Genetics Flashcards
Exome
Protein coding genes represent 1-2% of genome (3 billion base pairs, 22-25k genes)
Polymorphism
iv. Differences that occur at a frequency of > 1% in a population are often referred to as polymorphisms
Chromatin
DNA and protein (histones) packaged to form a coiled structure
Form chromosomes
DNA bases
- Purines = adenine + guanine
2. Pyrimidines = cytosine + thymine (Ys)
Chromatid
One copy of the duplicated chromosome
Chromosome sizes
Largest -> smallest, therefore chromosome 1 = biggest (not including sex chromosomes)
Mitochondrial DNA
i. Consists of 37 genes, 13 of which encode proteins
ii. No introns
iii. 93% of mitochondrial genome is coding DNA (nuclear 2%)
iv. This genetic material is maternally inherited (sperm mitochondria are in the tail)
RNA
i. Peptide (protein) via intermediate messenger RNA (mRNA)
1. Complementary to strand of DNA
2. Contains uracil instead of thymine
3. Travels to the ribosomes and is translated into a protein (see below)
ii. Directly for ribosomal RNA (rRNA) – involved in translation
iii. Directly for transfer RNA (tRNA) – involved in translation
a. mRNA – messenger RNA contains genetic information and is a copy of portion of DNA. Functions to carry genetic information from DNA out of nucleus into cytoplasm for translation
b. rRNA – ribosomal RNA is structural component of ribosomes. Doesn’t contain genetic material
c. tRNA – functions to transport amino acids to the ribosomes during protein synthesis
d. snRNA – complexes with protein producing small nuclear ribonucleoproteins (snRNP). Act to modify RNA transcript
Promoter region
5’ ie upstream of the first exon – often TATA box (5’ TATAA 3’)
1. Recruit RNA polymerase factors and transcription factors
Codon
i. Sequence of bases along the mRNA is read in groups of 3 (triplets) called codons
ii. Each codon specifies an amino acid and ultimately the sequence of the amino acids along a peptide
iii. There are 43 (64) possible codon combinations - 61 specify amino acids + 3 specify stop signals
1. Redundancy present
2. AT(U)G = methionine = start codon
3. TAA, TAG, TGA = stop codons
iv. Modifying the first nucleotide position more likely to change the AA
Transcription
a. Messenger RNA is transcribed from the DNA – occurs in the nucleus
b. Transcription is initiated by attachment of RNA polymerase to the promoter site
i. Regulatory proteins/ transcription factors bind to region to either repress or activate transcription
c. Antisense strand of DNA read 3’ to 5’ by RNA polymerase
i. mRNA is then synthesized in a 5’ 3’ direction
d. Same structure as DNA except that uracil replaces thymine
e. A 7-methylguanosine ‘cap’ is added to the 5’ end of RNA and several hundred adenine bases are added to the 3’ end after transcription (polyA tail)
Translation
a. mRNA is then translated into amino acid sequence at the ribosomes – occurs in the cytoplasm
b. Each codon (3 bases) = one amino acid
c. Every codon is recognized by a transfer RNA with complementary anticodons and bind corresponding amino acid
d. Post translational modifications – such as glycosylation – can occur
DNA replication/enzymes
a. Helicase opens up the DNA at the replication fork.
b. Single-strand binding proteins coat the DNA around the replication fork to prevent rewinding of the DNA.
c. Topoisomerase works at the region ahead of the replication fork to prevent supercoiling.
d. Primase synthesizes RNA primers complementary to the DNA strand.
e. DNA polymerase III extends the primers, adding on to the 3’ end, to make the bulk of the new DNA.
f. RNA primers are removed and replaced with DNA by DNA polymerase I.
g. The gaps between DNA fragments are sealed by DNA ligase
Complementary DNA
Synthesised from single stranded RNA via reverse transcriptase
Mitosis
a. The production of 2 identical daughter cells produced from a single parent cells
b. DNA replication occurs during interphase of S phase of the cell cycle – prior to mitosis
c. Consists of prophase, metaphase, anaphase and telophase
d. Prophase = pair
i. Chromosomes condense and become visible
ii. Centrioles form and move towards opposite ends of the cell
iii. Nuclear membrane dissolves
iv. Mitotic spindle forms from centrioles (spindle fibres made of microtubules)
v. Spindles attach to each sister chromatid at kinetochore
e. Metaphase = middle
i. Centrioles complete their migration to poles
ii. The chromosomes line up in the middle of the cell
f. Anaphase = apart
i. Spindles (microtubules) attach to kinetochores begin to shorten - exerts force on sister chromatids that pulls them apart
iv. This ensure each daughter cell gets identical sets of chromosomes
g. Telophase = two
i. Chromosomes decondense
ii. Nuclear envelope forms
iii. Cytokinesis reaches completion, creating two daughter cells
Meiosis
a. The process of cell division to form four haploid cells (eg gametes)
b. Two cell divisions involved
c. Females = begins in fetal life, completed with ovulation
d. Males = occurs over a few days
e. Meiosis I = homologous chromosomes pair
i. Prophase I = homologous chromosomes pair
ii. Metaphase I anaphase I telophase I
iii. Recombination occurs in this stage = exchange between homologous chromosomes
iv. In oogenesis, one daughter cell receives most of the cytoplasm and becomes the egg, the other becomes the first polar body
f. Meiosis II
Ovum development
c. Complete the first stage of prophase I by fifth month of development to form 1-2 million oocytes (92 chromosomes)
d. After puberty, the oocyte divides (completes meiosis I) to form a large ovum and a small polar body (46 chromosomes)
e. Secondary oocyte undergoes a second meiosis
f. Meiosis is completed only if the ovum is fertilized
Non disjunction
i. Failure of homologous chromosomes in meiosis I / sister chromatids in meiosis II to separate during anaphase
ii. Results in aneuploidy (unequal number of chromosomes in each cell)
iii. Occurs more commonly in female gametogenesis – in eggs
iv. Increasingly common with age
Variant vs mutation
- Variants = alteration to DNA sequence
- Mutation = disease-causing variant
- Variants contribute to natural phenotypic differences between individuals
- 5x106 variants between individuals (1-2%)
- Variants responsible for evolutionary changes
Single gene mutation
- Definition = affect a single base (point mutation), a small number of bases, or very large sequences
- Classification
a. Base substitutions
a. Base substitutions
i. Silent = changes that do not affect the amino acid production by a codon
ii. Nonsense = changes amino acid to produce a stop codon abolish protein production (eg. thalassaemia)
iii. Missense = changes amino acid and alters the protein (eg. sickle cell)
b. Deletions/ insertion
i. These can alter reading frame which would result in a completely different sequence of amino acid, and completely alter the protein or result in a downstream STOP codon = frameshift mutation
Chromosomal abnormalities
- Key points
a. Chromosomal abnormalities occur in 1-2% of live births, 5% of still births and ~50% of early fetal losses
ii. 50% of all miscarriages due to fetal aneuploidy
iii. Chromosome abnormalities are uncommon at birth, but common at conception
iii. Acrocentric chromosome – when short arm contains insignificant genetic material – chromosomes 13, 14, 15, 21, 22 (involved in Robertsonian translocations) -> negligible effect of lost material
a. Gain/loss of an entire chromosome (= aneuploidy)
i. Aneuploidy = abnormal number of chromosomes
ii. Eg. Trisomy - T13, T21, T18 compatible with embryogenesis
- monosomy incompatible with life (except turner)
2. Classification
a. Ploidies = multiples of the 23 chromosome set
b. Somy = copies of individual chromosomes
- Sex chromosome aneuploidy
a. X inactivation – only one X chromosome is expressed in each cell
b. 47,XXY – asymptomatic
c. 47,XYY – fertility and reproduction issues; can lead to atypical presentations of X-linked disorders
d. 47, XXY – Klinefelter
i. With each X chromosome beyond normal number – IQ drops 10-20 points
ii. Most common cause primary male hypogonadism
e. 45, X – Turner
b. Structural abnormalities (= translocation, inversion)
i. Rearrangement of whole or part of chromosomes
ii. Caused by chromosomal breakage during crossing over
iii. May be balanced or unbalanced – balanced typically has no phenotype
iv. Eg. Translocation, inversion
c. Gain/loss of part of chromosome (= microduplication/ deletion)
i. Eg. 22q22
b. Deletions <5 Mb – NOT visible on conventional karyotype
- microdeletions: William, DiGeorge
- duplications: Charcot Marie Tooth type 1
Copy number variations (CNV)
= submicroscopic genomic differences in the number of copies of one or more sections of DNA that result in DNA gains or losses
i. Outcome varies = pathogenic, disease susceptibility, disease resistance, silent
Contiguous gene disorder
= when deletion + duplication of several genes in the same chromosomal region each play a role in the resulting clinical features
Inversion
= single chromosome is broken, at two points, piece is inverted and joined back
a. Pericentric = breaks are in 2 opposite arms of the chromosome and include the centromere
b. Paracentric = occur only in one arm
c. Carriers are phenotypically normal, but are at increased risk of miscarriages (paracentric) and abnormal offspring (pericentric)
Deletions
= loss of chromosome material, which can be terminal (ends of chromosomes) or interstitial
a. Often associated with mental retardation
b. Most common deletions are distal
c. Can be detected with FISH or microarray
Insertions
= piece of chromosome is broken and incorporated into a break in another part of chromosome
a. Can occur between 2 or 1 chromosome
b. Insertions are RARE
c. Carriers are at risk of having offspring with deletions/ duplications of the inserted segment
Ring chromosome
a. Ends of a chromosome are deleted + ends joined to form a ring
b. Can have normal phenotype/ congenital abnormalities depending on amount loss
Clinical genetics definitions
- Genotype = genetic constitution of an organism
- Phenotype = physical characteristics
- Locus = position of a gene on the chromosome
- Allele = an alternative variant of a particular gene
• Homozygous = at a particular locus there are two copies of the same allele
• Heterozygous = at a particular locus there are two different alleles
• Hemizygous
o Only carrying one copy of a genomic region due to deletion or altered function of the corresponding region on the other chromosome
o Males – a mutation in any gene on the X chromosome
o Female – a mutation in any gene on the X chromosome ONLY if Turner’s syndrome
• Compound heterozygote = at a particular locus there are two different mutations
• Polymorphism = where there are at least two, or more, relatively common alleles of a gene in the population (>=1%)
o Eg. Different alleles of genes responsible for ABO blood groups
- Dominant = a phenotype is dominant if the trait can be seen in individuals who are heterozygous for an allele (ie only need one copy); NOTE: may not be inherited, can be de novo and so severe that the individual dies and does not pass on the allele
- Recessive = a phenotype is recessive if the trait is seen only individuals homozygous for the disease (ie need two copies)
- Codominant = a phenotype is co-dominant when the effects of both alleles are seen in the heterozygote
• Penetrance = proportion of people with a genotype who develop disease (black + white)
o For some disorders penetrance is 100% eg. NF-1, CF
o For other disorders lower penetrance eg. BRCA1, polydactyly
• Expressivity = how the phenotype is expressed in a different individual (shades of grey)
o Some disorders the expressivity is similar eg. NF-1 (variable), CF (consistent), HOCM/DCM
• Genetic heterogeneity = multiple genes converge on same phenotype
o Allelic heterogeneity = where different mutations of the same gene exist to cause the same phenotype (eg multiple mutations of the CFTR exist, causing the phenotype of CF)
o Locus heterogeneity = where multiple genes can be mutated in various ways to cause the same phenotype
Eg. LQT syndrome can result from genetic mutations in different sodium and potassium channels
Eg. ID, hearing loss, retinitis pigmentosa, epilepsy
• Digenic inheritance = disease caused by co-inheritance of mutations at two distinct loci (rare)
• Mosaicism = more than one genotype in different cells o Point mutation or chromosomal abnormality o Germline (gonadal) vs constitutional (somatic)
Mendelian vs non Mendelian inheritance
Mendelian
• Refers to the collection of patterns of expression of physical traits over two or more generations that follows the rules of parental-to-offspring transmission (autosomal or sex-linked, dominant or recessive), that Mendel first described
• Patterns attributable to the action of single genes
• Most clinically recognizable for rare, highly penetrant, monogenic diseases
EG: AD, AR, XD, XR, YD
Non-Mendelian
• Many instances of familial clustering of rare traits but pattern of inheritance does not follow Mendel’s laws
• Inheritance can appear to be non-Mendelian
o Multiple genes impact on phenotype expression
o Despite a disorder being monogenic additional factors impact the concordance between genotype + phenotype
EG: Incomplete penetrance, Sex-limited expression, Imprinting, Multigenic inheritance, Anticipation, Mitochondrial inheritance
Autosomal dominant traits
- Key points
a. Phenotype is dominant if the trait can be seen in individuals who are heterozygous for an allele
b. Common to have de novo mutations – occur and can create case without FHx – E.g. Noonan’s - Examples = NF1, Marfan, PCKD, TS, vWD, OI, hereditary spherocytosis, familial hypercholesterolaemia, HD, myotonic dystrophy, acute intermittent porphyria, hereditary haemorrhagic telangiectasia, Noonan syndrome
- Inheritance
a. If one parent affected 50% of children will inherit - Pedigree
a. Equal numbers of affected males and females
b. Vertical transmission of phenotype (>1 generation)
c. Male to male transmission occurs (this excludes X linked) + female to female transmission
d. Skipped generation may be due to incomplete penetrance
e. Most common form of inheritance (think: reproductive fitness) - Exceptions
a. De novo mutations
iii. The more severe the disorder, the more common de novo mutations are (those with severe disorders less likely/ never procreate – called low/zero fecundity)
iv. Examples - Achondroplasia 80% de novo
b. Gonadal mosaicism
Autosomal recessive traits
- Key points
a. Phenotype is recessive if the trait is only seen in individuals who are homozygous for the allele
b. Both parents need to be carriers
c. More severe than autosomal dominant (unlikely to reproduce with most AR conditions)
d. Less likely to be due to new mutations as need 2 new mutations of the same gene
e. Fewer variables within families
f. Heterozygotes typically not affected and asymptomatic but can have late effects – mild disease in adults
g. Consanguinity increases risk of AR conitions - Examples = deafness, albinism, Wilson disease, sickle cell disease, thalassemia, haemochromatosis, PKU, alpha-1-antitrypsin deficiency (+ other IEM), CF, Friedreich ataxia, homocystinuria
- Pedigree
a. Horizontal appearance of phenotype especially among siblings
b. Equal number of males and females
c. Consanguinity (mating of related individuals) may be present
d. Heterozygotes are carriers, and are generally healthy - Note
a. Biallelic phenotype = 2 different mutations
i. More likely if there is high prevalence in the community, usually due to low severity disease
b. Pseudo-dominant conditions
i. Recessive conditions in more than one generation by bad luck
ii. Pedigree looks dominant but is actually AR
iii. More common with common and less severe disorders (eg haemacrhomatosis)
Hardy Weinberg equation
o The allele and genotype frequencies in the population
o p2 + 2pq + q2 = 1
o Represents frequency of alleles in population in one gene
P = incidence of one allele
Q = incidence of second allele
p2 = number of unaffected individuals in a population (assume 1 for rare AR condition) = homozygous for allele 1
q2 = incidence of disorder = homozygous for allele 2
2pq = carriers = heterozygous for the 2 alleles
o Example = If the incidence of Tay Sachs in 1 in 10,000 Q2 = 1/10,000 Q = 1/100 P2 = 1 P = 1 2pq = 2 x 1 x 1/100 = 2/100 = 1/50 Therefore carrier frequency is 1/50
X-linked recessive traits
- Key points
a. Common to have de novo mutation
b. Female carriers may have mild phenotype OR be completely healthy
i. 50% of females with fragile X have ID - Examples = DMD, Fragile X, haemophilia A, adrenoleukodystrophy, X-linked hypohidrotic ectodermal dysplasia, G6PD, Fabry disease, ocular albinism, colour blindness, CGD
- Inheritance
a. Male with disorder
i. All female daughters are carriers
ii. None of sons inherit
b. Female carriers
i. 1/4 chance of having an affected child
ii. Males – 50% affected (ie. 25% chance of having affected male)
iii. Females – 50% carrier - Pedigree
a. Absence of father-son transmission
b. Affected males much more common; all their daughters are obligate carriers
Ratio of affected/hemizygous males to carrier/heterozygous females 2:1
Lyonisation and skewed X inactivation can lead to symptoms in female - rare, and usually more mild
Female dystrinopathy
- DMD/similar phenotype in females to males is RARE
- female dystrinopathies occur d/t:
1. Turner XO
2. Translocations b/w X and autosomal chromosomes
3. Skewed X inactivation
4. Homozygous mutations in dystrophin gene
X linked dominant traits
- Key points
a. Less common clinically
b. Phenotype consistently in females and males
i. If not lethal for males – males will have the more severe phenotype
ii. If lethal for males – only females will be affected
c. Common to have de novo mutations - Examples = X-linked hypophosphataemic rickets, incontentia pigmenti (males lost as miscarriages)
- Inheritance
a. Affected males
i. 100% daughters affected
ii. 0% sons affected
b. Affected females
i. 50% sons affected
ii. 50% daughters affected – less severe - Pedigree
a. As common in females and males HOWEVER often lethal in males
Penetrance and expressivity
- Key points
a. Terms that describe how the disease genotype correlates with clinical phenotype
b. Alterations in penetrance or expressivity can make monogenic traits appear to be transmitted in a non-Mendelian pattern - Penetrance
a. Penetrance = proportion of individuals who carry the causative genotype who manifest disease (0-1)
b. For most disorders, complete penetrance is the exception and not the rule
c. Classification
i. Full penetrance = genotype status predicts development of disease; can be reliably used for genetic counselling (HD, TaySachs)
ii. Incomplete penetrance = penetrance values of <1, in which expression of disease NOT always observed among individuals who carry the disease associated genotype
iii. Variable penetrance = penetrance levels that change across ethnic groups of within families (BRCA1) - Expressivity
a. Expressivity refers to clinical or phenotypic differences of disease manifestation when the condition is present
b. Common among diseases which effect multiple organ symptoms
Pleiotropy
- Pleiotropy = ability of variants in a single gene to produce more than one or multiple phenotypic effects, often in different tissues or organs
a. Distinct from variable expressivity, which describes how two individuals with the same pathogenic variant (or combination of variants) can manifest different phenotypic effects or different degrees of disease expression despite identical genotypes - Example = Marfan syndrome - pathogenic FBN1 variants can cause cardiac manifestations (aortic dilatation and rupture), ocular manifestations (ectopia lentis and severe myopia), and connective tissue findings (joint hyperextensibility and arachnodactyly)
Anticipation
- Key points
a. Anticipation = phenomenon in which successive generations display accelerated, earlier-onset, or more severe disease manifestations
b. Often first recognized in the most severely affected offspring – milder disease forms in parents/grandparents - Examples
a. Trinucleotide repeat expansion
b. Short telomere syndrome eg. dyskeratosis congenita
Mosaicism
- Key points
a. Mosaicism = state of having two populations of genetically distinct cells in an individual who arose from a single fertilized egg
b. Occurs due to several mechanisms in the developing blastocyst or embryo
c. Usually caused by mitotic non-disjunction
d. Events that occur later during development affect a smaller proportion of cells and a more limited number of cell lineages
e. Classic feature is hypomelanosis of Ito (Blaskhoid hypomelanosis)
i. Congenital skin disorder affected M+F
ii. Associated with chromosomal mosaicism + translocation
iii. Patterned, hypopigmented macules over the body surface in demarcated whorls, streaks and patches
iv. Often associated with: ID, seizures, microcephaly, muscular hypotonia
- Inheritance
a. Individuals with mosaicism can only transmit the variant to the next generation if it is present in the gametes. - Diagnosis – can be made on microarray + next generation sequencing
- NOTE
a. Chimerism = uncommon state of having two or more populations of genetically distinct cells due to fusion of two or more fertilized egg
Mitochondrial inheritance
- Key points
a. Mitochondrial inheritance = traits due to genetic variation in the mtDNA rather than the nuclear genome - Mitochondrial inheritance
a. Exclusively inherited through maternal line (ie. from egg)
b. Heteroplasmy = more than one type of mitochondria (affected or unaffected by the variant) in each cell
c. Females with a mitochondrial variant who exhibit heteroplasmy will pass on varying numbers of affected or unaffected mitochondria to their eggs -> substantial variation in the contribution of the mitochondrial variant to each offspring - Mitochondrial diseases
a. 1000-2000 mitochondrial cell
b. Mitochondrial failure -> cell injury
c. Disease commonly affects brain, heart, liver, muscle, renal, endocrine, respiratory - Pedigree
a. All a mother’s children affected
b. No descendants of an affected male have the disease - Mitochondrial vs X linked
a. No male to male in either
b. X linked = males affected exclusively (or more severely) than females
c. Mitochondrial = males and females affected to the same extent
d. Mitochondrial = no descendants of an affected male have the disease, whereas this can happen in X linked conditions
Sex limited expression
• The expression of some traits, regardless of their chromosomal location, can be restricted to one sex, likely due to critical physiologic, anatomic, or hormonal differences
• Examples
o Male pattern baldness – can be inherited as AD trait
o Familial male precocious puberty – variants of GNAS1 gene
o Juvenile hypertrophy of breast – limited to females
Multigenic disorders
- Key points
a. Caused by the combined effects of >1 gene – multigenic or complex disease - Classification
a. Digenic
i. Pathogenic variants at two distinct loci required for disease to manifest
ii. Many exhibit classic AR inheritance pattern
iii. Example = digenic form of retinitis pigmentosa, Usher syndrome
b. Triallelic
i. Rare type of inheritance that requires three gene variants for disease to manifest - Two pathogenic variants at one locus and one additional variant at a different locus
- Example = Bardet-Biedl
a. Most individuals homozygous or compound heterozygotes for a pathogenic variant in one gene consistent with AR
b. Families described in which three variants in two genes segretgate with the disease phenotype
Polygenic disorders
- Key points
a. Characterised by familial clustering, but non-Mendelian patterns
b. Due to multiple genes with small effects
d. Examples = DM, CVS disease, asthma, MS etc - Characteristics
a. Similar rate of recurrence among all first-degree relatives
b. Identical twin risk is not 100%, but is more than sibling risk
c. Often susceptibility alleles in non-coding regions (SNPs) - SNPs
a. Occur every 1/300 base pairs
b. Most common type of genetic variation
c. Each individual has 10 million SNPs
d. Usually in non-coding regions
f. Often used in association studies – Genome Wide Association Study (GWAS)
Translocation pedigrees
- May be inherited from a carrier or appear de novo
- Carriers of a reciprocal translocation are phenotypically normal, with an increased risk for miscarriage and bearing affected children
• Pedigree o Males = females o Multiple miscarriages o Parents unaffected o Offspring 2/6 normal (50% carrier) 1/6 unbalanced = affected 3/6 non-viable = miscarriage
Epigenetics and imprinting
- Definitions
a. Epigenetics = alteration of gene expression (rather than DNA itself)
i. Transcribed genes need to be accessed by transcription factors, and so the chromatin is more open
ii. Methylation of cytosines in promoter region contributes to ‘silencing’ of genes
b. Imprinting = epigenetic marking of a gene based on its parental origin and results in monoallelic expression
i. For imprinted genes, expression is determined by the parent of origin of the chromosome
ii. Exception NOT the rule – 1% genome is imprinted
c. Mechanism of imprinting is usually due to parental specific methylation of CpG-rich domains AND modification of histone proteins
d. This is reset during gamete formation
i. Genetic imprinting occurs early in the formation of eggs/sperm
ii. Imprinting then occurs again in the next generation when that person produces his/her own eggs/sperm ie. maternal or paternal imprint is sex specific in relation to the parent the allele is inherited from NOT the offspring
iv. Father passes on paternally imprinted genes
v. Mother passes on maternally imprinted genes
- Imprinting disorders
a. Imprinting disorders occur when there are INAPPROPRIATELY two active copies or two inactive copies of the imprinted gene (ie. group of disorders based on inappropriate gene dosage)
i. Eg. normal maternal imprinting – you are relying on the paternal copy to work – therefore if something goes wrong with the paternal copy there is a problem
c. Maternal vs paternal imprinting
i. Maternal imprinting = maternal gene silencing (and paternal gene expression) – a maternally imprinted gene means that when inherited from the mother it is NOT expressed, and vice versa
d. Imprinting silences one gene
a. Imprinting = DNA sequence will be normal, but the relevant allele is switched off methylation testing required
Uniparental disomy
= both genes are inherited from the one parent (maternal UDP = two maternal copies)
i. Is the presence of two chromosomes/ two alleles inherited from one parent
ii. Effect of this varies, can result in:
1. An imprinting type disorder
2. Uncovering of autosomal recessive disorder
iii. Is usually maternal, due to non-disjunction during meiosis
1. Error in meiosis I two copies of material from the same grandparent (uniparental isodisomy)
2. Error in meiosis II one copy of material from each maternal grandparent (uniparental heterodisomy)
iv. This means the maternal gamete has an extra set of chromosomes, with uniparental disomy arising due to fertilization with nullisomic gamete OR trisomic rescue (most common)
v. Note that the terminology is the opposite to imprinting:
1. Maternal UPD = two copies of maternal chromosomes, absence of paternal genes
2. Paternal UPD = two copies of paternal chromosomes, absence of maternal genes
c. Uniparental disomy = FISH or SNP array
i. NOTE: SNP detects some but not all UPD
ii. Can do specific UPD studies
Prada Willi syndrome
- PWS and Angelman syndrome occur due to absence of monoallelic expression of key genes at 15q12
- Some genes in this location are only active on the paternal copy, and some on the maternal copy
- Absence of PATERNALLY functioning genes
- Deletion on paternal 15 – OR both 15s are maternal
• Mechanism
o 70% paternally derived deletion of 15q12
o 25% maternal UDP 15 - increasing due to increasing maternal age
o <1% imprinting defect
Paternal imprinting = silencing
• Key features o Floppy baby (hypotonia) o Voracious appetite (hyperphagia) - most common syndromic form of obesity o Obesity, short stature o Moderate ID o Hypogonadism, cryptorchidism - hypopigmentation vi. Depigmentation of the skin or eyes relative to familial background in 30-50% - small hands and feet
Other features:
- neuro/psych: OCD, epilepsy (25%)
- facies: almond shaped eyes
i. Premature adrenarche (pubic and axillary hair), but other secondary sexual characteristics are delayed or incomplete
- Investigations
a. Methylation analysis: detects all cases
b. Microarray abnormal in deletions + and some UPD
c. Deletions can also be detected via FISH
d. In practice, PWS panels will perform karyotype, methylation studies FISH + microsatellite probes for maternal uniparental disomy - Treatment
a. Growth hormone
i. Does not require formal GH deficiency testing
ii. Subsidized in genetically confirmed PWS until the age of 18 years
v. Require sleep study prior to use
vi. Contraindications: uncontrolled DM, respiratory compromise, severe sleep apnoea (IGF-1 stimulates adenotonsillar hypertrophy)
vii. Series of increased fatality seen initially within commencement of GH treatment, usually related to severe OSA + intercurrent URTI - Prognosis
a. Mortality up to 3%, average age of death is 33.2
Angelman syndrome
- PWS and Angelman syndrome occur due to absence of monoallelic expression of key genes at 15q12
- Some genes in this location are only active on the paternal copy, and some on the maternal copy
- Absence of MATERNALLY functioning genes (UBE3A)
- Deletion on maternal 15 – OR both 15 are paternal
• Mechanism o 70% maternally-derived deletion of 15q12 o 5-10% UBE3A mutation o 5% patUDP15 o 3% imprinting defect o 10-20% unknown
• Key features
o Severe ID
o Lack speech + inappropriate laughter - behavioural “happy puppet”
o Unsteady gait/ataxia
o Epilepsy
- postnatal microcephaly, delayed and disproportionate
- hand flapping
- seizures in 80%, and abnormal EEG even in absence of seizures
- Investigations
a. Methylation testing of 15q11.2-13 (will pick up 70%)
b. UBE3A single gene sequencing (will pick up 10%)
BWS and Russel Silver syndrome - difference
- BWS and Russel-Silver syndrome are caused by the same gene (11p15) – location of IGF-2 (paternally expressed growth factor)
- Usually only the paternal copy is active
- Loss of maternal copy (eg. paternal UDP) = paternal over-expression = BWS (big)
- Loss of paternal copy eg. imprinting defect, both copies maternal imprint = paternal under-expression = Russel silver (small)
Beckwith Weiderman syndrome
- Absence of MATERNAL gene
- Disrupting imprinting of 2 neighbouring domains on 11p15 (paternal allele growth promoting, maternal allele growth suppressing)
- Key point = association with IVF (loss of IC2 methylation)
c. Overactivity of IGF-2 (growth factor)
d. Imprinted genes = IGF2, gene H19 (involved in IGF2 suppression), WT1 (Wilms tumour gene), many others
• Mechanism
o 50% loss of methylation at mat IC2 on 11p
o 20% paternal UPD 11
o 5% gain of methylation at mat IC1 on 11p
o 5-10% CDKN1C mutation
• Key features o Overgrowth disorder o Macrosomia, neonatal hypoglycaemia o Hemihypertrophy o Macroglossia, visceromegaly o Predisposition to embryonal malignancies (Wilms, hepatoblastoma, neuroblastoma) - screening every 3mo - exomphalos - ear creases/pits - naevus flammeus - cognitively can be normal, mild-mod ID
- Investigations
a. Methylation testing – diagnostic
b. SNP array is abnormal in rare microdeletions/duplications and some patUDP11 - Prognosis
a. Generally good prognosis if survive past infancy
i. Apnoea/cyanosis may occur -> 21% infant mortality
b. Follow-up tumours with USS and AFP
i. Nowadays JUST do USS every 3/12 until age 8 years
Russel-Silver syndrome
• Absence of PATERNAL gene
• Mechanism
o 50-60% 11p methylation defect
o <10% maternal UPD7
o Rest unknown
• Key features
o Short stature
o IUGR
o Asymmetry
o Triangular face (prominent forehead, pointed chin)
o Macrocephaly (preserved HC despite IUGR)
- hemihypertrophy as well
- clinodactyly (bending/curving of finger)
- Investigations
a. Methylation testing 11p
b. UPD7 studies (DNA from parents)
c. May detect UPD7 on SNP array - Treatment
a. GH treatment effective
Imprinting pedigree features
- For imprinting it is the gender of the parent of origin of the gene that matters – NOT the gender of the child
- Equal number of males and females
• Key points
o No affected children from the gender that is imprinted (no affected children from females if maternal imprinting, no affected children from males if paternal imprinting)
o Imprinting is reset when passed to the next generation
o If a pedigree shows a disorder inherited from both male and female parents, it cannot be an imprinting disorder
• Maternal imprinting = genes inherited from the mother are switched off
o Mutation in a maternally imprinted gene will result in the condition in
HALF of the children of a male with a mutation
NONE of the children of a female with the mutation (mutation imprinted)
• Paternal imprinting = genes inherited from the father are switched off
o Mutation in paternally imprinted gene will result in the condition in:
HALF of the children of a female with the mutation
NONE of the children of a male with the mutation
Trinucleotide Repeat Expansion Disorder
b. Classification
i. Normal range (stable range in mitosis and meiosis)
ii. Intermediate (mutable) range / permutation repeat size is unstable but does not result in a phenotype
iii. Full mutation
c. Allele expansion often dependent on gender of transmitting parent
i. Maternal = myotonic dystrophy, FRAX, Friedreich ataxia (lager repeats)
ii. Paternal = CAG repeat disorders such as HD, SCA (smaller repeats)
ii. CANNOT use the repeat size to predict phenotype with accuracy eg. myotonic dystrophy prenatal, HD predictive test
- Classification
a. Repeat Codon CAG (glutamine) = polyglutamine, e.g. HD, SMA
b. Non-CAG, e.g. FRAX, FA, myotonic dystrophy
Genetic markers/linkage
• Linkage = the use of ‘markers’ to follow gene/mutation through a family
o Marker is generally polymorphic section of DNA in/near a gene
• Polymorphic = section of DNA that differs in different people
o SNP = single nucleotide polymorphism
o Short tandem repeats
• Linkage disequilibrium
o Tendency for alleles of genes or genetic markers to be inherited together in a non-random fashion
o Occurs when two genes or genetic markers are in close chromosomal position – particular patterns of markers are unlikely to be separated by the random assorting of chromosomes by cross-overs at meiosis
o The closer together two genes or genetic markers the higher the linkage disequilibrium
Definitions - sequence, syndrome, association
i. Sequence = pattern of structural defects caused by a single problem in morphogenesis (eg Pierre Robin)
ii. Syndrome = pattern of multiple defects due to a known cause, e.g. Down syndrome = T21
iii. Association = pattern of structural defects that are statistically related, not due to a known sequence or syndrome (eg VACTERL) i.e. cause unknown
Palpebral fissures
iii. Palpebral = line from inner to outer canthus
1. Normal: 1:1 with inner canthus
2. Upslant – T21
3. Downslant – Noonan
4. Short – fetal alcohol syndrome
Epicanthal fold
= a fold of skin coming from upper eyelid, in front of medial canthus
Low set ears
= below level of inner canthus
- Noonan, OAVS, 22q11, T21
- Posteriorly rotated – Noonan
Single maxillary incisor
Midline abnormality – think holoprosencephaly
Bifid uvula
May have associated muscular defect in soft palate
“Dactyly” definitions
i. Clinodactyly = medial or lateral curve to toe or finger (usually 5th) due to hypoplasia of middle phalanx
1. Down syndrome, Russell-Silver, Klinefelter’s
ii. Syndactyly = incomplete separation of fingers (usually 3rd/4th) or toes (2nd/3rd)
1. Apert’s – mitten syndactyly, Carpenter’s, Cornelia de Lange, trisomies, Smith-Lemli-Opitz
iii. Camptodactyly = abnormal persistent flexion of fingers or toes
iv. Polydactyly = extra finger or toe (usually 5th)- simple or complex, family history common
1. Carpenter syndrome, trisomy 13, Rubenstein-Taybi, Smith-Lemli Opitz, Bardet-Biedl
vi. Trident hand = achondroplasia
Pharmacogenomics (carbamazepine, aza, warfarin, tamoxifen)
Carbamazepine
HLA-B1502
Risk of SJS
More frequent in patients of Han Chinese, Thai and Malay background
Testing prior to patients of Asian ethnicity
Warfarin Cytochrome P450 (CYP2C9) Affects warfarin dose requirements Variable evidence for clinical utility of genotype guided vs. clinical dosing
Azathioprine
TPMT polymorphism
Risk of drug accumulation and severe myelosuppression if low functional enzyme activity
Can measure enzyme activity or via genotyping
Tested prior to prescribing
Tamoxifen Cytochrome P450 (CYP2D6) Variants may influence efficacy, as the active metabolite of tamoxifen (endoxifen) is generated by genetic metabolism
Cytogenetics - tests
• Cytogenetics
o Karyotype
• Molecular cytogenetics
o FISH = fluorescent tagged DNA probes to visualize particular areas
o MLPA = targeted probes to detect copy number changes at the exomic level
o Molecular karyotype (microarray) = virtual karyotype from array of many thousand tagged DNA probes
Karyotype
a. Identifies
i. Aneuploidy
ii. Large chromosomal imbalances (5 Mb or greater)
iii. Balanced AND unbalanced translocations
b. Does NOT identify
i. Microdeletions/ duplications
ii. Single gene mutations
iii. Triplet repeat expansion
iv. Imprinting disorders
Level of analysis Chromosomes
Examples T21 Klinefelter Turner Balanced translocation
FISH
a. Identifies
i. Presence/ absence of specific DNA sequences on chromosomes
ii. Now good for localization + looking for balanced rearrangement
iii. Resolution up to a few Mb (50-200 b of DNA) (1 megabase = 1,000,000 bases)
b. Does NOT identify
i. Unknown mutation - must use specific prob
- Method
a. RAPID result
b. DNA probes made for a specific target
c. Probes bind to specific target and are fluorescent labelled - Note
a. Often used for rapid diagnosis of trisomies and prenatal diagnosis (<24 hours)
Level of analysis Chromosomes to submicroscopic chromosomal
Examples Whole chromosome (trisomy) Microduplications/ deletions (eg. 22q, Williams)
Multiplex Ligation-Dependent Probe Amplification
- Standard MLPA
a. Modified PCR amplification
b. Each amplification product has a unique length
c. Amplification products separated by electrophoresis
d. Reflects the relative copy number of target sequences (eg. duplications/ deletions)
e. Cannot detect sequence changes or large copy number changes
f. NOTE: outdated, not commonly used, largely replaced by microarray - Methylation sensitive MLPA
a. Can detect methylation – uses an enzyme that only amplifies targets that are unmethylated
b. Used for imprinting disorders
Examples Duplication/ deletion of any gene
Microarray
- Key points
a. Identifies differences in the amount of genetic material – gains or losses
b. Copy number variation (CNV) = difference in the number of copies of one or more sections of DNA that result from DNA gains or losses
c. Variations of unknown significance = VOUS - Method
a. CGH array
i. Compare DNA (genome) from two sources – test sample (green) and patient (red)
- green = loss of material, red = gain, yellow = equal
Detects
Microdeletions + microduplications
Monosomies + trisomies
Variations that may not be clinically significant
b. SNP array
i. Identifies variation in a single nucleotide at a specific locus
iv. Detects whether the 2 allelic copies of a single base pair are homozygous (same) or heterozygous (different)
1. Loss of heterozygosity eg. UPD in Angelman/ BWS
2. Mutated copy of tumour suppressor gene
i. Better, higher resolution test than CGH
ii. Get some sequence information – not just dosage (cf. CGH)
iii. Identifies consanguinity (loss of heterozygosity), some cases of UDP, mosaicism
Detects
Copy number neutral variation with genotype abnormalities
Allelic imbalance (are 2 copies of allele the same or different)
b. Cannot detect
i. Balanced karyotypes – translocations, inversions
ii. Point mutations (Marfan syndrome, N, Fragile X
iii. Triplet repeat expansion disorders - Fragile X, Myotonic dystrophy
iv. Spatially localise chromosomal rearrangements
v. Methylation changes – BWS, RSS, PWS/AS
vi. Small deletions
Next generation sequencing
- Key points
a. DNA sequencing technologies used to analyse multiple genes
b. Multiple reactions take place quickly and simultaneously
c. Allows rapid and inexpensive DNA sequencing of whole genome/ exome
d. High throughput – more economical than Sanger sequencing of genes individually and sequentially - Method
a. Break DNA of the genome into multiple fragments
b. Massive parallel sequencing of DNA fragments
c. Computer reassembles sequence, and reads for changes - Types
a. Whole genome = exon + intron
i. Gold standard of sequencing
ii. Expensive
b. Whole exome sequencing = exon only
i. Majority of what is done in clinical practice
ii. Sequences 1-2% of genome
iii. Clinically there are targeted exome panels – eg for cardiomyopathy, arrhythmias, SCD - Utility
a. Missing DNA or sequence changes in multiple genes
b. Useful for genetically heterogenous conditions
c. Cannot detect triplet repeats or methylation defects
Trinucleotide repeat analysis
- Utility
a. Trinucleotide repeat disorders
b. Examples = Fragile X, Huntington Disease, spinocerebellar ataxia, Friederich Ataxia, myotonic dystrophy - Method
- PCR then Southern Blot
Blots e.g. Southern
Method of transferring DNA/RNA/protein onto specific membrane then visualised with specific probes
DNA/protein denatured -> gel electrophoresis -> label added
Southern = DNA (Dandenong is south)
Northern = RNA
Western = protein (Perth is west)
- e.g. DMD/BMD
Linkage analysis - indirect genetic testing
- Key points
a. Not commonly used now we can sequence genes
b. Indirect method – relies on the fact that genes that are close together are inherited together (chromosome exchange occurs at meiosis)
c. Does not assess gene of interest but markers around it – usually SNP or short tandem repeat - Utility
a. Know the disease, and want to find position of the disease gene (gene discovery in population)
b. Know the parents have the genetic mutation, and want to find out if the offspring have inherited the abnormal haplotype (direct mutation analysis not always possible) - Linkage disequilibrium
a. The tendency for alleles of genes/ genetic markers to be inherited together in a non-random fashion
b. Occurs when two genes or genetic markers are close in chromosomal position unlikely to be separated by random assorting of chromosomes / crossovers at meiosis if they are close
c. The closer together two genes or genetic markers, the higher the linkage disequilibrium
d. Working out linkage equilibrium of two polymorphisms = % polymorphism 1x % polymorphism 2 if higher than this number, unlikely to be present due to chance
Prenatal genetic testing
- Methods
a. CVS
i. 11-15 weeks
ii. Needle into placenta
iii. 1/500 miscarriage risk
iv. Diagnose = chromosomal abnormalities, DNA studies, biochemical studies
b. Amniocentesis
i. 15-20 weeks
ii. Needle into uterus
iii. Take 15ml sample of fluid
iv. 1/1000 miscarriage risk
v. Diagnose = chromosomal abnormalities, DNA studies, biochemical studies
c. Maternal blood = NIPT
i. Available from 10 weeks gestation
ii. Fragments of placental DNA extracted from maternal blood
iii. Diagnose = aneuploidy, sex chromosomes, deletion syndromes - Testing
a. Karyotype
b. FISH
c. Microarray – from CVS/ amniocentesis - Pre-implantation Genetic Diagnosis
a. Performed in context of IVF
b. Testing by embryo biopsy
c. Can detect chromosomal abnormalities, single gene disorders
d. No apparent increase in birth defects
i. 97% diagnostic accuracy
ii. 20% pregnancy rate per cycle
iii. CF the most common indication
Pre-symptomatic genetic testing
- Key points
a. Presymptomatic genetic testing is for children who have a family history of a heritable condition but no signs or symptoms of the condition – that they will certainly develop if they have the mutation
i. Examples include FAP, Huntington, spinocerebellar ataxia
b. Predictive testing is where a person with the mutated gene has an inherited predisposition to the condition (but may never develop).
i. E.g. BRCA1/BRCA2 - Indications
a. Conditions for which there is potential medical benefit in the immediate future
i. E.g. surveillance for FAP
b. Testing for a condition that has its onset before adolescence - Contraindications
a. There are no treatments to alter the natural history of the condition
i. E.g. Huntington
b. Potential benefits do not occur until adulthood - testing should be delayed until adulthood to allow the child to make their own decision
Short stature syndromes
Proportionate • Turners • Noonan • Fanconi anaemia • Williams, 22q and other CNVs
Disproportionate
• Russel Silver
• Achondroplasia and other skeletal dysplasias
Tall stature syndromes
- Marfan syndrome = joint laxity, superior lens dislocation, normal IQ
- Homocystinuria = joint contractures, inferior lens dislocation, low IQ, stroke risk
- Klinefelter = non-dysmorphic, eunuchoid habitus, mild learning difficulties, pubertal delay, infertility
- Sotos = macrocephaly, not Marfanoid habitus, dysmorphism, advanced bone age
- BWS = coarse facial features, abdominal wall defect, hypoglycaemia, asymmetry
Obesity syndromes
- Prader Willi = hypotonia, hyperphagia, obesity, undescended testes, dev delay
- Bardet Biedl = polydactyly, renal anomalies
Hypotonia in infancy syndromes
- T21 = dysmorphism, congenital cardiac lesion
- Prader Willi = undescended testes, micrognathia
- Myotonic dystrophy = hypotonia, maternal percussion myotonus over thenar eminence
- SMA = alert and interactive infant with profound hypotonia and weakness
- Peroxisomal disorders (eg. Zellweger) = tall forehead, abnormal brain (screen VLCFA)
- Congenital disorders of glycosylation (screen with transferrin isoforms)
Pubertal delay syndromes
- Turner = short, non-dysmorphic (heart shaped face), web neck, shield chest, wide nipples, normal IQ
- Klinefelter = tall non-dysmorphic male, eunuchoid habitus, small testes, low IQ, impulsive behaviour
• Syndromes with short stature often cause pubertal delay
Radial ray defect syndromes
- Fanconi
- Thrombocytopenia and absent radius (TAR syndrome) = absent radius, normal thumb
- VACTERL
- Blackfan Diamond (anaemia) = thumb abnormal, triphalangeal thumb
- Goldenhar (OAVS)
- Holt Oram
Deafness syndromes
External ear normal
• Waardenburg = iris heterochromia, white forelock
• Jervell-Lange-Nielson = long QT
• Usher = retinitis pigmentosa
• Pendred = hypothyroidism
• Alport = haematuria, anterior chamber eye abnormalities
• NF2 = later onset deafness, CAL patches, caracts
• T21/multi organ syndrome
External ear abnormal
• Goldenhar = microtia, epibulbar dermoid, vertebral abnormalities
• Treacher-Collins = bilateral microtia, hypoplastic zygoma
• Brachio-oto-renal
Non-syndromic
• GJB2 gene (=Cx26) = commonest cause, AR 1/30 carrier frequency
• CMV
Cleft lip/palate syndromes
- 22q11 = cleft palate ONLY
- Stickler
- Pierre Robin
- T13 = CL and CP
- Kabuki
Eye defect syndromes
Coloboma
• Cat eye syndrome (del 22) = inverted duplication of part of chromosome 22
• CHARGE (Coloboma, heart, atresia choanae, retardation of growth, genitourinary, ear)
• Teacher Collins
Cataracts • T21 • Smith Lemli Optiz = 7 dehydrocholesterol, cataracts, dysmorphic features, organ malformation • NF-2 • Cockayne syndrome
Lens dislocation
• Marfan’s = Upwards
• Homocystinuria = Downwards
Cafe au lait spots syndromes
- NF1 = short with big head, neurofibromas, Lisch nodules, axillary/inguinal freckling, learning difficulties, optic gliomas
- NF2 = less common
- Fanconi anaemia = short with small head
- McCune-Albright = skeletal polyostotic fibrous dysplasia, coast of Maine CAL, endocrine hyperfunction/precocious puberty
- Legius syndrome
- LEOPARD syndrome
- Bloom syndrome
- Watson syndrome
- Russel-Silver syndrome
Butterfly vertebrae syndromes
- VACTERL
* Alagille’s
Trisomy 13 - Patau syndrome
- Epidemiology
a. Prevalence in liveborn infants is 1/5000 - Genetics
a. Trisomy 13
b. Mechanism = non-disjunction, rarely translocation (e.g. Robertsonian with 13 and 14) - Clinical presentation
a. Severe, multiple congenital anomalies – midline defects
b. Normally grown (cf. T18)
Key features
- micro/anophthalmia
- cleft lip/palate
- postaxial polydactyly
- heart abnormalities
- scalp defects (absent hair/skin)
- Prognosis
a. Median survival 10 days
b. 80% die by 3 months
c. 92% die by 1 year
d. Profound intellectual disability in survivors
Trisomy 18 - Edward syndrome
- Genetics
a. Trisomy 18
i. Meiotic nondisjunction
ii. Translocation involving chromosome 18
b. Second most common trisomy observed in live births after T21 - Clinical presentation
a. Prenatal
i. IUGR
ii. Low estradiol, PAPP-A, bHCG, increased inhibin A = same as T21
b. Birth with IUGR, dysmorphism + multiple anomalies
Key features
- affects any organ system
- majority die in utero or w/i 48 hours
- 5-10% survive beyond 1 year
- Rockerbottom foot
- fisted hand
- wizened features
- cardiac malformations
- IUGR
- GIT in 75% (Meckels, malrotation, omphalocele)
- Prognosis
a. Death within first 2 weeks = 50%
b. Death within first 3 months = 80%
c. Death within first 12 months = 90%
d. 5-10 % survive the first year, have severe ID
Trisomy 21 - Down syndrome
- Epidemiology
a. 1/800
b. Most common cause of intellectual disability
c. Increased prevalence with increasing maternal age - Genetics
a. Trisomy 95%
i. Extra from Mum 96% meiotic nondisjunction (recurrence rate 1% for aneuploidy, age effect)
b. Translocation 2.5%
i. Most common 14;21
c. Mosaic 2.5% - Clinical presentation
a. Prenatal
i. Increased or absent nasal bone on SS
ii. Combined screening
b. Birth = hypotonia, dysmorphism, malformation
Key features
- dysmorphism (upslanting palpebral fissures, epicanthal folds, low ears, short neck with excess nuchal skin, sandal gap, simian crease)
- grimace when crying
- low IQ (avg 45)
- hypotonia
- hearing and vision impairment
- CHD (AVSD)
- autoimmune disease (thyroid, coeliac, T1DM)
g. Haematological
i. Transient leukaemia (normal Hb and platelets)
ii. AMKL (acute megakaryoblastic leukaemia) – 1/50-200 children DS (500x risk general population)
iii. ALL / AML – (10-20x risk general population)
- Investigations
a. FISH – quickest result
b. Microarray/ Karyotype – important to determine if cause is translocation (microarray won’t detect balanced translocations)
Antenatal screening
- Possible indications
a. Offered to all
b. Maternal age >35years (considered risk of invasive diagnostic procedures equal to risk of DS)
c. Previously affected pregnancy
d. Known chromosomal translocation/inversion/aneupliody in parents
e. Anomalies on structural scanning - First trimester combined screening
a. 9-13weeks gestation
b. US – nuchal translucency + gestational age (crown-rump length)
c. Serum markers – Pregnancy associated plasma protein A (PAPP-A down) or bHCG (up) - Second trimester integrated test
a. For neutral tube defects and trisomy 21
b. US 10-13weeks– nuchal translucency
c. Serum markers 15-18weeks – PAPP-A (down), AFP (down trisomy, up NTD), unconjugated estriol (down), inhibin A (up)
d. Highest detection rate 85-95% - Used to determine probability of Trisomy 21 (and usually 18) in pregnancy
b. First trimester screening – means can have CVS (higher risk fetal loss but earlier option termination) offered to those high risk (>1/50)
c. Second trimester screening – means amniocentesis for diagnosis – FISH for chromosomes 13, 18, 21, X and Y - Screening results
a. Negative – risk <1/250, doesn’t exclude
b. Positive – risk >1/250
AFP
Alpha fetoprotein
Synthesized in yolk sac, GIT and liver of fetus,
Peak 10-13weeks, then decline
Elevated: Neural tube defect Congenital skin defects (abdominal wall) GI defects (obstruction)
Depressed:
Chromosomal trisomy
bHCG
beta human chorionic gonadotropin
Released by syncytiotrophopblast after implantation
Rapid risk to 8/40, then decreased until 20/40
Elevated:
Trisomy 21
Twin pregnancy
Molar pregnancy
Depressed:
Trisomy 18
T21 screening for comorbidities
- Hypothyroidism
a. 13-63% prevalence
i. Congenital hypothyroidism - 28x population risk (1.5-6.1% prevalence)
- ↑TSH ↓ T4
b. Hypoplasia most common cause; Dyshormogenesis is NOT common
ii. Subclinical hypothyroidism - High prevalence 7-40%
- Mildly ↑TSH normal T4
- Asymptomatic
iii. Auto-immune hypothyroidism - 2-28%
- TPO-Ab appear from 8 years onwards – increase with time
iv. Autoimmune hyperthyroidism - Coeliac disease
a. Celiac disease more common in T21 – prevalence 3-18% (vs. 1% in general population)
f. Diagnosis = IgA-tTG preferred single test
g. Screening
i. HLA typing first line – if negative no serological testing
ii. If positive 2-3 yearly serological testing - OSA
b. Prevalence = up to 100%
c. Associations
i. Pulmonary hypertension
ii. Reduced verbal IQ
iii. Reduced executive functioning
d. Screening
i. PSG in all children over 4 years
e. Treatment
i. Tonsillectomy resolved 30-50% of OSA
ii. 50-75% had persistent OSA
iii. Early use of CPAP recommended - Atlanto-axial instability
c. Incidence
i. 1-2% of children with DS develop symptomatic AAI – features consistent with cervical myelopathy and/or cervical instability (torticollis, decreased neck ROM)
ii. 10-30% of DS have asymptomatic AAI on screening
d. Screening
i. Flexion/extension X-rays = demonstrates excessive movement of C1 relative to C2 implying instability
f. Guidelines
i. New guidelines suggest NO routine screening
Klinefelter - XXY
- Key points
a. Klinefelter syndrome (KS) = chromosomal disorders in which there is >=1 extra X chromosome
b. Undiagnosed in most males
c. Most common cause of primary male hypogonadism
c. The greater the number of X chromosomes, the greater the phenotypic consequences - Clinical presentation
a. Normal phenotype and go unrecognized for life
b. Learning difficulty in childhood (but most have normal IQ)
c. Delayed puberty at adolescence (primary hypogonadism - hypogonadotrophic)
d. Infertility as adult (atrophy of seminiferous tubules)
Key features
- eunochoid body habitus (tall, slim and underweight, with long legs and long arms)
- gynaecomastia
- small testes
- IQ decreased
- behavioural phenotypte
- Investigations = karyotype, microarray
- Management
a. Testosterone, LH and FSH levels – check at age 11-12 years
i. Replacement therapy with testosterone therapy once LH and FSH begin to rise above normal
b. Aromatase inhibitors – treatment for gynacomastia
c. Screening for complications
i. Fasting glucose, lipids HbA1c – at risk of metabolic syndrome
ii. DEXA - Prognosis
a. Increased morbidity in later life from pulmonary diseases, cancers (including breast), diabetes, SLE (extra X chromosome)
Turner syndrome XO
- Epidemiology
a. Occurs in 1/5000, most spontaneously abort (95-99%) - Genetics + pathogenesis
a. 45,X (monosomy X) = 45%
i. X chromosome is derived from mother in 2/3
b. 45,X mosaicism = 50%
i. Examples – 45X/46XX or 45X/47XXX
ii. Results from sex chromosome non-disjunction during post-zygotic cell division
iii. Presence and degree of mosaicism differs among different tissues
iv. Normal karyotype on peripheral blood sample does NOT preclude mosaicism in other tissues - Clinical presentation
a. Congenital lymphedema (puffy hands and feet at birth)
Key features
- short stature (95-100%)
- growth failure
- ovarian dysgenesis (streak gonads) and infertility (95%)
- ovarian failure (90%)
- delayed puberty (only 1/3 spontaneous)
- increased upper:lower segment
- defective dental development
- recurrent otits media (50-70%)
- SNHL (50% by adulthood)
- cardiac malformations (50%) (arch abnormalities, elongated, coarctation, bicuspid aortic valve)
- renal anomalies (Horseshoe kidney, collecting system abnormality)
- generally normal IQ
- Investigations
a. Standard karyotype
i. Peripheral blood mononuclear cells - To detect mosaicism minimum of 30 cells in metaphase should be scored
ii. If negative and high suspicion – perform using a different tissue such as skin fibroblasts or buccal mucosal cells - Management
a. Growth
i. GH – should be started when height < 5th centile: increase rate of growth without increasing bone age
iv. Commencement of oestrogen leads to growth plate closure
b. Puberty
i. Oestrogen should be commenced for 2/3 who do not enter spontaneous puberty between 12-14 age - Complications
a. ↑ risk of autoimmune problems (hypothyroidism, coeliac disease)
b. ↑ risk of aortic dissection
47, XYY
- Tall stature
- Mild delay in motor and language
- Normal puberty + fertility
- NO increase in aggression
47, XXX
- Most common sex chromosome abnormality in females
- Usually incidental diagnosis
- May have slightly lower IQ 15-30 than siblings
45,X/46,XX mosaicism
- Most common sex chromosome mosaicism diagnosed by amniocentesis + prenatal karyotype
- Mild clinical features of Turner syndrome
- Many women undergo spontaneous puberty and are fertile
William syndrome
- Genetics
a. Heterozygous micro‐deletion 7q11.23
c. AD – most cases are de novo, very rarely transmitted - Clinical presentation
a. Irritable infant
b. Child with short stature and developmental delay
c. Specific behavioural profile – overfriendliness, social disinhibition, excessive empathy, attention problems, non-social anxiety
Key features
- Elfin-like facies (periorbital fullness of SC tissue i.e. puffy eyes, long flat philtrum)
- CHD (supravalvular AS, peripheral PS, RAS, HTN)
- endocrine (hypercalcaemia)
- neuro and behaviour (as above, mild-mod ID, cocktail party personality)
- Investigations
a. Microarray OR FISH OR duplication/deletion testing - Treatment
a. Nothing specific
22q11.2 deletion
= DiGeorge syndrome = Velocardiofacial Syndrome
- Epidemiology
a. 1/4000 - Genetics
a. Continugous gene deletion syndrome
b. Deletion
i. Heterozygous 22q11 deletion
c. AD – 93% de novo, 7% inherited
d. DiGeorge syndrome = neonates with thymic hypoplasia and hypocalcaemia
e. 3rd and 4th pharyngeal POUCH fail to develop - Clinical presentation
a. Neonate with congenital abnormalities
b. Older child with developmental delay or short stature
Key features = catch 22
- C: cardiac (conotruncal anomalies, truncus arteriosus is pathognomonic, TOF, interrupted arch, VSD)
- A: abnormal facies (cleft palate but NOT lip, bifid uvula)
- T: thymic hypoplasia (impaired T cell function)
- C: cleft palate
- H: hypocalcaemia (parathyroid hypoplasia)
- 22: 22q11.2 deletion
Other features
- cognitive impairment
- psychiatric e.g. schizophrenia
- Investigations
a. FBE - lymphocytes
b. CMP – calcium
c. CXR - thymus, cardiomegaly
d. Renal USS
e. Echocardiogram
f. FISH / microarray for diagnosis
i. Test parents
g. NOTE: must assess for immunodeficiency prior to live vaccine - Prognosis
a. Mean IQ is 75: 30% have intellectual disability, 75% have learning difficulties, nonverbal IQ < verbal IQ
b. 20% have ASD
c. 60% have a psychiatric illness (25% schizophrenia)
Cornelia de lange syndrome
- Genetics
a. Single gene mutation
i. Usually de novo (pts do not reproduce)
ii. Risk to siblings 1.5% due to possible germline mutation - Clinical manifestations
a. Severe intellectual disability + microcephaly
b. Growth retardation
a. Dysmorphism
i. Unibrown (synophrys), arched eye brows
ii. Long eyelashes
iii. Hirsutism
b. Musculoskeletal
i. Ulnar ray defects
c. Other
i. Severe GOR
iii. Infertility - Investigations
a. Single gene sequencing (cannot do microarray)
b. Whole exome - Treatment
a. Developmental
b. Monitoring – GOR, cardiac, developmental, hearing, vision
Noonan syndrome
- Genetics
a. AD – 2/3 de novo mutation - Complications
a. Face
b. Physical features
i. Short stature
ii. Broad or webbed neck
iii. Widely spaced nipples
c. Congenital heart disease
i. Pulmonary valve stenosis
d. Other
i. Cryptorchidism in males
ii. Developmental delay - Investigations
a. PTPN11 gene sequencing
b. Noonan gene panel
c. Whole exome - Management
a. Coags – risk of bleeding (d/t coag defect as part of syndrome)
b. No screening recommended for leukaemia
LEOPARD syndrome
Noonan with multiple lentigines
L = lentigines (Lentigines, or liver spots, are benign lesions that occur on the sun-exposed areas of the body) E = ECG conduction defects / HOCM O = occular hypertelorism P = pulmonary stenosis A = abnormalities of genitalia R = retarded growth D = deafness
Costello syndrome
- Clinical manifestations
a. FTT = due to severe postnatal feeding difficulties
b. Developmental delay or ID
c. Physical features
i. Loose, soft skin with deep palmar and plantar creases
ii. Papillomata of face and perianal region
d. Musculoskeletal
i. Diffuse hypotonia and joint laxity
ii. Hold hand in ulnar deviated position
e. Cardiac
f. Malignancy
i. 10-15% tumour risk - Rhabdomyosarcoma
- Ganglioneuroblastoma
- Bladder carcinoma
ii. Screen with 3/12 USS until 6-8 years of age
Cardiofaciocutaneous syndrome
- Clinical manifestations
a. Prolonged feeding abnormality FTT
b. Developmental delay
c. Seizures
d. Facies
e. Cutaneous
i. Xerosis
ii. Hyperkeratosis
iii. Dystrophic nails
f. Cardiac
i. HOCM > PS
g. Malignancies
i. ALL
Sotos syndrome
- Genetics
a. NSD1 mutation - >95% de novo
b. If neither parent have the mutation – risk to siblings is <1% - Clinical manifestations
a. Facial features
i. Broad and prominent forehead + large head
ii. Sparse frontotemporal hair (high anterior + temporal hair line)
b. Learning disability
c. Overgrowth
i. Height and/or head circumference >2 SD above the mean
ii. Height may normalize in adulthood
iii. Macrocephaly usually present in all ages - Diagnostic criteria
a. Overgrowth – height and or HC >2 SD above the mean typically prenatal onset
b. Facial gestalt – high bossed forehead, sparse frontotemporal hair, long narrow face, downslanting palpebral fissures, prominent jaw
c. Learning disability – mild to severe - Investigations
a. Microarray (10%)
b. Single gene NSD1 sequencing (90%)
c. Overgrowth ‘panel’ via clinical exome
Marfan syndrome
- Genetics
a. AD
b. FBN1 gene (chromosome 15q21.1) – 75% have one affected parent, 25% de novo mutation
c. Defective fibrillin, component of connective tissue - Clinical manifestations
a. Ocular
i. Ectopia lentis – 50-80% (UPWARD)
b. Cardiac
Dilatation of aortic root predisposing to aortic tear and rupture, enlargement of proximal PA
ii. MVP +/- MR, Tricuspid valve prolapse
c. Skeletal
i. Bone overgrowth, arm span > height
ii. Arachnodactyly
iii. Joint laxity – see scoring system
Chest wall deformity
d. Other
i. IQ normal
ii. Spontaneous pneumothorax - Investigations
a. FBN1 gene sequencing - Treatment
a. Cardiology
i. Aggressive control of blood pressure – ARB/ACE-I/ beta blocker
ii. Usually started if any evidence of aortic dilatation
iii. Annual echocardiogram to monitor for aortic root dilatation
b. Opthal = annual examination
c. Orthopaedic surgeon = evaluation for scoliosis and management of lax joints
Marfan syndrome - dx criteria / scores
- Diagnosis = Ghent criteria
a. In presence of family history (first degree relative), one of the following diagnostic:
i. Lens ectopia
ii. Systemic score >=7 (points to a number of clinical features)
iii. Aortic root enlargement (Z score >2.0 in those >20 years, or >=3 in those <20 years)
b. In absence of family history, one of the following:
i. Aortic root enlargement (Z score >2.0) + ectopic lens
ii. Aortic root enlargement (Z score >2.0) + systemic score >7
iii. Aortic root enlargement (Z score >2.0) + causal FBN1 mutation found
iv. Ectopic lens + causal FBN1 mutation found
Systemic Score
- 3 points: wrist and thumb sign
- 2 points: pectus carinatum, hind food deformity, pneumothorax, dural ectasia, protrusion acetabula
- 1 point: reduced upper segment lower segment ratio and increased arm span height ratio, scoliosis/kyphosis, reduced elbow extension, facial features, skin striae, myopia, mitral valve prolapse
Homocystinuria
- Genetics
a. CBS mutation
b. AR
c. Cystathionine beta-synthase (CBS) deficiency
d. Homocysteine is an intermediary amino acid, formed by conversion of methionine → cysteine - Classification
a. B6 responsive milder phenotype
b. B6 non-responsive - Clinical manifestations
a. Ocular
i. Ectopia lentis – downward dislocation
b. Skeletal system
i. Excessive height
ii. Long limbs
d. CNS
i. Developmental delay, ID
e. Other
i. Seizures - Investigations
a. Plasma total homocysteine and methionine = markedly elevated (do NOT test urine)
b. Most detected on newborn screening
c. CBS gene sequencing - Treatment
a. Vitamin B6 if responsive (CBS enzyme is pyridoxine dependent)
b. Methionine restricted diet
c. Folate + B12
Marfan syndrome versus homocystinuria
Homocystinuria = downward dislocation + down IQ (low IQ) + stiff
Marfan syndrome = upward dislocation + up IQ (high IQ) + stretchy
Marfan
- AD
- FBN1 mutation – chromosome 15
- IQ: Normal
- Hyperextensible joints
- Upward dislocation of ocular lens (ectopia lentis)
- Aortic root dilation/dissection
- Valvular insufficieny
- GHENT criteria
- Beta blockers for aneurysm +/- Surgery
Homocystinuria
- AR
- CBS mutation – chromosome 21
- Intellectual disability
- Rigid joints
- Downward dislocation of ocular lens (ectopia lentis)
- Vaso-occlusive disease
- High plasma/urine levels of homocysteine and methionine
- Treat with high dose vitamin B6 (if responsive)
Ehlers Danlos syndrome
- Genetics
a. Classic EDS = AD
b. 50% de novo mutations
c. Common mutations – COL5A1, COL5A2
Multiple types:
Classic (EDS I, EDS II) = skin+joint
Hypermobility (EDS III) = joint+ANS dysfunction
Vascular (EDS IV) = vessel/viscous rupture
Kyphoscoliosis (EDS VI) = hypotonia, joint laxity, kyphoscoliosis
Arthrochalasia (EDS VIIA, EDS VIIB) = short+contractures+fractures+hypotonia
Dermatosparaxis (EDS VIIC) = saggy skin+hernias+blue sclerae
- Clinical manifestations
a. Skin
i. Poor healing
ii. Easy bruising and fragility
iii. Soft, douching skin
iv. Abnormal scar formation – hypertrophic
v. Translucency
vi. Skin spheroids
vii. Stretchy – defined >4cm from neutral site until feeling resistance
b. Joints
i. Hypermobility – (Beighton hypermobility scale)
ii. Multiple dislocations – shoulder, patella, TMJ
c. Marfanoid phenotype
i. Pes planus
ii. Pectus excavatum
iii. High arched palate
d. Eye
i. Myopia
ii. Lens dislocation
e. Cardiac / vascular
i. MVP
ii. Aortic root dilation
iii. In vascular form – prone to arterial rupture (spleen, iliac, renal), prone to viscus rupture
f. Prolapses
i. Hernias
ii. Cervical insufficiency
iii. Uterine prolapse
iv. GIT/bladder diverticulae
g. ANS dysfunction
i. Delayed gastric emptying / IBS
ii. POTS
Osteogenesis imperfecta
- Key points
a. Spectrum from perinatal lethality -> severe skeletal deformities -> mild predisposition to fractures with normal stature lifespan - Genetics
a. AD – most, mostly de novo, COL1A1 and COL1A2 - Pathogenesis
a. Collagen forms extracellular matrix of most tissues (teeth, sclera, ligaments, blood vessels, skin) and organic part of bone - Clinical presentation
a. Prenatal – short long bones
b. Childhood – multiple fractures
a. Triad
i. Fractures with minimal or absent trauma – any bone, most common extremities
ii. Variable dentogenesis imperfecta (DI) – grey or brown teeth that may appear translucent
iii. Hearing loss (adulthood)
Key features: fractures, dental anomalies, hearing loss, blue sclerae, osteoporosis, Wormian bones
- Classification
a. Type I: classic non-deforming OI with blue sclerae
b. Type II: perinatally lethal OI
c. Type III: progressively deforming OI
d. Type IV: common variable OI with normal sclerae
e. Type V-8: uncommon - Investigations
a. Antenatal (Severe forms)
b. Radiographic
i. Fractures of varying ages and stages of healing
Wormian bones = sutural bones which are 6x4mm (in diameter) or larger, in excess of 10 in number, with a tendency to arrange in a mosaic pattern
iii. Osteopaenia
iv. Spine: Scoliosis, “Codfish” vertebrae (result from spinal compression fractures), Compression fractures
v. Chest = Pectus excavatum or carinatum
c. Molecular genetic testing
i. OI gene panel
ii. COL1A1 and COL1A2 sequencing
d. Biochemical - vitamin D, CMP, ALP typically normal
i. May have elevated ALP or hypercalciuria as a marker of increased bone turnover - Treatment
a. Non-pharmacological
i. Bracing of limbs
ii. Orthotics to stabilise lax joints
Physical + OT
b. Surgical = correction of deformity and fracture
c. Medical
i. Bisphosphonates - IV pamidronate most commonly used
Blue sclera - differentials
Blue sclerae are characteristic of a number of conditions, particularly connective tissue disorders.
Osteogenesis imperfecta
Ehlers Danlos syndrome
Scleritis
Marfans
Achodroplasia
- Epidemiology
a. The most common form of short limbed dwarfism: 1/15000-1/40,000 - Genetics + pathogenesis
a. Mutation in FGFR3 - fibroblast growth factor 3 receptor (FGFR3)
b. AD - however 80% de novo
c. Gain of function mutation: leads to activation of the receptor in the absence of FGF
d. Homozygous mutations are usually lethal in the newborn period - Clinical presentation
a. Prenatal (late) or neonatal presentation (most common)
b. First year of life with short long bones, hypotonia + gross motor delay but normal IQ - Clinical manifestations
a. Short stature
i. Rhizomelia (short arms and legs, proximal limbs more involved)
ii. Note birth length can be low-normal/ slightly less than normal
iii. Hyperextensible joints (extension restricted at the elbow)
iv. Delayed motor milestones with hypotonia
b. Midface hypoplasia
c. Macrocephaly
d. Intelligence is normal - Diagnosis
a. Skeletal survey
b. Genetic testing NOT used for diagnosis - Investigations
a. X-ray
b. Genetic = sequencing of FGFR3 - Complications
a. Spinal cord stenosis = compression at foramen magnum, hydrocephalus, lumbar canal stenosis
b. Sleep apnoea = hypoxemia during sleep
c. Restrictive pulmonary disease ( < 5%)
d. Middle ear disease - Prognosis
a. Normal life span
b. Some have tried surgical limb lengthening / growth hormone → controversial
Alagille syndrome
- Genetics
a. Single gene disorder
i. JAG1 = 90% - Point mutation 90%
ii. NOTCHC2 = 1-2%
b. 30-50% inherited, 50-70% de novo
c. AD - Clinical presentation
a. Neonate with cholestatic jaundice, bile duct paucity
b. Structural/ functional renal abnormality
Key features
- dysmorphic facies
- hepatic: intrahepatic biliary dysgenesis -> cholestasis
- vertebral: butterfly vertebra
- heart: pulmonary stenosis (peripheral)
- eye: posterior embryotoxin (a corneal abnormality)
- Investigations
a. Microarray – detects deletion (10%)
b. JAG1 sequencing
c. NOTCH2 sequencing - Treatment
a. MDT management
b. Ursodeoxycholic acid
c. Other medications for pruritis – cholestyramine, rifampicin - Prognosis
a. Good prognosis = 10% mortality – vascular accident, cardiac disease + liver disease result in death
b. Patients likely to have pruritis, xanthomas with markedly elevated serum cholesterol, neurological complications of vitamin E deficiency if untreated
CHARGE syndrome
- Genetics
a. CHD7 gene mutation – encodes chromodomain helicase DNA binding protein
b. AD – most de novo mutation - Clinical manifestations
- Coloboma
- Heart defect
- choanal Atresia
- Retarded growth/development
- Genital (e.g. cryptorchidism, hypogonadism
- Ear anomalies
- Other: cranial nerve anomalies, swallowing difficulty
Brachio-Oto-Renal syndrome
d. Abnormality of the 1st/2nd brachial arches
- Clinical manifestations
a. Ear
i. Deafness (conductive, sensorineural, mixed)
ii. Preauricular pits/tags
iii. Auricular deformity
b. Brachial fistulae/cysts
c. Renal malformations
i. Range from hypoplasia to bilateral renal agenesis
Alstrom syndrome
- Clinical manifestations
a. Cone-rod dystrophy
i. Visual impairment
ii. Photophobia
b. Obesity
c. Progressive SNHL
d. Dilated or restrictive cardiomyopathy
e. Insulin resistance syndrome
Bardet-Biedl syndrome
- Clinical manifestations
a. Rode-cone dystrophy
i. Night blindness by 7-8 years
ii. Legal blindness by 15 years
b. Truncal obesity
c. Postaxial polydactyly
d. Cognitive impairment + learning disability
e. Urogenital
- hypogonadotropic hypogonadism
a. Poor prognosis
Bloom syndrome
- Genetics + pathogenesis
a. AR
b. BLM gene mutation - encodes RECQl3
c. Results in genome instability – defects in the recognition and/or repair of damage to DNA - Clinical manifestations
a. Growth
i. Severe pre- and post-natal growth deficiency
b. Cutaneous
i. Erythematous skin
ii. Sun sensitive - malar distribution
iii. Telangiectasias, café au lait spots
c. Malignancy risk
i. 50% develop cancer by the age of 25 years
d. Facies
e. Normal IQ
f. Endocrinology
i. Primary hypogonadism
ii. Diabetes
iii. Infertility in men, severely reduced in female
g. Immunodeficiency
i. Recurrent sinuopulmonary infections
Cleidocranial dysostosis
- Genetics + pathogenesis
a. CBFA1 gene – responsible for initial differentiation of osteoblasts to form skeletal structures - Clinical manifestations
a. Bones
i. Defective bone formation
ii. Clavicles - hypoplastic/aplastic
iii. Large head with delayed suture closure
iv. Narrow pelvis
v. Spinal abnormalities
b. Short stature
c. Dental
i. Supernumerary teeth - Treatment
a. Extraction of supernumerary teeth
Holt-Oram syndrome
- Clinical manifestations
a. Skeletal malformations
i. Upper extremity malformation – involve radial, thenar or carpal bones - Thumb - absent, hypoplastic or triphalangeal
- Radius - absent or hypoplastic
ii. Syndactyly between 1st and 2nd fingers
b. Cardiac defect
i. Ostium secundum ASD
ii. VSD
iii. Cardiac conduction disease
Smith-Lemli-Opitz
- Genetics + pathogenesis
a. AR
b. Disorder of cholesterol synthesis - Clinical manifestations
a. Growth retardation
i. Microcephaly = 80-85%
b. Dysmorphic features
i. 2-3 toe syndactyly
ii. Post-axial polydactyly
c. Cardiac
d. Intellectual + behaviour = severe to mild
e. Congenital cataract
f. Genital abnormality
i. Hypospadias and/or cryptorchidism
ii. 46, XY sex reversal
iii. 46, XX bicornuate uterus - Investigations
a. Raised 7-dehydrocholsterol (7-DHC)
b. NOT DIAGNOSED genetically - Treatment
a. Cholesterol supplementation
Embryology of branchial arches - brief
- Weeks 2-6 of gestation – brachial arch develops
- Neck is hollow tube with arches, between which are clefts and pouches
- Clefts are on outside – ectoderm
- Pouches are on inside - endoderm
- Arches are neural crest in origin
First
- Cleft: External auditory canal
- Arch: Mandible, Muscles of mastication
- Pouch: Eustachian tube
Second
- Cleft: Sinus of His
- Arch: Muscles of facial expression, Malleus and incus, Hyoid bone
- Pouch: Palatine tonsil, Supratonsillar fossa
Third
- Cleft: Sinus of His
- Arch: Hyoid bone, Stylopharyngeus muscle
- Pouch: Inferior parathyroid glands, Thymus
Fourth
- Cleft: Sinus of His
- Arch: Epiglottis, Thyroid cartilage, Pharyngeal muscles, Aortic arch
- Pouch: Superior parathyroid glands
Craniofacial microsomia
- Included phenotypes
a. Hemifacial microsomia
b. Oculo-auriculo-vertebral spectrum
c. Goldenhar syndrome
d. First and second branchial arch syndrome
e. Otomandibular dysostosis
f. Facio-auriculo-vertebral syndrome
g. Lateral facial dysplasia - Clinical manifestations
a. Spectrum of malformations primarily involving structures derived from the 1st and 2nd branchial arches
b. Facial asymmetry = results from maxillary and/or mandibular hypoplasia
c. Pre-auricular or facial tags
d. Ear malformations
i. Microtia = hypoplasia of external ear
ii. Anotia = absence of external ear
iii. Aural atresia = absence of external ear canal
iv. Hearing loss
e. Cleft lip and/or palate
f. Non-craniofacial malformation = vertebral, renal, cardiac, limb
Goldenhar syndrome
• Sporadic – cause unknown • 1st and 2nd branchial arch maldevelopment • Clinical manifestations o Hemifacial microsomia o Ear anomalies – microtia, accessory preauricular tags/ pits/ middle ear defects Conduction hearing deafness o Mandibular abnormalities o Can be associated with cleft palate o Vertebral defects
Treacher Collins syndrome
- Genetics
a. TCOF1 (Treacher Collins-Franschetti Syndrome 1) mutation – chromosome 5 (most common)
b. Abnormal 1st and 2nd branchial arches
c. AD
d. Variable penetrance - Clinical manifestations
a. Face
i. Hypoplasia of zygomatic bones and mandible – mandibulofacial dysostosis
ii. Malar hypoplasia – small midface
b. Ear
i. External ear abnormalities, microtia
c. Eye
i. Coloboma (notching) of the lower eyelid
d. Other
i. +/- cleft palate
ii. Normal IQ - Diagnosis
a. Clinical
b. Can do genetic testing – TCOF1 sequencing
NOTE Nagar syndrome is similar: 2. Clinical manifestations a. Similar to Treacher Collins - distinguished from TSC by absence of eyelid colobomas b. Severe clef palate ALWAYS present c. Short stature d. Normal intelligence
Pierre Robin Sequence
- Key points
a. Due to mandibular hypoplasia (occurs < 9 weeks of development)
c. SEQUENCE – underdeveloped lower jaw begins a sequence of events, which leads to the abnormal placement of the tongue, resulting in the clef palate and respiratory obstruction - Clinical manifestations
a. Triad
i. Micrognathia
ii. Glossoptosis
iii. Cleft palate
b. Consequences
i. Airway obstruction = tongue prolapse backward
ii. Feeding difficulties
c. Often isolated abnormality but 1/3 have associated anomalies, Stickler syndrome, VCFS - get eye examined - Natural history
a. Major initial post-natal concern is airway obstruction
i. Posterior prolapse of the tongue (during inspiration) may cause life-threatening airway obstruction
b. There should be sufficient mandibular growth by 3-12 months of age to protect the airway
c. By age 4-6 of life, there has generally been sufficient mandibular growth to resemble a normal profile - Treatment
a. Prone positioning
b. Nasopharyngeal airway
c. Positive pressure ventilation (if required)
d. Surgical airway
e. Glossopexy (tong-lip adhesion) – tongue anchored to lower lib and mandible to relieve obstruction in infants with Pierre Robin sequence
f. Mandibular distraction (normally 9-18 months of age, unless airway concerns)
Stickler syndrome
- Key points
a. Commonest syndrome associated with Pierre Robbin Sequence - Genetics
a. Pathogenic variants in genes that encode type 2 collagen
ii. Type II collagen is a major component of cartilage, vitreous, nucleus pulposus - Clinical manifestations (eyes, ears, face, bones)
a. Ocular
i. Myopia
ii. Cataract
iii. Retinal detachment
b. Auditory
i. Hearing loss – high frequency
ii. Conductive and sensorineural
c. Craniofacial abnormality
i. Midfacial underdevelopment
ii. Cleft palate, submucous cleft, bifid uvula
d. Skeletal
i. SUFE or Perthes-like disease
ii. Scoliosis, spondylolisthesis, or Scheuermann-like kyphotic deformity
iii. Osteoarthritis <40 years
e. Other
i. MVP - Note
a. Marshall syndrome is a related CT disorder with overlapping characteristics
Fragile X/FMR-1 Related Disorders
- Spectrum
a. Fragile X syndrome
b. Fragile X-associated tremor/ataxia (FXTAS)
c. FMR-1 related primary ovarian insufficiency - Epidemiology
a. Most common form of inherited intellectual disability (accounts for 5% of males with ID) - Genetics
a. X linked disorder – X linked dominant (females can have symptoms)
b. Loss of function of FMR1 gene - CGG repeats + aberrant methylation
c. Classification
i. < 55 = normal, no risk for offspring
ii. 55-200 = premutation
iii. > 200 = full mutation - Clinical presentation
a. Typically present with developmental delay at 2-4 years
b. ID = IQ 30-50
c. Behaviour = ADHD, autistic traits, impulsive, anxious, shy - Clinical manifestations
a. Fragile X
- key features: large ears, macro-orchidism (POST PUBERTAL), long face and prominent jaw (post pubertal), ID, ASD (eye avoidant)
- behavioural abnormalities are a/the key presentation in pre-pubertal boys
b. Fragile X-associated tremor/ataxia (FXTAS)
i. Occurs in males (and some females) with FMR1 premutation
ii. Characterised by late-onset progressive cerebellar ataxia and intention tremor
iii. Males (45%), females (17%)
c. FMR-1 related primary ovarian insufficiency
i. Cessation of menses <40 years
ii. Occurs in 20% of females with FMR1 premutation
iii. About 5-10% of women with POI will conceive - Investigations
a. Triplet repeat analysis
i. Sizing of triplet repeat – PCR/Southern Blot
b. NOT DETECTED ON MICROARRAY/SEQUENCING
Huntington’s disease
- Genetics + pathogenesis
a. AD
b. CAG repeats
c. Huntingtin gene (HTT) = exon 1 HTT
d. Displays anticipation
e. Larger repeat = earlier onset disease
f. Fully penetrant if >=40 repeats - Clinical manifestations
a. Progressive disorder of motor, cognitive and psychiatric disturbance
b. Mean age of onset 35-45 years – median survival time 15-18 ears after onset - Treatment
a. No treatment available
Cri du chat syndrome
- Key points
a. MACROdeletion syndrome - Genetics
a. Partial deletion of the short arm of chromosome 5 = 80%
b. Translocation involving 5p = 5% - Clinical manifestations
a. High-pitched, cat like crying
b. Dysmorphic facies
i. Hypertelorism
ii. Round face
iii. Downslanting palpebral fissures
iv. Broad nasal bridge
v. Low set and/or malformed ears
c. Low birth weight
d. FTT
e. Hypotonia
f. Psychomotor delay
g. ID
h. Microcephaly
Foetal alcohol syndrome
- Key points
a. Leading preventable cause of birth defects and developmental disabilities - Pathogenesis
a. Alcohol is a teratogen with irreversible CNS effects
b. Results in reduced brain volume (specifically frontal lobe, striatum, caudate nucleus, thalamus + cerebellum) thinning of corpus callosum, and abnormal functioning of amygdala
c. “Safe” threshold has not been identified
d. Alcohol eliminated from fetal compartment at 3-4% of the maternal rate
e. Much of alcohol excreted by the fetus into the amniotic fluid is ‘recycled’ through fetal swallowing
f. Deleterious at all ages of gestation - Diagnostic criteria (“FAS” = face, abnormal learning, short)
a. Traditional criteria = all of the following
i. All 3 facial abnormalities = smooth philtrum, thin vermillion border, small palpaberal fissures
ii. Documentation of growth deficits
iii. Documentation of CNS abnormality (structural or fuctional)
b. More recent criteria = combination of scoring in 3 areas
i. Prenatal alcohol exposure
ii. Neurodevleopmental domains
iii. Sentinel facial features
VACTERL/VATER Association
- Key points
a. Group of birth defects which tend to co-occur
b. Association – NOT syndrome
c. No pathogenic cause to explain grouped inheritance - Clinical manifestations
a. Vertebral = 80%
i. Hypoplastic vertebrae or hemifertebrae
ii. May result in scoliosis
b. Anal = 55%
i. Imperforate anus
c. Cardiac = 75%
i. VSD, ASD, TOF most common
ii. Truncus, TGA less common
d. Tracheo-esophageal fistula = 70%
i. More likely to have cardiac anomaly
e. Renal = 50%
i. 35% have a single umbilical artery
ii. Incomplete formation of one or both kidneys
f. Limb = 70%
i. Displaced or hypoplastic thumb
ii. Polydactyly
iii. Syndactyly
iv. Radial aplasia
g. Extension
i. Single umbilical artery
ii. Ambiguous genitalia
iii. Abdominal wall defects
iv. Diaphragmatic hernia
h. Growth
i. Difficult to gain weight
