Syndromes based on features Flashcards
Holoprosencephaly, cleft palate
Trisomy 13 – Patau
Tri 13 vs 18 – which has female bias?
Tri 18
4F:1M
clenched hands at birth
Tri 18
Rocker bottom feet
Tri 18 (1 in 5-8k)
small for gestational age
Tri 18
amenorrhea, short stature
Turner
klinefelter, turner – recurrence risk?
Klinefelter – no evidence of increased risk
Turner – very low ;
fibrosis of seminiferous tubules (infertility)
Klinefelter (almost universal symptom)
what kind of cytogenetic change results in a dicentric chromosome?
90% of Robertsonian translocations are dicentric.
Frequency of Robertsonian translocation?
1 in 1,000
Frequency of Kleinfelter syndrome?
1 in 550
Frequency of Turner?
1 in 1500-6000 (but 3% of conceptuses)
Frequency of Robertsonian translocation (chr 13, 14, 15, 21, 22)
1 in 1,000
most commonly, 14/21 and 13/14
Frequency of balanced translocation
1 in 500
If one is a carrier for ___, a possibility is a child with UPD.
What are prenatal testing options for Uni Parental Disomy (UPD)?
Robertsonian translocation
NOT NIPT –> won’t tell you about UPD
UPD needs CVS/Amnio –> SNP CMA testing
At which step in the cell cycle does the majority of non-disjuction occur? In which sex does the majority occur?
Meiosis I, maternal
UPD from trisomy rescue happens more often with 2 maternal chromosomes
In non-disjunction,
If there is a trisomy rescue situation, uniparental disomy is more common from the ___’s chromosomes.
In contrast, in a monosomy situation, uniparental disomy is more common from the ___’s chromosomes.
Trisomy rescue –> UPD maternal
(UPD from trisomy rescue happens more often with 2 maternal chromosomes)
Monosomy duplication –> UPD paternal
…all because non-disjunction more commonly comes from mother’s side.
UPD is often diagnosed following which clues?
- discrepancies between CVS and amnio
- confined placental mosaicism
- imprinting-related phenotype
- recessive disease in child when a parent is only a carrier
Which chromosomes/conditions are associated with imprinting defects / imprinted genes expressed from which parent?
imprinted on __ results in ___
chr 15 - mat - Prader-Willi – [Prader needs Fader’s copy]
chr 15 - pat - Angelman – [man needs mam]
chr 7 - pat - Russel-Silver
chr 14 - pat - short/scoliosis/hypotonia/dev delay/prec puberty
chr 6 - mat - transient neonatal diabetes mellitus (also macroglossia)
chr 11 - mat - Beckwith-Wiedemann
chr 14 - mat - mental retardation, short-limb dwarfism
growth retardation - except head, triangular facies, limb/face asymmetry
Russel-Silver
can be caused by upd(7)mat
macroglossia, organomegaly, omphalocele, Wilm’s tumor
Beckwith-Wiedemann
short stature, developmental delay, hyperextensible joints, , hypotonia, minor facial dysmorphism
upd(14)mat
mental retardation, short-limb dwarfism with narrow thorax, scoliosis, low life expectancy due to due to respiratory issues
upd(14)pat –> more severe than upd(14)mat
neonatal hypotonia and poor suck with failure to
thrive, developmental delay and/or mental retardation, childhood-onset
obesity, short stature, hypogonadism, and severe
behavior problems.
Prader-Willli
upd(15)mat (30%)
deletion at 15q12 (70%)
imprinting defect (2%)
severe mental retardation with absent speech, ataxic movements
and gait, increased tone after infancy, seizures, and a
happy disposition with paroxysmal laughter
Angelman – paternally imprinted
deletion at 15q12 on mat chrom (70%)
UBE3A mutation (5%)
upd(15)pat (4%)
imprinting defect (3%)
unknown (12%)
chromosomes with proven imprinted genes
6, 7, 11, 14, 15
UPD testing guidelines
SUMMARY OF CLINICAL AND DIAGNOSTIC
CONSIDERATIONS
- Chromosomes of known clinical relevance include 6, 7, 11,14, and 15.
- UPD testing should be considered for
(a) patients presenting with prenatally detected mosaicism
or Robertsonian translocations for clinically relevant
chromosomes.
(b) patients presenting with features of disorders known to be associated with UPD. - Testing should be performed on DNA collected from the mother, father, and child/fetus using polymorphic markers.
- Reporting of results includes at least two fully informative markers from each chromosome of int
Robertsonian translocation t(14;21)) - risk of Down syndrome birth based on if from mom and dad
female carrier - 10-15% (true for all acrocentrics paired w chr 21)
male - 3%
Cri-du-Chat
—> mechanism? traits?
5p deletion
General
Cry - Mewing Of A Kitten
Craniofacial Dysmorphism:
Microcephaly
Moonlike Face
Hypertelorism
Micrognathia
Rare 1 in 40 k
Larynx -->Laryngealmalasia, Laryngeal Stridor
Distinctive Cry
Intellectual Disability (severe, IQ
Wolf-Hirschhorn –> mechanism?
traits?
4p deletion
General Severe growth retardation Sever intellectual disability Craniofacial Dysmorphism Microcephaly “Greek warrior helmet” ******** Genital abnormalities
Cardiac defects (~50%) *******
Defects in closure of scalp
Cleft lip and/or palate
Coloboma
Intellectual disability - Usually severe - IQ
Williams syndrome
- mechanism?
- features?
del(7)(q11.23q11.23) Submicroscopic: requires FISH Cardiac Defects Cardiac defects in 75% Supravalular aortic stenosis Elastin gene deletions Very outgoing, cute personality Infantile hypercalcemia Dysmorphic features Elfin facies
Velocardiofacial VS DiGeorge
Velocardiofacial Syndrome
Dysmorphic features Heart defect Ventricular septal defect Cleft palate Velopharyngeal incompetence Hypernasal speech Learning Disabilities (99%)
DiGeorge Syndrome
Dysmorphic features Heart defect -- Conotruncal Thymus hypoplasia/aplasia T-cell deficiency Hypoparathyroidism Hypocalcemia Intellectual disability --
22q deletion – prevalence?
1 in 2,000 !!
del(22)(q11.21)
One of the most common deletions (~1/2000)
Can be inherited from a parent (~10% are inherited)
Most not visible by routine cytogenetics
Diagnosed by FISH
Miller-Dieker
- mechanism?
- traits?
17p microdeletion
Type I lissencephaly
Can have isolated lissencephaly
Dysmorphic facies
Dysmorphic facies and lissencephaly – Miller-Dieker syndrome
Visible deletions – 50% of patients
FISH or molecular testing needed to detect all cases
Smith-Magenis
- mechanism?
- traits?
Dysmorphic facial features
Brachycephaly, flat mid-face, prognathism
Behavioral abnormalities
Self-destructive behavior
Seen in 75% of Smith-Magenis syndrome patients
Peripheral neuropathy
Sleep disorders
Intellectual disability
Deletion—17p11.2Prader Willi
- mechanism?
- traits?
UPD15mat – prader needs fader]
Moderate Intellectual disability Neonatal hypotonia Hypogenitalism Hyperphagia – obesity Short stature Small hands and feet Characteristic facies
Angelman
“Happy Puppet Syndrome” Severe Intellectual disability Seizures Absent Speech Paroxysms of laughter Tongue protrusion Stiff, ataxic gate Characteristic facies
mostly mat deletion (60%), some UPD15, some UBE3A deletion (10%)
del 1p36 syndrome: accounts for what percent of idiopathic ID? prevalence?
0.5-1.2% ;
1 in 5,000
del 1p36 syndrome
- traits? -mechanism?
Variable breakpoints – Different from many other contiguous gene syndromes
Maybe terminal or interstitial deletion
Maybe seen cytogenetically
Often missed with G-bands
Can be delineated by FISH
Telomeres studies
1p36.3 probe
Easily identified in array analysis
McDermid- Phelan syndrome
microdel 22q13
Hypotonia Severe Language Delay Mild Facial Dysmorphism Intellectual disability Deletion of SHANK3
ACMG recommends: “CMA [Cytogenetic microarray] testing for CNV [copy number variation] is recommended as a first-line test in the initial postnatal evaluation of individuals with the following:
- Multiple anomalies not specific to a well-delineated genetic syndrome
- Apparently non-syndromic DD/ID [developmental delay/intellectual disability]
- Autism spectrum disorders”
chance of finding CMA abnormality in population selected for
- pediatric
- ID/DD
17.4%
1q21.1
1q21.1 aberrations:
- Microdeletions and microduplications
Facilitated by low copy repeats
Patients with 1q21.1 deletion show variable phenotype
- Mild-moderate ID; microcephaly; cataracts; neuropsychiatric disorders; cardiac anomalies;
Patients with 1q21.1 duplication show variable phenotype
- ID/ASD; neuropsychiatric disorders; macrocephaly; dysmorphic features
Parents with aberrations may be mildly affected
15q13.3
Mostly associated with ~ 1.5 Mb deletion
Variable phenotype –not well defined
Mild ID (~50%); neuropsychiatric disorders; behavior problems; seizures
Many deletion inherited
Facilitated by low copy repeats
Non-allelic homologous recombination (NAHR)
CHRNA7 involved; but if only CHRNA7 syndrome not well defined
16p11.2
Microdeletions and microduplications
low copy repeats
Autism; minor facial anomalies; speech delay
parents may have no features
16p13.11
Microdeletions and microduplications
low copy repeats
Neuropsychiatric disorders; dysmorphic features; congenital heart defects
parents may have mild features
17q12 microdel
Renal cystic dysplasia; renal hypoplasia; abnormal renal function; cryptorchidism; elevated hepatic enzymes; MODY5
Similar to MODY syndrome
Minimal deleted region ~ 1.5 Mb
De novo or inherited
Facilitated by low copy repeats (in most cases)
Non-allelic homologous recombination (NAHR)
TCF2 and LHX1 involved
17q12 microDUP
Cognitive impairment, behavior abnormalities, epilepsy, renal abnormalities
Minimal deleted region ~ 1.5 Mb
De novo or inherited
Often inherited from parents with no or minimal features
Facilitated by low copy repeats (in most cases)
Non-allelic homologous recombination (NAHR)
15q24 microdel
Hypospadius; cryptorchidism; joint laxity; bowel atresia; scoliosis; growth hormone deficiency
DELAYED BONE AGE; ELEVATED TRIGLYCERIDES
Minimal deleted region ~ 1.7 Mb
All reported thus far - de novo
Facilitated by low copy repeats
Non-allelic homologous recombination (NAHR)
P450sec involved
1q41-1q42 del
Cleft palate; talipes; diaphramagmatic hernia
ENLARGED VENTRICLES; GYRAL MALFORMATIONS; SMALL CEREBELLUM
Similar to Fryns syndrome
Minimal deleted region ~ 1.17 Mb
All de novo
Mechanism of formation - unknown
DISP1 involved
2p15-2p16.1 microdup
Optic nerve hypoplasia; renal abnormalities; spasticity of legs; high palate; calcaneovalgus
PACHYGYRIA; ENLARGED 4th VENTRICLE; HYPOPLASIA OF CEREBELLUM AND BRAINSTEM
Minimal deleted region ~ 200 kb
All de novo
Mechanism of formation - unknown
VRK2 involved
if ultrasound abnormality, chance that CMA will yield DX that is NOT detectably by karyotyping?
6%
if AMA, chance that CMA will yield DX that is NOT detectably by karyotyping?
1.7%
When to use CMA in prenatal?
- > = 1 major structural abnormality on u/s
[replaces karyotype!] - diagnostic procedure with structurally normal fetus (CVS, amnio) – can do CMA or Karyo
- NO AGE LIMIT – not just for 35+ women
what is a molar pregnancy? how common is it? which test is necessary to detect it?
molar pregnancy, a.k.a., gestational trophoblastic disease (GTD)
1 in 1,000
rapid growth of large and random collection of grape-like cell clusters.
genetic issue - mostly placenta - rarely fetus also
needs SNP microarray, not just aCGH
advantage of SNP microarray over aCGH
- identity by descent (IBD)
- UPD
- contamination
- triploidy
bonus:
- complicated MCC delineation
- detection of complete mole
first cousins have +_____% risk of a kid with a congenital anomaly, relative to the general population
2-2.5% (due to recessive condition)
most common chromosome abnormalities at conception
Condition (% spontaneous abortion)
Total (94%)
- triploidy/tetraploidy (100%)–> thus importance of SNP CMA
- 45,X (99%)
- Tri16 (100%) –> most common trisomy in 1st trimester
- Tri18 (95%)
- Tri21 (78%)
- other Tri (99.5%)
- other sex chrom aneuploidy (21%) : XXY, XXX, XYY
- unbalanced rearrangements (85%)
- balanced rearrangements (16%)
Product of Conception –> why MCC studies done?
MCC = maternal cell studies
Cytogenetic studies on female POC can give false negative if contaminated with maternal cells. Need to also rule out complete moles.
Resolution of molecular methods
Metaphase banding
High-resolution banding
FISH
CMA
multicolor FISH
Metaphase banding / 5-10 Mb
High-resolution banding / 3-5 Mb
FISH / 35 Kb [1kb in research]
CMA / 200-500 Kb [1kb in theory]
multicolor FISH / 5-10 Mb
purpose of satellite in FISH
tracks centromeric regions for TOTAL chromosome count (generally)
what is a marker chromosome?
A marker chromosome (mar) is
a structurally abnormal chromosome in which no part can be identified.
The significance of a marker is very variable as it depends on what material is contained within the marker.
It is essentially a partial trisomy.
role of Y chromosome in Turner syndrome
Turner syndrome (TS) is one of the most common types of aneuploidy among humans, and is present in 1:2000 newborns with female phenotype. Cytogenetically, the syndrome is characterized by sex chromosome monosomy (45,X), which is present in 50-60% of the cases. The other cases present mosaicism, with a 45,X cell line accompanied by one or more other cell lines with a complete or structurally abnormal X or Y chromosome. The presence of Y-chromosome material in patients with dysgenetic gonads increases the risk of gonadal tumors, especially gonadoblastoma [ benign, but can turn into other malignant tumors]. The greatest concern is the high risk of developing gonadoblastoma or other tumors and virilization during puberty if chromosome Y-specific sequences are present.
significance of subtelomeric FISH
subtelomeric portions have higher rates of recombination, and are gene-rich – imbalances/rearrangements/tiny deletions are more likely to cause phenotype in these regions.
5% of unexplained MR caused by this.
Although CMA used, FISH still useful to find BALANCED rearrangements.
SNP array - what does log2 ratio tell you?
whether there is deletion/duplication in that area.
structural rearrangement breakpoints most often occur in these two places
- subtelomeric regions
- pericentromeric regions
i.e., near ends, or near center.
structural rearrangements: where most common? (“recurring”)
- Non-allelic homologous recombination (NAHR)–> most common. This means recombination between genes/repeats that are duplications of one another, at other cytogenetic locations - potentially on another chromosome.
- low-copy-number repeats –>reciprocal del/dup of regions between LCRs happens due to high homology of LCRs that “cross over”
- AT-rich palyndromes
- inversion polymorphisms
- non-homologous end joining (NHEJ)
- FoSTeS/MMBIR [e.g. X22q del/dup aka Pelizaeus-Merzbacher, MECP2dup, 17p13.3 del/dup]
FoSTeS: Fork stalling and template switching
MMBIR: microhomology-mediated break induced replication (MMBIR)
inverted Low-copy-number repeats (LCRs) on the same chromosome can lead to what genomic rearrangement for material between them?
inversion
inversion polymorphisms (submicroscopic) predispose to ___
which condition is classic example of inversion in parent predisposing to structural issue in child?
rearrangements
inversion polymorphisms arose through NAHR mediated by LCRs
Williams syndrome (28% of parents have inversion!) Sotos (100%)
non-homologous end-joining (NHEJ) is due to ____
conditions linked to NHEJ
LONG tandem repeats Alu repeats (short interspersed element - SINE) TTTAAA sequence --> curves DNA --> more prone to breaks
Duchenne
1p36
SAS - segmental aneusomy syndrome?
contiguous gene syndrome?
recurring SASs detectable by ____ technology
loss of gene or several genes resulting in a segment of aneusomy
several genes lost –> contigyous gene syndrome, e.g., 22q
1 gene –> e.g., Angelman
recurring SAS detectable by FISH
etiologies of deletion in child can be caused by:
- gonadal mosaicism
- de novo
- parent may be balanced rearrangement carrier –> therefore need karyotype OR FISH
- parent may carry it/be mildly affected if small del
asymmetric crying facies –> prompt you to look for issues with what organ system?
heart.
part of spectrum of 22q11.2 (formerly Cayler - asymmetric crying facies and heart stuff)
in setting of DD/ID/autism spectrum:
what percent of time will traditional cytogenetics (karyotype) yield a diagnosis?
5-10%, closer to 5%
in setting of DD/ID/autism spectrum:
what percent of time will FISH yield a diagnosis?
0.5-7%
in setting of DD/ID/autism spectrum:
what percent of time will oligo(aCGH) /SNP CMA yield a diagnosis?
15-20%
Puerto Rican grandma with dementia
PSEN1 - presenilin1
autosomal dominant form of early-onset (
Which ApoE allele is the risk allele for late-onset Alzheimers?
Which is the protective?
ApoE4 = risk (neither necessary, nor sufficient, though)
– 1 copy 3-5x risk
– 2 copies 10-15x risk
2/3 of AD patients have at least 1 copy
potential mechanism: decreasing age-at-onset
ApoE2 = protective, but associated with increased risk of apolipoproteinemia type 3
complex: ApoE2 is risk for macular degeneration, ApoE4 is protective.
ApoE - which pathway?
is testing it recommended (as of 2016)? In what cases?
ApoE in cholesterol pathway, risk factor for
Testing is NOT recommended due to limited cliinical utility and poor predictive value, even if a person is affected.
direct-to-consumer testing is not advised.
Parkinson Disease - recessive gene?
PARK2 - recessive - most inherited PD is caused by this.
the younger the age-at-onset, the more likely mutation in this gene (e.g., especially 20s)
Parkinson’s displays many inheritance patterns (AD, AR, XL)
Parkinson Disease - dominant gene?
LRK2 ~ reduced penetrance ~ 30-74%
- 5% of sporadic PD in USA
- 26% of familial PD in USA
15-20% of PD in Ashkenazi
30-40% of PD in North African
Parkinson Disease - can be symptom of which disease? Due to which gene?
Gaucher
GBA carrier status (glucocerebrosydase) ~
earlier onset
increased rate of dementia
~ 5x increased risk
FrontoTemporal Dementia can mimic which disease?
Parkinsons (symptoms)
Frontotemporal Dementia (FTD) - most common gene?
c9orf72 ~ autosomal dominant ~ GGG repeats
>30 repeats = “affected” , but typically see >1,000
found in sporadic FTD5%
found in familial 25%
Most common cause of sporadic ALS 5-10%
up to 50% of familial ALS is caused by ALS
onset 50s-60s
presentation: FTD and/or ALS +/- psychotic features
ALS -gene? (amyotrophic lateral sclerosis)
c9orf72 (expansions - most commonly)
SOD1 (20%)
TARDDP – makes tdp protein (1-4%)
c9orf72, SOD, TARDDP, etc can be also found in sporadic cases.
X-linked types, recessive (juvenile), dominant
PANEL APPROACH
familial 5%
c9orf72
expansion GGG - autosomal dominant
frontotemporal dementia and/or ALS w/w/o psychotic features
neuro genetic pedigree: things to focus on
age-at-onset
first symptoms
unaffected people – truly unaffected, or died young?
ancestry (Puerto Rican, Ashkenazi, N African)
diagnosis – never assume it is correct unless autopsy
(can see tau/beta - AD or lewey bodies - PD)
Gowers sign is indicative of ___ muscle weakness
proximal muscle weakness
Duchenne carrier females - are they followed?
yes, must monitor cardiac health
Limb Girdle
strictly clinical dx - very unspecific
Limb Girdle Muscular Dystrophy - why important to know subtype?
Because some subtypes have cardiac involvement - need to know for screening regimen.
Also because nocturnal hypoventilation possible in some types.
Type 1 A-H – dominant
Type 2A-Q – recessive
Limb Girdle (sarcoglycanopathies, types 2c -q) VS Duchenne – differences?
LG - recessive, not XL
LG - no cognitive impairment
which neuromuscular disorder comes with inability to release grip quickly?
Myotonic Dystrophy, type 1 ~ CPG expansion
“percussion myotonia” = grip symptom
mild myotonic dystrophy, type 1 can have which extra-muscular features, typically?
triplet repeat size correlates w severity of disease
cardiaca arrhythmias
cataracts
diabetes
hypothyroidism
myotonic distrophy – CPG repeat cutoffs
expands through which parent?
normal 5-37
premutation 38-49
mild 50-150 (20-70yo onset) – usually extramusuclar
classic 100-1,000 (10-30 yo onset) – muscle involvement
expands through mom (case reports of dad exist)
500+ cognitive impairment – disability
1,000-2,000: congenital presentation
myotonic dystrophy type 1:
if mom has >100 CPG repeats, what is chance that child will have congenital presentation of myotonic dystrophy?
1/2 * 60% = 30%
1 in 2 chance that she passes it on, and 60% that it will expand to 1,000.
main difference between DM1 and DM2
DM1 - distal muscles affected ; all types of onset ; CPG repeat ; repeat size correlates with severity
DM2 - proximal ; typically adult onset/no congenital ; CCTG repeat in CNBP gene ; 75-11k repeats/no correlation with severity - no anticipation - usually contraction across generations
Myotonic dystrophy features (muscular and extramuscular)
myotonia, slowly progressing weakness
cataracts
endocrine issues (diabetes, hypothyroid, male fertility)
heart (arrhythmias, AV conduction block, …)
CNS - learning disabilities to severe ID
LAMA2
autosomal recessive Merosin Deficient CMD contractures non ambulation in later childhood non-specific white matter changes - leukoencephalopathy - non-progressive can be mild-severe spectrum
Congenital Muscular Dystrophy (Ullrich) - is most characterized by which feature?
proximal contractures, distal hyperlaxity
skin findings due to COL6A1/2/3 (recessive or dominant) - scarring, soft skin, keratosis pilaris
early nocturnal hypoventilation !!! needs sleep study
no intellectual disability
