investigations and management of DMD

A
  • CK, genetic testing, muscle biopsy with stain for dystrophin
  • Management: maintain mobility, prevent contractures, steroids, genetic counselling (confirm if mother is a carrier), palliation
  • Emerging drug therapies: skip gene, make dystrophin
153
Q

Discuss the genetics + screening of Down syndrome

A
  • Trisomy 21
  • 95% nondisjunction trisomy - 1% recurrence risk, higher if Mother >40yo. Maternal ND 90%, paternal ND 10%
  • 2-3% translocation - 33% recurrence risk in siblings. Seen on karyotype, not microarray or FISH. Carrier has 45 chromosomes. Most commonly Ch 14 + 21
    - If mother carrier = 12% risk recurrence
    - If father carrier = 1% risk recurrence
  • 2% mosaic (due to trisomy rescue or non-disjunction early after conception)
  • Ix: karyotype, microarray, FISH
  • Antenatal screening: decr PAPPA+AFP, increased bHCG
  • Increased nuchal/absent nasal bone on USS
154
Q

What are the clinical features of Trisomy 21?

A
  • Upslanting palpebral fissures, epicanthic folds, small low set ears, flat nasal bridge, large tongue, sandal gap, curved 5th finger, brushfield spots
  • Mild-mod ID, 5-8yrs equivalent
  • Hypotonia, hyperflexible joints
  • 75% develop Alzheimer’s by age 60 (APP gene on Ch21)
  • CHD: AVSD > VSD > PDA > ASD > ToF, MVP in adolescent
  • Hypothyroidism 30%, coeliac
  • Duodenal atresia, TOF, Hirschsprung, imperforate anus
  • Leukaemia (AML = ALL) 1:300 (10-20x inc risk), but lower rates solid tumours. TMPD (10%) -> 20% of these will develop AML, polycythaemia, macrocytosis. Children with T21 and AML respond better to treatment.
  • Low immunity, recurrent low-grade infections e.g. viral
  • Occipito-atlanto-axial instability 15% - screening controversial. Can lead to subluxation and spinal cord injury. Hip issues.
  • OSA (anatomical + hypotonia) 50-70%
  • Hearing (conductive) and vision (refractory, cataracts) issues 60-70%
  • Short height, microcephalic, often obese by age 3-4y
  • Fertility: male infertile, females severely reduced (1/2 children with have T21)
155
Q

Most common cause of intellectual disability?

A
  • Trisomy 21 is most common genetic cause of ID

- Fragile-X is most common cause of inherited ID

156
Q

Discuss the genetics and diagnosis of Marfan syndrome

A
  • Single gene disorder, FBN1 mutation (can do Sanger sequencing)
  • AD, broad phenotype
  • 1:4000
  • Diagnosis in absence of FHx: aortic root enlargement (Z score >2) + one of: ectopia lentis, pathogenic FBN1 variant, systemic score >7
  • Diagnosis with FHx: 1st degree relative + ectopia lentis, systemic score >7, aortic root enlargement >3 if <20yo
157
Q

Key features of Marfan syndrome

A
  • Connective tissue disorder - tall and stretchy
  • Tall, long limbs, thin stature (increased LS and arm span ratios)
  • Joint hypermobility
  • CVS: aortic dilation/dissection, AR/MR
  • Pectus carinatum or excavatum
  • Superior lens dislocation
  • Wrist and thumb sign
158
Q

Discuss aortic root enlargement in Marfan syndrome

A
  • 250 times greater risk of dissection than normal population
  • Tx: prophylactic beta-blockers or ARBs to slow progress
  • Surgical repair
159
Q

Discuss the genetics of Turner syndrome

A
  • 45XO in 50%
  • Mosaic 45XO/46XX in 25%
  • 25% other karyotype with X chromosome structural abnormalities
  • Vast majority of 45XO miscarry, therefore do survivors have another cell line?
  • Diagnosis: karyotype, microarray, FISH
160
Q

Features of Turner syndrome

A
  • Short stature (average 20cm shorter than sisters) - require growth hormone
  • Gonadal dysgenesis, streak ovaries - primary amenorrhea, pubertal delay. May need oestrogen
  • Dysmorphology - webbed neck, shield chest, widely spaced nipples
  • Generally normal IQ, but defects in visuospatial functions. Verbal IQ > performance IQ
  • Urinary tract malformations in 30%, horseshoe kidney
  • Cardiac anomalies in 30% - aortic dilation, coarctation > bicuspid aortic valve > aortic stenosis, cardiomyopathy
  • Endocrine: hypo/hyperthyroid, diabetes, osteoporosis, coeliac
  • HTN
  • Congenital lymphoedema: puffy hands/feet at birth
161
Q

Discuss the features of Patau syndrome

A
  • Trisomy 13
  • Midline defects: holoprosencephaly, cleft lip/palate, heart abnormalities (VSD, PDA), scalp defect
  • Microcephaly, visual loss, polydactyly, low-set ears, cyclopia, rocker-bottom feet
  • Often multiple malformations in neonatal period
  • Genetics: nondisjunction event, rarely translocation
  • Test: karyotype, microarray, FISH
  • Median survival 10 days, 92% die by 1 year
  • Profound ID in long-term survivors
162
Q

Discuss the features of Edward syndrome

A
  • Trisomy 18
  • IUGR, wizened features (small palpebral fissures, microstomia), prominent occiput, overlapping fingers, rocker-bottom feet, multiple malformations, microcephaly
  • VSD/ASD
  • Present with IUGR or abnormal maternal serum screening (low oestradial, PAPPA, beta HCG, AFP)
  • Genetics: nondisjunction event
  • Test: karyotype, microarray, FISH
  • Median survival 14 days, 92% die by 1 year
163
Q

Discuss the features of 22q11 microdeletion

A
  • Cardiac - conotruncal, aortic arch defects, TA, ToF, AVSD
  • Abnormal facies - low set and rotated ears, hypertelorism, high nasal bridge, micrognathia
  • Thymic hypoplasia - variable levels of T cell function, complete with SCID in only 1%
  • Cleft palate (not cleft lip)
  • Hypocalcaemia - abnormal parathyroid glands
  • Up to 5% have a 10p13 microdeletion
  • Developmental delay, cognitive impairment 75%
  • Psychiatric illness in 60%
  • Test: microarray, FISH, need to check parents
  • Critical genes; TBX1 (cardiac), COMT (behaiour/psych). More than 35 genes involved in common deletion
164
Q

What are the features of Williams syndrome

A
  • Elfin facies, blue eyes, coarse facial features as age, periorbital puffiness, wide mouth
  • Supravalvular aortic stenosis
  • Long philtrum, upturned nose, widely spaced teeth
  • Short stature and developmental delay
  • Over-friendly, cocktail personality, non social anxiety
  • Heterozygous microdeletion on 7q11.23
  • Test: microarray or FISH
  • Mild ID, hypothyroid, hypercalcaemia, joint laxity, hypertension later
165
Q

Prader-Willi features

A
  • Neonatal hypotonia, undescended testes, poor suck and weak cry
  • Hyperphagia and obesity after infancy
  • Intellectual disability, skin picking
  • Hypopigmentation, small hands and feet
  • 15q, loss of paternal allele
  • Microarray picks up deletions and some UPD, methylation testing
  • Often require growth hormone
166
Q

Features of Cornelia de Lange syndrome

A
  • IUGR, hirsutism, ulnar ray defects, severe GOR, severe intellectual disability, autistic traits
  • Short nose, long philtrum, unibrow (synophrys), arched eyebrows
  • Single gene disorder, mutations in NIPBL 75%
  • Test via single gene sequencing
167
Q

Features of Sotos syndrome

A
  • Overgrowth, advanced bone age, high anterior and temporal hairline, frontal bossing, long narrow face, pointed chin, tall stature, large head
  • Mild-severe ID
  • NSD1 mutations (90% point mutations, 10% deletions) - test via microarray or single gene sequencing, or “overgrowth” panel
  • Adult height variable
168
Q

Discuss homocysteinuria

A
  • Tall and stiff, tall stature with long limbs, ID, ectopia lentis down, severe myopia
  • AR metabolic condition
  • Test plasma total homocysteine (not urine), detected on newborn screening
  • Can’t process certain amino acids, accumulate homocysteine
  • Need protein restriction, folate/B12 supps, methionine-restricted diet
  • Can get thrombus (CVA), seizures
169
Q

Discuss osteogensis imperfecta

A
  • Brittle bone disease, short long bones, multiple fractures
  • Dental abnormalities, hearing loss, blue sclera, osteoporosis, wormian bones
  • Short stature and scoliosis
  • Single gene disorders of gene encoding collagen proteins COL1A1/ COL1A2, most AD, if de novo then gonadal mosaicism risk 3-4%
  • Broad phenotypic severity
  • OI gene panel or single gene sequencing
  • Tx: bisphosphonates
  • 1 mild, 2 severe, 3 progressive and deforming
170
Q

Discuss achondroplasia

A
  • Short stature, disproportionate short limbs
  • Hypotonia and gross motor delay, normal IQ
  • Macrocephaly, flat nasal bridge, trident hand, normal trunk with rhizomelic (proximal) limb shortening
  • AD, FGFR3 mutations
  • Single gene sequencing, skeletal survey is diagnostic test
  • Complications: stenotic spinal canal (can cause hydrocephalus and foramen magnum compression), OSA, middle ear disease
  • International rial of vosoritide (inc growth velocity)
171
Q

Discuss fetal alcohol syndrome

A
  • Short palpebral fissures, flat philtrum, thin lip
  • Jittery, learning disability, DD
  • IUGR, microcephaly, short stature
  • May have seizures
172
Q

Syndromes with short stature

A

Proprotionate:

  • Turners
  • Noonans
  • Fanconi anaemia
  • Williams

Disproportionate:

  • Russell Silver
  • Achondroplasia/skeletal dysplasias
173
Q

Discuss the features of Fanconi Anaemia

A
  • AR, mutations in DNA repair genes - susceptibility to cancer
  • Test: chromosomal breakage studies, Fanconi panel
  • Short stature, microcephaly, developmental delay
  • Abnormal thumb/radius, renal anomalies, GI atresias
  • Freckles, cafe au lait
  • Bone marrow failure, pancytopenia (may not present with all cell lines) in 1st decade
174
Q

Syndromes with tall stature

A
  • Klinefelter
  • Marfan
  • Homocystinuria
  • Sotos
  • Beckwith-Wiedemann
175
Q

Syndromes associated with obesity

A
  • Prader-Willi

- Bardet-Biedl

176
Q

Syndromes with infantile hypotonia

A
  • Prader-Willi
  • Myotonic dystrophy
  • SMA
  • Peroxisomal disorder (Zellweger)
  • Congenital disorders of glycosylation (hypotonia, big ears, abnormal fat pads over iliac crest)
177
Q

Discuss Zelweger syndrome

A
  • Severe hypotonia, tall forehead, abnormal brain MRI
  • AR
  • Abnormal VLCFAs
178
Q

Syndromes assocaited with pubertal delay

A
  • Turner - streak ovaries
  • Klinefelter - hypogonadism
  • Any syndrome associated with short stature often causes pubertal delay
179
Q

Syndromes associated with aortic stenosis

A
  • Williams - SVAS

- Storage disorders (MPS) - AS

180
Q

Syndromes associated with pulmonary stenosis

A
  • Noonans
  • Williams
  • Alagille (supravalvular pulmonary artery stenosis)
  • Tuners
  • Downs
181
Q

Syndromes associated with atrial/ventricular septal defects

A
  • T21
  • 22q11
  • Fetal alcohol syndrome
182
Q

Syndromes associated with coarctation

A
  • Turners

- Kabuki (short stature, cleft, CHD, interrupted eyebrows, dysmorphism)

183
Q

Syndromes associated with aortic dilation

A
  • Marfans (also MVP, MR, AR)
  • Ehlers Danlos - connective tissue
  • Loeys Dietz - Marfan-like, bifid uvula
  • Turners
184
Q

Syndromes that cause radial ray defects

A
  • Fanconi anaemia
  • TAR - thrombocytopenia with absent radius (thumb normal)
  • VACTERL
  • Blackfan diamond - thumb abnormal
  • Goldenhar
185
Q

Syndromes associated with deafness

A

External ear normal:

  • Waardenburg - iris heterochromia, white forelock
  • Alports - haematuria
  • Jervell-Lange-Nielsen - long QT
  • Pendred - hypothyroidism
  • NF2 - late onset deafness
  • T21

External ear abnormal:

  • Goldenhar - microtia, fatty eye lumps, vertebral abnorm
  • Treacher-Collins - bilateral microtia, hypoplastic zygoma
186
Q

Discuss Waardenburg syndrome

A
  • Heterochromia iridis, white forelock, sensorineural hearing loss, bright blue eyes
  • AD, single gene disorder PAX3 and SOX10
  • Test: gene sequencing panel
187
Q

Discuss Goldenhar syndrome

A
  • Oculo-auriculo-vertebral dysplasia (OAVD)
  • 1st and 2nd branchial arch maldevelopment
  • Hemifacial microsomia, conductive deafness, vertebral defects, sporadic/cause unknown
  • Fatty eye lumps (epibulbar dermoid), microtia
188
Q

Discuss Treacher Collins syndrome

A
  • Single gene disorder
  • Symmetrical mandibulofacial dysostosis
  • Sloping eyes, lower lid coloboma, small midface, microtia
  • Conductive hearing loss
  • Normal IQ
  • Single gene sequencing TCOF1 gene
189
Q

Syndromes associated with cleft lip/palate

A
  • 22q11.2 - palate only
  • Stickler syndrome - severe myopia and retinal detachment
  • Pierre Robin sequence - cleft palate secondary to mandibular hypoplasia
  • Trisomy 13 - lip and palate
  • Kabuki syndrome - coarctation
190
Q

Syndromes associated with eye defects

A
  • Coloboma - cat eye syndrome, CHARGE, treacher collins
  • Lens dislocation - Marfans (up), homocystinuria (down)
  • Cataracts - T21, Smith-Lemli-Opitz
191
Q

Syndromes associated with haematological anomalies

A
  • Red cells: Fanconi (pancytopenia), Diamond-Blackfan (BMF, triphalangeal thumbs)
  • White cells: 22q11 (thymus, T-cell), CHARGE (leukopenia)
  • Platelets: TAR, Wiskott Aldrich
192
Q

Syndromes associated with leukaemia

A
  • T21 (AML, ALL, transient myeloproliferative disease)
  • Ataxia telangiectasia (leukaemia, lymphoma, sensitive to x-rays)
  • Fanconi anaemia
  • Noonans
193
Q

Syndromes associated with cafe-au-lait spots

A
  • NF1
  • McCune-Albright - coast of Maine
  • Fanconi anaemia
194
Q

Malformation vs syndrome

A
  • Malformation: organ abnormality caused by intrinsically abnormal development
  • Syndrome: recognisable pattern of malformations
195
Q

Midline defects in holoprosencephaly spectrum

A
  • Coloboma, clefts, hypotelorism, absent olfactory lobes, solitary central incisor
196
Q

What is a sequence?

A
  • Pattern of multiple abnormalities derived from a single known anomaly or mechanical factor
  • Describes the pathogenesis, not the cause e.g. prune-belly sequence, Pierre-Robin sequence
197
Q

Discuss Stickler syndrome

A
  • Commeest syndrome associated with Pierre-Robin sequence
  • Cleft palate/submucosal cleft/bifid uvula
  • Myopia, retinal detachment, staring eyes
  • High frequency hearing loss
  • Femoral head failure, scoliosis, osteoarthritis
198
Q

What are assocaitions

A
  • Nonrandom occurrence of multiple anomalies not known to be a sequence or syndrome
  • e.g VACTERL (note CHARGE thought to be association until gene discovered, not it is a syndrome)
199
Q

What is telecanthi?

A

Lateral displacement of the inner canthi - look they are hyperteloric but aren’t. Can’t see white of eye in medial aspect.

200
Q

Upslanting vs downslanting palpebral fissures

A
  • Up = Down syndrome

- Down = Noonans

201
Q

Short palpebral fissures are seen in?

A

Fetal alcohol syndrome

202
Q

Rhizomelia vs mesomelia vs achromelia

A
  • Rhizomelia - short proximal segment - achondroplasia, skeletal dysplasia
  • Mesomelia - short middle segment
  • Achromela - short distal segment (hands and feet)
  • Requires skeletal survey
203
Q

What is the mode of inheritance for Apert syndrome?

A

Autosomal dominant

204
Q

Discuss Costello syndrome

A
  • AD, usually de novo
  • Infantile FTT, loose skin, papillomata
  • Severe feeding difficulties, look emaciated
  • Ulnar deviation of wrist
  • HOCM, arrhythmia, valve abnormalities
  • 10-15% tumour risk: rhabdo, bladder carcinoma

Costello syndrome is caused by an activating mutation in the oncogene HRAS.
• Features include short stature, relative macrocephaly, feeding difficulties, developmental disability and
• Epicanthal folds, flat nasal bridge, full lips, large mouth, soft skin with excess palm skin with deep palmar creases.
• Increased risk for tumour development, particularly rhabdomyosarcoma

205
Q

Which conditions are classed as Rasopathies?

A
  • In the Ras/MPK signal transduction pathway
  • Noonans generally least severe
  • Costello syndrome, cardiofaciocutaneous syndrome
  • NF1
  • Legius syndrome
206
Q

Asymmetric crying facies and squared-off ears are features of?

A

CHARGE syndrome (CHD7 gene)

207
Q

Allelic heterogenity vs locus heterogeneity

A
  • Allelic heterogeneity: many different types of mutations in a gene can result in the same condition
  • Locus heterogeneity: mutations in many different genes can result in the same disorder
208
Q

What is the most common aneuploidy in humans?

A

Ch 16 - all abort 2nd trimester

209
Q

Discuss the features of Holt-Oram syndrome

A
  • AD, also called heart-hand syndrome
  • ASD, VSD, heart blocks
  • Absent radius, often thumb abnormalities
  • Mutation in TBX-5 gene
210
Q

Discuss Cardiofaciocutaneous syndrome

A
  • AD, usually de novo as don’t reproduce
  • Cardiac: HCMO>PS
  • Face: tall forehead, low ears, nasal bridge, curly sparse and brittle hair, dry skin
  • Prolonged feeding abnormality -> failure to thrive.
  • Developmental delay and seizures
  • Pectus excavatum.
  • Gene defect in RASMAPK pathway (same as Noonans and Costello)
211
Q

Discuss Alstrom syndrome

A
  • AR
  • Short stature & obesity
  • Type 2 diabetes
  • Dilated cardiomyopathy
  • Hearing impairment
  • Cone-rod ocular dystrophy
212
Q

Discuss Bloom syndrome

A
  • Autosomal recessive– chr 15 = DNA fragility
  • Chromosome breakage disorder, inc cancer risk (lymphoma, leukaemia, carcinoma, Wilms)
  • Short stature (usually only feature present at birth)
  • Telangiectatic erythema of the face (malar rash), photosensitive -> butterfly distribution then limbs
  • Microcephaly, prominent ears, malar hypoplasia, abnormal dentition, contractures of hands & feet, acanthosis nigricans/ café au lait/ ichthyosis, polydactyly
  • IgM and IgA -> immunodeficiency in all patients.
213
Q

Discuss Cleidocranial Dysostosis

A
  • AD, defect in CBFA 1 gene
  • Responsible for differentiation of osteoblasts to form skeletal structures
  • Defective bone formation, hypoplastic clavicles, large head, delayed suture closure, narrow pelvis, spine abnormalities
  • Short stature
  • Supernumerary teeth, defective cementum formation
  • Think: photo with shoulder dislocated forward
214
Q

NF2

A

NF-2 may be diagnosed when 1 of the following 4 features is present:
(1) bilateral vestibular schwannomas;
(2) a parent, sibling, or child with NF-2 and either unilateral vestibular schwannoma or any 2 of the following:
• meningioma
• schwannoma
• glioma
• neurofibroma
• or posterior subcapsular lenticular opacities;

(3) unilateral vestibular schwannoma and any 2 of the following:
• meningioma, schwannoma, glioma, neurofibroma, or posterior subcapsular lenticular opacities;

(4) multiple meningiomas (2 or more) and unilateral vestibular schwannoma or any 2 of the following:
• schwannoma 
• glioma
• neurofibroma
• or cataract
215
Q

Gorlin Syndrome

A

Gorlin syndrome is a multisystem disorder associated with mutations in the patched PTCH gene. The major diagnostic criteria are:

  1. Multiple basal cell carcinomas
  2. Odontogenic keratocyst or polyostotic bone cyst 3. Palmar or plantar pits (>3)
  3. Ectopic calcification
  4. First degree relative affected
216
Q

Short stature, relative macrocephaly, feeding difficulties, developmental disability, epicanthal folds, flat nasal bridge, full lips, large mouth, soft skin with excess palm skin with deep palmar creases.

Which syndrome

A

Costello syndrome is caused by an activating mutation in the oncogene HRAS.
• Features include short stature, relative macrocephaly, feeding difficulties, developmental disability and
• Epicanthal folds, flat nasal bridge, full lips, large mouth, soft skin with excess palm skin with deep palmar creases.
• Increased risk for tumour development, particularly rhabdomyosarcoma

217
Q

Diagnosis PCOS

A

Otherwise unexplained combination of:

  1. Abnormal uterine bleeding pattern:
    a. Abnormal for age or gynaecologic age.
    b. Persistent symptoms for 1-2years.
  2. Evidence of hyperandrogenism
    a. Persistent testosterone elevation above adult norms in a reliable reference laboratory is the best evidence.
    b. Moderate-severe hirsutism is clinical evidence of hyperandrogenism.
    c. Moderate-severe inflammatory acne vulgaris an indication to test for hyperandrogenaemia.
218
Q

Syndromes with hypo plastic / absent radii

A
  1. TAR (thrombocytopenia absent radii ; have normal thumbs)
  2. VACTERL
  3. FANCONI
  4. Holt Oram ( Cardiac, skeletal)
219
Q

Short stature, fused cervical vertebrae, scoliosis,

A

Klippel Feil syndrome

Also Cardiac (VDS), Renal
Scoliosis >50%
Sprengel deformity is a congenital deformity where the scapula fails to descend to it’s correct position.
220
Q

Most common genetic cause of hypogonadism and infertility in males

A

Klinefelters

221
Q

Triad of

  1. Port wine stains (cutaneous vascular malformation)
  2. Bony and soft tissue hemihypertrophy
  3. Venous varicosities
A

Klippel trenaunay weber syndrome

222
Q

LEOPARD Syndrome

A 
Lentigenes
ECG abnormality
Ocular hypertelorism
Pulmonary stenosis
Abnormal genitalia
Retarded growth
Deafness
223
Q

Absence of pectorals muscle seen in..

A

Polands syndrome

224
Q

Rubinsteins Taybi syndrome

A 
Dysmorphic - beaked nose, prominent columella, downslanting palpebral fissures, high eyebrows, Long lashes
Abnormal thumbs  - short and broad
Intellectual disability
Developmental delay
Short stature, microcephaly
Hirsutism
Feeding difficulties

Mutation CREBBP gene

225
Q

Smith Lemli Optiz

A

AR defect cholesterol metabolism
Elevated serum 7 DHCR

Short, GDD, ID
Ambiguous genitalia males
Syndactylyl 2nd/3rd toes ; skin photosensitivity 
cataracts
Cardiac
Neuro
226
Q

Stickler syndrome

A

Pierre robin sequence ; mid face hypoplasia
EYES: Abnormal architecture vitreous gel, myopia, retinal detach
Joint hypermobility
EARS: SNHL

COL2A1 mutation, AD

227
Q

Duane syndrome

A

congenital strabismus due to abnormal development of CN6.

The characteristic features of the syndrome are:
• Limitation of abduction (outward movement) of the affected eye.
• Less marked limitation of adduction (inward movement) of the same eye.
• Retraction of the eyeball into the socket on adduction, with associated narrowing of the palpebral fissure (eye closing).
• Poor convergence.
• A head turn to the side of the affected eye to compensate for the movement limitations of the eye(s) and to maintain binocular vision.

While usually isolated to the eye abnormalities, Duane syndrome can be associated with other problems including cervical spine abnormalities Klippel–Feil syndrome, Goldenhar syndrome, heterochromia, and congenital deafness.

There are three types and there is a helpful mnemonic to remember this:
children with type 1 have difficulty with abduction (one D in abduction), Approximately 80% of cases are type 1.
type 2 have difficulty with adduction (two Ds in adduction) and
type 3 have difficulty with both (3 Ds in abduction and adduction).

228
Q

Purines

A

Adenine and Guanine

229
Q

Pyrmidines

A

THYMINE AND CYTOSINE

Paeds (25 decks)

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