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FRCPath Part 1 Genetics > Chromosome Disorders > Flashcards

Chromosome Disorders Flashcards

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1
Q

1p36 deletions (contiguous gene disorder)

A

Variable size (common bp: 1p36.13-1p36.33)
Mostly De Novo (80%)
0.5-0.7% of idiopathic ID
Variable Phenotype: Dev Delay, Hypotonia, Delayed speech, microcephaly.

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2
Q

Proximal Interstitial 1p36 deletion

A

Features: Dev delay, Hypotonia, characteristic facies (microcephaly, frontal bossing…), Hirsutism, Structural heart defects.
Multiples candidate genes including KCNAB2 for epilepsy.

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3
Q

1p36 duplication

A

1p36 duplication
Very rare
Milder phenotype compared to deletions
Variable phenotype including dev delay, hypotonia, congential cataracts and choanal atresia (back of nasal passage blocked).
Tetrasomy reported once (severe ID, seizures)

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4
Q

1p32-p31 deletion syndrome

A 
Haploinsufficiency of NFIA
Size
Features:
Corpus Callosum dysgenesis
Ventriculomegaly
Dev Delay
Seizures
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5
Q

1q21 region

A

complex
4 blocks of LCR - NAHR
Class I: distal 1q21.1 del/dup 1.8Mb
Class II: larger ~2.7Mb (includes TAR + distal region)

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6
Q

Distal 1q21 microdeletion syndrome

A

Rare
Very variable phenotype; contiguous gene deletion
Incomplete penetrance: Can be inh from normal/mild parents
Up to 50% de novo rate
Features:
Microcephaly
Dev delay
Mild dysmorphic facial features - frontal bossing, deep set eyes
Behavioural issues (ADHD, ASD)
?genes: GJA5, GJA8, HYDIN2

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7
Q

1q21 Microduplication syndrome

A 
Rare
Mirrors 1q21 deletion syndrome
Incomplete penetrance and variable expressivity
Macrocephaly
TOF
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8
Q

Thrombocytopenia Absent Radius Syndrome (TAR)

Proximal 1q21 deletion

A

“Compound biallelic inh model” - 2 non-coding SNPs on other allele cause diminished RBM8A transcription
~200kb deletion in proximal 1q21.1
~11 genes including RBM8A (also TAR mutns in this gene)
Incomplete penetrance
Features:
Absent radii with presence of thumbs
Congential or early onset thrombocytopenia
Heart defects (TOF, ASD)

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9
Q

1q43q44 deletions

A 
Very rare
Majority terminal (some interstitial)
Variable phenotype
Features:
MR
Agenesis/hypogenesis of the corpus callosum
little or no speech
Microcephaly
Seizures
Heart defects (VSD and ASD)
Gene Candidates: AKT3 (microcephaly), ZNF238 (absence of corpus callosum)
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10
Q

1q41q42 deletions

A 
Very rare
Variable phenotype including:
Dev delay
Seizures
Cleft palate
Club feet
DISP1 haploinsufficiency (craniofacial/neuro features)
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11
Q

1q duplications

A

1q11-1q32: Micrognathia, high/cleft palate, hydrocephalus, absent speech, heart defects
1q23-1q41: Micrognathia, high/cleft palate, heart defects, mild LD
1q31-qter: Growth retardation, macrocephaly, micrognathia, heart defects, kidney defects, polydactyly
1q4-qter: Macrocephaly, FTT, LD, speech delay, heart defects

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12
Q

Supernumerary ring chromosome 1

A 
Mostly de novo (can be inh - mostly mat)
Varying size of ring therefore pheno
Features:
Dev del
Hypotonia
Sacral dimple
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13
Q

Trisomy 2

A

Only compatible with life in mosaic form.
Will be largely confined to placenta (In CVS but not amnio; IUGR)
Contributes to 1T pregancy loss
Feature in AML

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14
Q

UPD2

A

6 reported cases
Maternal
No associated imprinting effects

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15
Q

Inversion 2

A

Large blocks of segmental duplications

Common Variant inv(2)(p11.2q13)

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16
Q

2p15-2p16.1 deletion syndrome

A

All reported cases de novo.
3.9Mb critical region ~15 coding genes incl. BCL11A
Features:
Microcephaly
Vision problems
Dysmorphic (high forehead, ptosis, downslanting palpebral fissures)
Cortical dysplasia (assoc with VRK2 deletion)

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17
Q

2p16.3 deletion

A

NRXN1 gene
Encodes a cell surface receptor that binds neuroglins
Deletions of entire gene and multiexon reported
Features:
ID
Psychiatric disorders
Language delay
ASD
Seizures
Hypotonia
Reduced penetrance and/or variable expressivity

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18
Q

2q13 deletion

A 
Segmental duplications flank region - NAHR.
~1.7Mb recurrent region
BCL2L11 - neuronal apoptosis
ACOXL - neural development
FBLN7 + TMEM87B Congenital Heart Defects
Features
Dev delay
Dysmorphic - micrognathia, low set ears
Macrocephaly
Tall stature
Hypotonia
Cardiac + CF ab incomplete penetrance
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19
Q

2q13 duplication

A 
Segmental duplications flank region - NAHR.
~1.7Mb recurrent region
BCL2L11 - neuronal apoptosis
ACOXL - neural development
FBLN7 + TMEM87B Congenital Heart Defects
Features:
Dev delay
Dysmorphic features - hypertelorism, micrognathia
Microcephaly
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20
Q

Mowat Wilson 2q22 deletion

A 
AD caused by haploinsufficiency of ZEB2
NS, FS, deletions (15-20%) or gene disruption (2%)
Majority de novo
Features:
Hirschsprung disease
Genitourinary anomalies (e.g. hypospadias)
Congenital heart defects
Agenesis of the corpus callosum
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21
Q

2q23.1 deletion syndrome

A 
Prevously known as "pseudo-Angelman syndrome"
Partial or complete deletion of MBD5 (methyl CpG binding protein). Expressed in brain, fetal testes + ovaries
Other genes modify phenotype e.g. EPC2
Features (variable phenotype):
Severe MR
Speech delay
Short stature
Microcephaly
Seizures
Disturbed sleep patterns
Repetitive behaviours
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22
Q

2q32q33 deletion syndrome

A

Includes SATB2 (craniofacial + brain development).
Other genes contribute to phenotype e.g COL3A1, COL5A1, CREB1
Features:
Moderate to severe dev delay
Sig LD
Dysmorphic features - micrognathia, cleft palate
Impaired dentition/crowding
Thin and sparse hair
Behavioural - hyperactivity, sociable happy personality, repetitive behaviours

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23
Q

2q37 deletion syndrome (also called Albright-like syndrome, Brachydactyly Mental Retardation syndrome (BDMR)

A 
Variable deletion size - no common breakpoints
Up to 80 genes involved.
Very variable phenoytpe.
Usually de novo
Features:
Dev delay
Growth delay
Hypotonia (infancy and childhood)
Facial dysmorphism (round face, sparse hair)
Skeletal malformations
Behavioural problems
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24
Q

Disorders with genes on chromosome 2

A

Alport syndrome
Classical Ehlers Danlos syndrome (COL5A2) 2q31
Vascular Ehlers Danlos syndrome (COL3A1) 2q32.2
Waardenburg syndrome (PAX3) 2q36.1

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25
Q

Trisomy 3

A

Only compatible with life in mosaic state
CPM for chr. 3 normal outcome but IUGR/IUD seen.
CVS Primarily of mitotic origin
3 cases of postnatal mosaic trisomy 3 - all severely affected.

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26
Q

UPD3

A

single case reported.

Dev del - homozygous for rare cytogenetic polymorphism carried by one parent.

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27
Q

Ring Chromosome 3

A

Supernumerary ring - few cases reported
Non-supernumerary ring (with partial del):
10 patients in literature
Delayed psychomotor development + growth failure similar to 3p monosomy.

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28
Q

3pter-3p25 deletion syndrome

A 
Very rare
Distinct clinical syndrome
Loss of SETD5 (3p25.3)
Features:
Low birth weight
MR
Microcephaly
Speech delay
Congential heart disease (AVSD)
Seizures
Microdeletions of p25.3 similar phenotype
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29
Q

3p26 deletion

A

Similar to 3p25 deletions
Incomplete penetrance
Reported inh from normal parents

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30
Q

3p14 Waardenburg Syndrome type 2

A

AD
Mutations in Micropthalmia-assocated TF gene (MITF)
Key TF of melanocyte development
Features:
Hearing loss
Changes in pigmentation of hair, eyes and skin.
3% of congenital deafness

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31
Q

3p14 Waardenburg Syndrome type 2

A

AD
Mutations in Micropthalmia-assocated TF gene (MITF)
Key TF of melanocyte development
Features:
Hearing loss
Changes in pigmentation of hair, eyes and skin.
3% of congenital deafness

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32
Q

3p25-26 Von Hippel -Lindau

A

1 in 36,000; 90% penetrance by age 65
Type 1 - large deletion or truncation mutns
Retinal and CNS haemangioblastomas
RCC (in 70% of VHL) but not pheochromocytoma
Type 2 - missense mutns
Includes pheochromocytoma

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33
Q

3q13.31 deletion syndrome

A 
Hypotonia
above av. growth
Dev delay
Facies - short philtrum, high palate
Abnormal male genitalia
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34
Q

3q22.3 Blepharophimosis, ptosis and epicanthus inversus (BPES)

A

AD
Mutations in FOXL2 gene (incl deletions + trans)
Features:
Blepharophimosis (narrowing of the eye opening)
ptosis (droopy eyelids)
epicanthus inversus (upward fold of the skin of the lower eyelid near the inner corner)
Type I: female infertility/ovarian failure
Type II: Major features BPES

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35
Q

3q29 microdeletion syndrome

A 
rare; "genotype first"
Common deletion ~1.6Mb ?NAHR due to LCRs
Majority de novo (some inherited)
No antenatal abnormalities
22 genes involved (no single one for all pheno)
PAK2, DLG1 - homologues of X-linked MR genes
?loss of PAK2 or DLG1 causes MR
Very variable phenotype including:
Dev delay
Microcephaly
Mild dysmorphology
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36
Q

3q29 microduplication syndrome

A 
Variable size 200kb to 2.4Mb
25% are reciprocal of recurrent 1.6Mb microdel
Majority are familial
?Incomplete penetrant or modifier
Variable phenotype including:
Dev delay
Ocular anomalies (DLG1)
Learning difficulties (PAK2 and ZDHHC19)
Cardiac abnormalities
Microcephaly
Hypotonia
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37
Q

Wolf-Hirschhorn Syndrome (WHS) chr. 4

A 
4p deletion 
Key region WHSCR2 300-600kb 1.9Mb from telomere
Features:
"Greek warrior Helmet-like" hypertelorism, prominet glabella, high forehead
MR
Growth delay
Seizures
May have other major midline malformations:
midline scalp defects
agenesis of corpus callosum
cleft palate
hypospadias
CHD
Renal abnormalities
Skeletal abnormalities
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38
Q

Wolf-Hirschhorn Syndrome Etiology

A

Unbalanced translocation product:
der(4)t(4;8)(p16;p23) mat origin
NAHR involving Olfactory Receptor (OR) on 4p and 8p
or maternal inversion polymorphism in 4p16.

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39
Q

WHS Genotype-Phenotype correlations

A

Mild - deletion <3.5Mb at 4p16.4-4pter
Classical - deletions 5-18Mb
Severe delay, absent speech, late walking
Severe - 22-25Mb deletion at 4p15-4pter

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40
Q

4q21 microdeletion syndrome

A 
1.37Mb region
Key genes: PRKG2 and RASGEF1B
Features:
Neonatal hypotonia
Psychomotor retardation (RASGEF1B)
Progressive growth restriction (PRKG2)
Facies: frontal bossing, broad forehead, hypertelorism, short philtrum
Absent/severely delayed speech
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41
Q

Mosaic Trisomy 4

A

Very rare; may be seen at CVS.
1 case of liveborn reported.
UPD4 possible by trisomy rescue.
Poor outcome.

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42
Q

4p duplications

A 
very rare (as isolated rearrangements)
Features:
Dev delay
Speech delay or absence
Genital ab in males
Facies: microcephaly, bulbous nose tip
Hand or foot anomalies
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43
Q

Facioscapulohumeral Muscular Dystrophy (FSHD) 4q35

A

4q35
Type 1: Heterozygous partial deletion of a critical number of repetitive elements (D4Z4)
D4Z4 regions comprises 11-150 repeated segments each 3.3kb long. Normally hypermethylated.
In FSHD region is hypomethylated - contains 1-10 repeats instead of >11.
Type 2: Mutations in the SMCHD1 gene (which normally hypermethylates the D4Z4 region).

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44
Q

Cri du Chat Syndrome (5p) Clinical Features

A

82% diagnosed in 1st year of life
High pitched monotone cry
Microcephaly
Severe psychomotor and MR
Low birth weight and hypotonia
Facies: round face, large nasal bridge, hypertelorism, epicanthal folds, micrognathia
Prognosis: Survival expectation high (up to ~50 years); morbidity low.

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45
Q

Cri du Chat Syndrome (5p) Aetiology

A

Variable deletion size 5-40Mb (occasionally smaller)
1/37,000-1/50,000
80% de novo (recurrence risk v.low except gonadal mosaicism)
15% result of balanced familial translocation (recurrance risk (8.7-18.8% dependent on size of translocation)
~5% rare cytogenetic aberrations

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46
Q

Cri du Chat Syndrome (5p) Critical Regions

A

Contiguous gene region
5p15.31 (1.5Mb) associated with cat-like cry
5p15.2 associated with dysmorphism, microcephaly and MR
SEMA5A: cortical development
CTNND2: neuronal development

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47
Q

Sotos Syndrome (5q35 deletion syndrome)

A

AD; 1/10,000-1/14,000
Haploinsuffiency of NSD1 (histone MT regulates growth genes)
95% de novo
Recurrent 1.9Mb 5q35 microdeletion commonly observed in Japanese ethnicity; other ethnicities mainly sequence mutations.
Clinical Features:
Excessive physical growth
Advanced bone age
Facies: large and long skull, head with high bossed forehead.
Hypotonia
Poor feeding
Normal life expectancy

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48
Q

5q14.3 deletion

A

1/1,000,000 incidence
MEF2C haploinsufficiency (early neuronal differentiation)
Deletions and heterozygous mutations
Clinical Features:
Severe MR
Marked Dev delay
Brain ab on MRI
Dysmorphism (high wide forehead, flat nasal bridge)
Stereotypic movements and poor eye contact - ASD
Early and severe hypotonia
Epilepsy

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49
Q

Cornelia de Lange Syndrome 5q13.2

A

1/10,000-1/30,000
60% have mutations in NIPBL (including dels)
Other genes: SMC1A 5% (X-linked); SMC3 <1%(10q25.2)
Delangin protein involved in chr. segregation + repair of damaged DNA.
Sequence analysis first then del/dup NIPBL
Clinical Features vary widely:
Slow growth
ID
ASD
Skeletal abnormalities
Facies: arched eyebrows, low-set ears, widely spaced teeth, upturned nose.
Hirsutism

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50
Q

Trisomy 6

A

Full trisomy not viable.
Several prenatally reported cases of mosaicism.
PM with +6 in 13% amnio and 40% cord blood had multiple congential anomalies

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51
Q

UPD6 paternal

A

Neonatal benign transient diabetes
Low birth weight
Overexpression of paternally expressed imprinted genes at 6q24.
(also diabetes from mat hypomethylation/paternal duplication)

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52
Q

UPD6 maternal

A

Only a couple of cases reported

IUGR

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53
Q

Subtelomeric 6p24-q25 deletion

A 
Rare (50 cases in lit)
Clinical features:
Dev delay
Facies: hypertelorism, downslanting palpebral fissures
Hearing impairment
Brain anomalies (Dandy Walker malformation)
Eye abnormalities
Heart conditions
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54
Q

Interstitial 6p22-24 deletions

A 
Features:
Orofacial clefting
Clinodactyly/Syndactyly
Brain defects
Heart defects
Kidney defects
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55
Q

6q11-14 deletion

A 
Contiguous gene deletion syndrome
Deletions of varying size (av. 13.9Mb)
Clinical Features:
Hypotonia
Short stature
limb/skeletal abnormalities
Dev delay 
3.7Mb minimal deletion including 16 genes (COL12A1)
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56
Q

Interstitial 6q24-25 deletion

A 
Contiguous gene deletion syndrome
Variable breakpoints/size
850kb region at 6q25 critical for Heart defect includes 5 candidate genes (incl. TAB2)
Clinical Features:
Cardiac defects (ASD/VSD)
Short Stature
IUGR
Agenesis of the corpus callosum
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57
Q

Subtelomeric 6q27 deletion

A

Many different breakpoints
Not a clearly defined condition
Some associated phenotypes:
In babies: microcephaly, hypotonia, feed diff
Older children: Dev delay, ab of brain structure and size, seizures.

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58
Q

Disorders with genes on chromosome 6

A 
Spinocerebellar Ataxia 1 SCA1  6p22
Lafora's myoclonus epilepsy EPM2A  6q24
AR juvenille parkinsonism (AR-JP) PARK2  6q25.2-q27
Xeroderma Pigmentosum POLH  6p21.1
Huntington disease like 4 TBP  6q27
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59
Q

Ring Chromosome 6

A 
Rare; typically de novo
Variable phenotypes:
ID
Microcephaly
Prenatal growth failure
retarded bone age
Prenatally: hydrocephalus, cortical atrophy, ventriculomegaly
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60
Q

Mosaic trisomy 8 (Warkany syndrome)

A

Only compatible with life in a mosaic form
1:25,000
Clinical Features:
Skeletal anomalies
Facies: prominent forehead, hypertelorism, bulbous nose
LD
Congenital anomalies eg. cardiac, renal, CC
Deep creases in palms and soles

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61
Q

8p23.1 region

A

Unequal crossovers between 2 olfactory receptor (OR) gene clusters on 8p
REPD - distal repeat
REPP - proximal repeat
Can result in:
inv dup del (8p)
8p23.1 microdeletion/microduplication syndromes
Supernumerary marker chromosome +der(8)(8p23.1pter)
Recurrent t(4;8) reciprocal translocation

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62
Q

inv dup del (8p)

A 
Usually a recombinant from a parental inversion.
Clinical features caused by duplication rather than deletion include:
Dev delay
Learning difficulties (STMN4)
Speech delay
Hypotonia
Agenesis of CC
Microcephaly (MCPH1)
CHD
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63
Q

8p23.1 microdeletion/microduplication

A 
Mediated by NAHR
Majority of deletions are terminal.
Microduplication ~3.75Mb between REPD and REPP.
Microduplication 1 in 58,000 prevalence
Features:
Dev delay (SOX7)
Behavioural issues (MCH1/TNKS)
CHD (GATA4)
Diaphaphragmatic hernia
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64
Q

Roberts Syndrome (Pseudothalidomide Syndrome; 8p21.1)

A

AR; v rare (150 cases in lit)
ESCO2 gene mutations (regulates sister chromatide cohesion)
Cytogenetically:
C-banding shoes premature centromere separation and separation of heterochromatic regions.
Many chromosomes appear as “railroad track”.
Severe: stillborn or die in neonatal period
Phenotypic features:
Hypomelia (shortening of the arms and legs)
Dysmorphism: hypertelorism and micrognathia
Cleft lip/palate
Microcephaly

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65
Q

Key Disorders on chromosome 8

A

FGFR1 (8p12): Pfeiffer syndrome, Jackson-Weiss syndrome, Antlery-Bixler syndrome etc.

CHARGE syndrome CHD7 (8q21):
AD; usually de novo.
Coloboma, cHd, choanal Atresia, Retarded growth, Genital abnormalities, Ear anomalies.

Brachiootorenal syndrome EYA1 (8q13.3):
AD; very variable phenotype
40% change in EYA1.
Ear and Renal anomalies

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66
Q

Trichorhinophalangeal syndrome type II (8q23.3)

A

Contiguous microdeletion syndrome with LGS syndrome (EXT1).
Loss of TRPS1 gene
Clinical Features:
Facies: large ears, bulbous nose, thin upper lip
Sparse scalp hair
Short stature
Skeletal anomalies

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67
Q

Langer-Giedion Syndrome (8q24.11)

A

Contiguous microdeletion syndrome with TPS syndrome (TRPS1)
Phenotype:
Multiple cartilaginous exostoses (formation of new bone on the surface of a bone).

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68
Q

Trisomy 9

A

24 cases without demonstrable mosaicism (likely have low level cell line present)
Assoc. with advanced maternal age
Most liveborn die within first few weeks to hours.
Clinical Features
Microcephaly
Male genital hypoplasia
Facies: dolichocephalus, wide cranial sutures, severe micrognathia
Scoliosis
Heart and renal defects

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69
Q

Mosaic Trisomy 9

A 
>60 reported cases
Via meiotic error and post-zygotic non-disjunction
Clinical Features - Prenatal:
Severe IUGR
Ventricular Septal defect
Micrognathia
Single umbilical artery
Clinical Features - Postnatal:
Growth retardation
Microcephaly
Severe MR
Craniofacial ab
Heart and renal ab
Orthopaedic ab
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70
Q

Trisomy 9p

A 
Compatible with long-term survival
Complete or partial gain; 9p22 critical for 9p phenotype
Clinical features:
Growth retardation
MR
Facies: downslanted palpebral fissures, bulbous nose
Brachcephaly
Microcephaly
Hand abnormalities
Delayed bone age
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71
Q

Tetrasomy 9p

A 
Extra isochromosome; short arm of 9.
Range of severity
Highly selective for certain tissues
Clinical Features - Prenatal:
Absent nasal bone
IUGR
Ventriculomegaly
Cerebellar abnormalities
Clinical Features - Postnatal
Micrognathia
Hypertelorism
Facies - broad nasal root, bulbous nose
Limb defects
Dev delay
Growth delay
CHD
GI defects
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72
Q

9p deletion syndrome (Alfi’s syndrome)

A 
>140 patients
Various BP from 9p22 to 9q24 (800-12.4Mb
Clinical Features
Triangular forehead (CER1)
Mod to severe MR (?DOCK8)
Severe language and speech dev (FOXD4)
Facies - upslanting palpebral fissures, long philtrum
Abnormal genitalia (DMRT1)
9p critical region 9p22.3-9p23
?Critical genes: CER1, FOXD4, DOCK8, DMRT1
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73
Q

9p24 and XY gonadal dysgenesis

A

Deletions of 9p24 with XY gonadal dysgenesis without other 9p deletion features.
Sex reversal region at 9p24.3: DMRT genes
Deletions of DMRT1, DMRT2 and DMRT 3.
Telomeric deletion in regulatory region also reported to cause XY gonadal dysgenesis phenotype

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74
Q

Kleefstra Syndrome

A

de novo to date
Haploinsufficiency of EHMT1 gene
75% have 9q34.3 microdeletion; 25% intragenic mutn
Features:
Mod to severe ID
Severe expressive language delay
Hypotonia
Behavioural problems
Facies: Brachycephaly, broad forehead, midface hypoplasia
Behavioural and motor deficiencies increase over time

75
Q

Chromosome 9 ring

A 
Loss of material from ends of 9 in ring formation
Variable phenotype - may be 'normal'
Clinical Features:
Craniofacial malformations
Microcephaly
Triangular forehead
Slanting palpebral fissures
Growth retardation
Skeletal ab
Genital abnormalities
Mod to Severe MD
76
Q

Trisomy 7

A

Rare at birth - lethal in embryogenesis
CVS - Mitotic origin often CPM
Amnio - usually cultural artefact
True mosaic trisomy 7 assoc with a <20% risk of phenotypic abnormality.

77
Q

Silver Russell Syndrome (mat UPD7)

A 
~10% of cases of RSS
Clinical features:
severe IUGR
Postnatal short stature
Retarded bone age
Relative macrocephaly
Prominent bossed forehead
Micrognathia
78
Q

Greig Cephalosyndactyly (7p13 deletion)

A 
AD; mutation at GLI3 locus
Development gene
Deletion via rearrangement
Contiguous gene deletion GLI3 + other genes causes more severe form.
Clinical Features
Limb ab
Seizures
Dev delay
ID
79
Q

Saethre-Chotzen Syndrome (7p21.1 deletion)

A 
Mutns and microdeletions
TWIST gene
Craniosynostosis
Normal intelligence
Larger deletions can include ID.
Incomplete Penetrance
80
Q

7p21.1 duplication

A

Underdevelopment of cranial bones

81
Q

7q11.22 deletion/gene disruption

A 
AUTS2
Deletion or interruption of gene by small dup
Clinical Features:
ID
Behavioural issues
ASD
Dev delay
82
Q

7q11.23 Williams Beuren Syndrome

A 
1.5-1.8Mb deletion (critical region); LCRs.
28 coding genes; ELN key
90% cases have ~1.55Mb deletion
5% cases have larger ~1.84Mb deletion
Rare atypical deletions include ELN and adjacent gene.
Clinical Features:
"Cocktail party personality"
Pixie-like features
Supravalvular aortic stenosis
Hypercalcaemia
ADHD
Minimal prenatal phenotype
83
Q

7q11.23 duplication Syndrome

A 
v. few reported cases (~5)
Reciprocal duplication to Williams Beuren Syndrome
Clinical Features (very broad):
Language delay
Dev delay
Autism
MR
Dysmorphism
GTF2I and CyLN2 implicated for LD
84
Q

7q21.3 deletion Ectrodactyly Plus syndrome

A

Ectrodactyly (Split hand/split foot malformation SHFM)
One of the syndromic ectrodactylies
SHFM1 locus is at 7q21.3; 1.2Mb critical region
AD; reduced penetrance, variable expressivity
Candidate genes:
DLX5, DLX6 and DSS1 - ?position effect mutation affecting DLX5/DLX6 homeobox genes.
Null mice similar phenotype.

85
Q

Holoprosencephaly Plus syndrome (7q32-qter)

A

de novo deletion; HPE3 haploinsufficiency
Absence of Sonic Hedgehog (SHH) @ 7q36
Holoprosencephaly
Variable effects:
from single central front tooth, cleft palate and no sense of smell to failure of brain to develop into 2 hemispheres.

86
Q

Other genes on chromosome 7

A

SBDS (7q11.21) Shwachman-Diamond syndrome
AR; neutropenia, pancreatic insufficiency, increases risk MDS and AML.

SGCE (7q21.3)
Paternally inh; myoclonus dystonia, need anti-epileptic drugs

KRIT (7q21.2) Cerebral cavernous malformations
Role in formation of blood vessels
Headaches, seizures, paralysis, hearing or vision deficiencies

87
Q

BRAF (7q34)

A 
Oncogene
Cardiofaciocutaneious syndrome
Multiple letigines syndrome (LEOPARD)
Noonan syndrome
Langerhans cell histiocytosis
Melanoma and astiocytomas
88
Q

DLD (7q31-32) Maple Syrup Urine Disease

A

Mutations in DLD lead to lactic acidosis

Prevents BCKD enzyme complex breaking down valine, isoleucine and leucine - build up of byproducts.

89
Q

Ring 7

A

46, r(7): Microcephaly and ID

47, +r(7): language acquisition difficulty, ?STX1A and LIMK1

90
Q

10p13 deletion DiGeorge Syndrome 2

A 
Very rare
DGCR2 region; ?NEBL
More severe phenotype that DiGeorge
Clinical Features:
MR
Facies: hypertelorism, micrognathia
Cardiac defects
Hypoparathyroidism
Hypoplastic thymus - T-cell defect
Hypocalcaemia
Genital anomalies
91
Q

Barakat Syndrome/HDR syndrome (10p14 deletion)

A

Haploinsufficiency of GATA3 gene; AD
H - Hypoparathyroidism (results in low calcium level)
D - deafness
R - Renal abnormalities

92
Q

10q22.3q23.2 microdeletion syndrome

A

V. rare
Incomplete penetrance; ~7.25Mb deletions; LCRs
3 groups:
Deletion of BMPR1A deletion alone (mild)
Deletion of PTEN alone
Deletion of both genes
Further candidate gene: GRID1 neurobehavioural development

Clinical Features:
Speech and language problems
Mild to mod dev delay
Macrocephaly

93
Q

Duplications of 10q22q23

A 
v. rare
Variable phenotypic penetrance
Features:
Dev delay
Speech delay
Microcephaly
94
Q

10q25q26 Deletion Syndrome

A 
Contiguous gene deletion syndrome
Variable phenotype
Terminal or interstitial deletions
Clinical Features:
IUGR
Feeding difficulties
Hypotonia
LD
Renal abnormalities
Genital anomalies (EMX2)
Facies: Triangular face, prominent nasal root, beaked nose (FGFR2)
95
Q

Proximal 10q duplications (10q11-10q22)

A 
Clinical Features:
Short stature
Microcephaly
Dev delay
LD
Eye defects
Heart defects
Facies: prominent forehead, iris coloboma
96
Q

10q24-q26 duplication

A 
Mild Clinical Features:
Dev Delay
LD
Delayed speech
Slightly dysmorphic face
97
Q

10q25-26 duplcations

A

Similar to 10q24-26 duplications but milder includes:
Feeding difficulties
Dysmorphic face: round, flat face, narrowed eyes, ptosis
Dev delay
LD

98
Q

RIng chromosome 10

A 
~20 cases reported
Features (dependent on BP):
LD
Short stature
Microcephaly
Growth retardation
Cardiac
Renal
Undescended testes + hypoplastic scrotum
99
Q

FGFR2 Crouzon Syndrome (10q26.13)

A

Premature fusion of skull bones (craniosynostosis)

Cleft lip and palate

100
Q

WAGR Syndrome (11p13 deletion syndrome)

A 
Contiguous gene deletion syndrome
Minimum region ~700kb
Wilms tumour (nephroblastoma) in 45-60%
Aniridia (PAX6 deletion/mutation)
Genitourinary anomalies eg. hypospadias
Mental Retardation (normal to severe MR)
(WAGRO - Also includes obesity if BDNF deleted 11p14.1)
101
Q

Potocki-Shaffer Syndrome (11p11.2-11p12)

A 
Contiguos gene deletion syndrome
Interstitial deletion of variable size (160kb to 8.4Mb)
Clinical Features:
Enlarged parietal foramina (ALX4)
Exostoses (EXT2)
ID (PHF21A)
Dev delay
Skeletal abnormalities
Seizures
GU abnormalities
102
Q

Jacobsen Syndrome (11q23.3-11qter)

A

Contiguos gene deletion syndrome
~5-16Mb (170-340 genes)
85% de novo terminal deletions incl. FLI-1
15% deletion results from unbalanced segregation
10% expansion of (CGG)n repeat in 5’ untranslated region of the CBL2 proto-oncogene (11q23.3) causing expression of the folate-sensitive FRA11B site.
?smaller dels via LCRs, PATRRs, ORGC
More likely to be of maternal origin for BP proximal to 11q23.3.

103
Q

Chromosome 11 disorders

A 
Beckwith Wiedemann (11p15.5)
Russell Silver Syndrome (11p15.5)
Ataxia Telangiectasia
Emmanual Syndrome
Smith-Lemli-Optiz syndrome (11q13)
Microcephaly, micrognathia, ABGEN, syndactyly, cardiac defects
104
Q

Mosaic trisomy 12

A

Found on CVS + AF. TFM for 12 most freq described mosaicisms at AF. High/moderate risk of abnormal outcome.
Very variable clinical outcome.
Lethality in newborn to detection @infertility.

105
Q

UPD12

A

No apparent UPD syndrome or phenotype

106
Q

Ring 12

A

Varying phenotypes
Growth retardation
ID

107
Q

Pallister-Killian Syndrome/Mosaic Tetrasomy 12p/+i(12p)

A 
Rare; de novo; maternal meiosis II origin
Rarely seen in cultured peripheral blood lymphocytes.  See in amniotic fluid and skin fibroblast samples.
Frequency of i(12p) decreases with age in blood.
Could also do buccal smear cells
Skin biopsy is the most reliable tissue source - gold standard
Phenotype variable: IUD to very mild
Prenatal: DIAPHRAGMATIC HERNIA
Postnatal:
Hypotonia
Dev delay
MR
Speech delay/absence
Facies: Hypertelorism, low set ears
Hypo/Hyper skin pigmentation
Polydactyly of fingers and toes
Hearing loss
Seizures
108
Q

12q14 microdeletion syndrome

A

Rare (~18 on Decipher).
Variable deletion size 3.44Mb-6Mb; non-recurrent.
Emerging phenotype:
IUGR (HMGA2)
Osteopoikilosis (sclerosing dysplasia of bone) (LEMD3)
Melorheostosis (cutaneous/soft tissue lesions) (LEMD3)
Feeding problems
ID (GRIP1)
Speech delay
Dev delay (DCTN2, KIF5A)

109
Q

12p13.33 microdeletion

A 
V. rare ~4 case reports
Speech delay (childhood Apraxia of speech CAS) ELKS/ERC1 candidates for CAS
ID
Non-specific dysmorphism
Variable expressivity
110
Q

Other genes on chromosome 12

A 
Noonan Syndrome PTPN11 (12q24.13)
Noonan Syndrome KRAS (12p12.2)
Holt Oram TBX5 (12q14.1)
Joubert 5 CEP290 (12q21.32)
Stickler type 1 COL2A1 (12q13.11)
DRPLA ATN1 (12q13.31)
111
Q

Patau Syndrome Trisomy 13

A

75% 47,+13; 20% due to rob trans - mostly de novo.
90% of +13 are of mat origin, due to no-dysjunction in mat meiosis I or mitotic non-dysjunction.
Recurrence risk very low <1%
Rob trans. carriers der(13;14)(q10;q10) have a small increased risk in each pregnacy ~1%
Phenotype - Prenatal:
CHD
Polydactyly
Holoprosencephaly

Phenotype - Postnatal:
Holoprosencephaly
Polydactyly
Rarely survive infancy.

Majority result in spontaneous abortion. From 2T onwards ~64% risk.

112
Q

Mosaic Trisomy 13

A

May be CPM or may reflect foetus.
High risk of ab if found at AF.
Phenotype very variable from ‘normal’ to full T13.

113
Q

13q14 deletion syndrome

A

Phenotype varies dependent on size of deletion
Clinical Features:
Retinoblastoma (leukocoria)
Mild to mod dev delay
Language delay
Short stature
Facies: high broad forehead, broad nasal bridge, prominent philtrum.

114
Q

13q22-33 deletion

A

Critical for development of Dandy Walker malformation

Group 1 - proximal dels not extending to 13q32
Variable dysmorphism, mild/mod MR and GR

Group 2 - del includes at least part of 13q32
Most severe phenotype including MR, GR, malformation of brain, eyes, distal limbs, GU and GI tracts.

Group 3 - more distal del
GR and severe MR without gross malformations

115
Q

Genes on chromosome 13

A

CX26/DFNB1A (13q12.11)
CX30/DFNB1B (13q12.11)
FLT3 (13q12.2)
BRCA2 (13q13.1)

116
Q

Mosaic Trisomy 14

A 
Seen in CVS=CPM - risk of UPD14
At AF=risk of foetal ab + UPD14
Dev delay
Short stature/FTT
Asymmetrical growth
Ab skin pigmentation
Slight dysmorphism
117
Q

UPD14 Maternal (TEMPLE syndrome)

A

Generally mild phenotype; may be undiagnosed.
Pre/Postnatal GR
mild ID
Subtle dysmorphism

118
Q

UPD14 Paternal (WANG syndrome)

A 
More severe phenotype than mat
Obstetric complications - polyhydramnios + premature labour
Low birth weight
THoracic and ab wall defects
Subtle dysmorphism
119
Q

Imprinted region 14q32

A

Contributes to UPD14 phenotype
Critical region for UPD phenotype - 40Mb between 14q23.3-qter.
Paternally expressed: DLK1, DIO3 and RTL1
Maternally expressed: GTL2, PEG11 and antisense RTL1

120
Q

Ring chromosome 14

A 
BP usually at 14q32.2 or 32.3; rarely 14q31 and 14q24
Phenotype:
Seizures
Mild/mod MR
Dev delay
Slow growth
Repeated respiratory infections
Microcephaly
Subtle facial dysmorphism
121
Q

14q11-22 deletion syndrome

A 
Very rare; half of q arm!
Phenotype:
Dev delay
Dysmorphism - hypertelorism, epicanthic folds
Partial agenesis of CC
Blindness
Hearing impairment
Seizures
Apnoea
122
Q

14q22-23 deletion syndrome

A 
Central q arm.
<1 in 1,000,000; almost all cases sporadic
Phenotype:
Bilateral anophthalmia (no eye) (OTX2/BMP4)
Cerebral malformations
Pituitary abnormalities (BMP4/SIX6)
Short stature
CLP
Ear ab (SIX6)
Dev delay
Epilepsy
Oldest survival to 19 years old.
123
Q

14q32.3-32.3 deletion

A 
Terminal 14q deletion
Critical region of 250kb; CRIP2, MTA1 and TMEM121
Features:
Hypotonia
Single palmar crease
Feeding difficulties
Eyesight problems
ID
124
Q

Genes on chromosome 14

A

alpha-1 antitrypsin deficiency SERPINA1

FOXG1 syndrome (14q12); mutations or microdeletion.
Features: GR, severe brain ab, severe ID.
125
Q

15q11.2 Deletion syndrome (BP1/BP2)

A

Susceptibility loci
300-500kb;
TUBGCP5, NIPA1, NIPA2 and CYFIP1
Increase in susceptibility to neuropsychiatric or neurodevelopmental problems

126
Q

15q11.2 Duplication syndrome (BP1/BP2)

A

CNV not sufficient for phenotype; increase in susceptibility.
TUBGCP5, NIPA1, NIPA2 and CYFIP1

127
Q

15q13.3 microdeletion syndrome (BP4/BP5)

A

1:30,000-40,000 - as common as AS/PWS
Recurrent 1.5-2Mb deletion; 6 known genes incl CHRNA7
Haploinsufficiency of CHRNA7 may be responsible for features.
Larger BP3-BP5 deletion similar features.
25% de novo; 75% inherited in AD with variable expressivity and incomplete penetrance.
Wide spectrum of developmental disorders
Subtle dysmorphic features

128
Q

Homozygous deletion of 15q13.3

A

More severely affected with significant global dev delay, severe hypotonia and seizures

129
Q

15q13.3 duplications (BP3/BP5)

A

Very rare; 0.5Mb to 2.5Mb
Incomplete penetrance, variable expressivity.
May be normal; may have dev delay, ID, communication difficulties, insomnia and seizures.

130
Q

Distal 15q deletion: 15q15-22

A 
Growth delay
Truncal obesity
Scoliosis
Craniosynostosis
Seizures
Motor delay
131
Q

15q22-q26 (pale section of 15q)

A

Feeding difficulties
Dev delay
IUGR
Diaphragmatic hernia

132
Q

15q24 microdeletion syndrome

A 
1/1000 with ASD
1.7Mb to 6.1Mb from NAHR
Critical region spans 1.2Mb + several candidate genes
Features:
Growth delay
Microcephaly
Speech delay
Hypermobility
Hypotonia
Hearing loss
Hypospadias
133
Q

15q26 deletion

A 
Pale tip of 15q; IGFR1 gene
Features:
IUGR (IGFR1 gene)
Micrognathia
Triangular face
Low set ears
Feeding difficulties
134
Q

15q21/q22 duplication

A 
Central dark band of 15q.
Dev delay
LD
Seizures
CLP
Scoliosis
135
Q

BP between 15q15 and 15q24 with terminal duplication

A 
Dev delay
LD
Unusual fingers
Born normal weight/height but growth slows
CHD
Microcephaly
Hypotonia
Scoliosis
136
Q

BP at 15q25 (distal dark band) or 15q26 (pale tip) and terminal duplication

A 
Involved IGFR1 gene (insulin growth receptor type 1)
Opposite phenotype to deletion
Large at birth
Macrocephaly
Overgrowth
ID
137
Q

idic (15)/sSMC (small supernumerary marker chromosome)
47,XX,idic(15)(q11)dn
47,XX,+psu dic(15)(q11q13)
47,XY,+inv dup (15)(q13q13)
47,XY.ish idic(15)(q13)(D15Z1x2, SNRPNx2,PML-)

A

1 in 30,000; large idic(15) usually sporadic.
Most commonly involves 15q11-13 and PWACR.
If it does not contain PWACR - minimal impact
Most children with idic(15) four copies of PWACR region
50% of SMCs are idic(15) (previously called inv dup (15))
Larger idic(15) phenotype:
severe DD, hypotonia, autism and epilepsy.
UPD and mosaicism may have an impact on phenotype
SMCs appear bi-satellited and pseudodicentric.

138
Q

Important genes on Chromosome 15

A 
Bloom Syndrome (15q26)
Mutation of BLM - genomic instability, chr. breakage
Marfan syndrome (15q21.1)
Mutn in FBN1 - connective tissue disorder.

Tay-Sachs disease (15q24.1)
HEXA - progressive fatal AR disease of nerve cells + brain.

139
Q

Down Syndrome Trisomy 21

A

Phenotype:
ID
FAcies: microcephaly, flat facial profile, epicanthic folds, upward slanting palpebral fissures, brushfield spots
Tranverse palmar crease
Males infertile; females fertile.
Av age. 55-68 years
Cardiac ab (ASD/VSD)
Transient leukaemia @ birth (neutropenia, thrombocytopenia)
Increased risk of acute megakaryoblastic leukaemia
Eye disease
hearing loss
Decreased risk for atherosclerosis, HD, alcohol + drug abuse.

140
Q

Trisomy 16

A 
Most commonly observed trisomy in spontaneous abortuses - over 30% if the autosomal trisomies
Mitotic nondisjunction
UPD risk
High risk of abnormal outcome:
IUGR
Preeclampsia
Preterm delivery
IUD
Dev delay
CHD
Mosaic 16: majority mild phenotype and positive prognosis
141
Q

16p11.2 Microdeletion syndrome

A

Common recurrent 600kb del/dup
Flanking segmental dups - NAHR
Variable features:
Speech language delay, cognitive impairment, motor delay, seizures, behavioural problems, congenital anomalies, autism, macrocephaly

142
Q

16p11.2 Microduplication syndrome

A 
NAHR mediated common recurrent dup (600kb)
Variable features:
Motor delay
ADHD
Congenital anomalies
Seizures
Microcephaly
143
Q

16p11.2 duplication syndrome

A 
Can be mistaken for euchromatic variants of proximal 16p11.2 (not by FISH/aCGH!)
8-9Mb from 16p11.2 to 16p12.1/2 (NAHR)
May be inherited
Features:
Dev delay
Autistic
Repetitive behaviour
Facies: microcephaly, short stature, low set ears
144
Q

16p11.2-p12.2 Microdeletion syndrome

A 
7.1-8.7Mb NAHR
Does not overlap with 16p11.2 microdeletion/duplication
Features:
Minor facial anomalies
feeding difficulties
Delay in speech
Recurrent ear infections
145
Q

16p11.2 Distal deletion

A 
220kb
SH2B1 gene
Features:
Obesity
Dev delay
Behavioural problems
146
Q

16p12.1 Microdeletions

A 
520.8kb; NAHR
Most inherited from parents.  Probands likely to carry additional large CNV.  23% of probands inh microdel from parent with psychiatric disease.
Independent risk factor - 2 hit model.
Variable features:
Neurobehavioural abnormalities ADHD
ID
Seizures
Schizophrenia
147
Q

Rubinstein-Taybi syndrome (16p13.3)

A

1 in 100,000 to 125,000
AD; Majority de novo
LOF mutations/Haploinsufficiency
CREBBP (60%) and EP300 (5-8%)

Archetypical syndrome - mutliple congenital mal and intellectural impairment
Features:
ID
Craniofacial features
Growth delay
Skeletal abnormalities
Naevus Flammeus (birthmark)
Facies: Distinctive - microcephaly, epicanthic folds, hooked nose,
148
Q

16p13.3 Contiguous deletion syndrome

A 
Severe form of Rubinstein-Taybi syndrome
40kb to >3Mb; 
Include 5' CREBBP gene + DNAse1 TRAP1
Add features:
FTT
Seizures
Intractable infections
149
Q

16p13.11 Deletions

A

One of 3 most common epilepsy microdeletions
1% frequency
Deletion of NDE1
ID
Autism
Schizophrenia
More severe brain phenotype can indicate second genomic events (Severe microcephaly, agenesis CC…)

150
Q

Duplication of 16p13.3

A 
Interstitial 16p13.3 duplications encompassing CREBBP
0.043% freq in DD
No recurrent BP - Non-homologous end joining
Features:
Mild to mod ID
Normal growth
Craniofacial dysmorphism
Limb anomalies
151
Q

21q22 Deletion

A 
Includes RUNX1 gene -thrombocytopenia + predisposition to myeloid leukemia
Features:
Behavioural problems
No speech
Microcephaly
Feeding problems
Obesity
VSD
Epilepsy
Thinned CC
152
Q

Trisomy 21 (Down Syndrome) Aetiology

A 
Nondisjunction (95%) (~1% recurrence risk):
     Mat MI (70%)
     Mat MII (20%)
     Pat MI and Pat MII (5%)
     Mitosis (5%)

Robertsonian (5%):
de novo (75% of robertsonians):
der(14;21) - 1005 in maternal germline; adjacent seg.
der (21;21)
i(21;21)
Inherited (25% of robertsonians):
10-15% recurrence risk except 21;21 with 100% risk

Rarely - reciprocal translocation (Interchange Trisomy)

153
Q

Partial Monosomy 21

A

21cen to 21q22.11: Severe; CHD, psychomotor delay

21q22.11 to 21q22.13

154
Q

Smith Magenis Syndrome (17p11.2)

A 
Virtually all de novo (rare fam chr rearrange)
1 in 15,000
90% due to interstitial deletion 
Mostly 3.7Mb (~70%); some smaller/larger
Point mutations in RAI1 (5%)
Haploinsufficiency for RAI1 responsible = most features
Features:
ID
Speech and language delay
Facies: midface hypoplasia, brachycephaly (flat back of head), depressed nasal bridge
Sleep disturbances
Behavioural problems
Hoarse voice
155
Q

Miller Dieker Syndrome (microdeletion 17p13.3)

A 
Rare; 1 in 100,000
Contiguous gene deletion syndrome
Key gene: PAFAH1B1 (LIS1)
PAFAH1B1 sole deletion = isolated lissencephaly
Severe Features (rarely survive beyond childhood):
Prenatally - polyhydramnios
Lissencephaly
Brain malformations
Microcephaly
Seizures
Facies
CHD
156
Q

HNPP (Hereditary Neuropathy with liability to pressure palsies) 17p12 microdeletion

A 
Deletion of PMP22 ~1.5Mb in 80% of cases
Small deletions/mutations 20%
Can be de novo; often inherited (50% recurrence risk)
Presentation:
Numbness of nerves following pressure on nerves
~15-20 years
Pes Cavus
Scoliosis
Deafnesss
157
Q

NF1 microdeletion syndrome (17q11.2)

A

1 in 2500
Contiguous gene syndrome encompassing NF1
5-20% NF1 patients have 1.4Mb deletion of 17q11.2
Type 1 (60-70%): 1.4Mb del by NAHR between LCRs NF-REP1a and REP1c
Type 2 (10-20%): 1.2Mb; BO in SUZ12 and its psedogene. Characterised by somatic mosaicism; early post zygotic mitotic origin.
Type 3: Variable in size with non-recurrent BPs.

158
Q

Koolen de Vries syndrome (17q21.31 recurrent microdel)

A

AD; almost all de novo
500-650kb deletion of 17q21.31 incl KANSL1
Haploinsufficiency of KANSL1 sufficient for pheno
LCRs responsible for phenotype
900kb inversion polymorphism at 17q21.31 in 20% caucasian population (H2 haplotype).
H2 haplotype results in directly orientated LCRs that can undergo deletion rearrangement by NAHR
Low recurrence risk but greater than general popn.
Features:
Dev del
Mild to mod ID
Hypotonia
Facies
ASD/VSD
Urological abnormalities
Seizures.

159
Q

Renal Cysts and Diabetes syndrome (RCAD)/Maturity onset diabetes of the young (MODY5)
17q12 microdeletion

A

Variable clinical spectrum + variable expressivity
Non diabetic renal disease (cysts, aberrant nephrogenesis)
Diabetes diagnosed at 10-40 years
Haploinsufficiency of HNF1B causative of RCAD
(entire gene, exon 1 or small mutation)
Possible association with LD/autism

160
Q

Potocki-Lupski Syndrome (microduplication 17p11.2)

A

Contiguous gene syndrome
~60% are reciprocal duplication of SMS region (3.7Mb)
NAHR between paralogous sequence repeats

Features:
FTT
Hypotonia
CHD
Mild MR
Behav problems
Dev delay
161
Q

Charcot Marie Tooth Disease (CMT1A)

17p12 microduplication

A

CMT1A most common form of CMT
Age dependent penetrance and variable expressivity
1.4Mb duplication at 17.12 including PMP22
Reciprocal to HNPP deletion
Increased levels of PMP22 cause phenotype
Features:
Distal muscle weakness and atrophy
Mild to mod glove and sensory loss

162
Q

Reciprocal NF1 Microduplication syndrome (17q11.2 microduplication)

A

Few cases reported
Variable ID
1.5Mb duplication corresponding to Type 1 NF microdeletion (NAHR mediated)

163
Q

Trisomy 18 (Edward Syndrome)

A 
95% spontaneously abort
Mean survival ~3 days (8% live longer than a year)
90% due to mat non-disjunction
females>males
Recurrence v.rare (only 1 or 2 case reports)
Features:
IUGR
Low set ears
Micrognathia
Rocker bottom feet
Exomphalus
clenched fist
Heart defects
CHD (@U/S)
CNS ab (@U/S)
164
Q

Tetrasomy 18p/Isochromosome 18p

A 
~250 families worldwide
Mostly de novo; low recurrence risk
Mechanism: Nondisjunction during maternal meiosis II followed by centromeric misdivision
Features:
Neonatal feeding difficulties
Hypotonia
Scoliosis
Strabismus
Dev delay
Mod to Severe MR
165
Q

18p deletion syndrome

A 
Terminal 18p deletion; no common BP
Mostly de novo simple terminal deletions
Mental dev critical region p11.1 to p11.21 - distal deletions have normal intelligence
2 haplolethal regions - cen to 18q11.2 and in 18q21.1
Features:
Short stature
Microcephaly
Large low set ears with detached pinnae
10-15% holoprosencephaly (TGIF and HPE4)
166
Q

Proximal 18q deletion

A 
BP between 18q12.2 and q21.2
Less freq than distal 18q dels; less severe
SETBP1 (18q12.3) ID and language delay
Features:
Dev delay
Seizures (~50%)
Hypotonia
Thin CC
167
Q

18q11.2 deletion

A

Features:
CHD
Kidney defects
GATA6 Candidate gene

168
Q

Pitt Hopkins Syndrome

A 
HI of TCF4
Most seq mutations but some genomic dels obs.
Features:
Severe epileptic encephalopathy
Psychomotor retardation
Breathing abnormalities
169
Q

Genes on chromosome 18

A

SMAD4 (18q21.2)
Associated with Juvenille Polyposiss and Hereditary Hemorrhagic Telangiectasia syndrome
Inactivated in ~50% pancreatic cancer.

170
Q

Microdeletion of 19p13.2

A 
Variation in size of microdeletion
"Sotos syndrome 2" or "Malan syndrome"
Candidate gene NFIX
Features:
Macrocephaly
Delayed speech
ID
171
Q

Microduplication of 19p13.2

A

Variable neuro-cognitive disability, overgrowth

172
Q

19p13.13 Microdeletion/duplication

A 
Contiguous gene deletion syndrome
Candidate genes: MAST1, NFIX, CALR
Microdeletion Features:
Dev delay, overgrowth, GI findings, eye findings
Microduplication Features:
Growth delay, microcephaly
173
Q

Microdeletion 19q13.11

A 
Candidate genes: 5 zinc finger genes
Features:
Growth deficiency
Microcephaly
Dev delay
Speech disturbance
Genital malformations (hypospadias) in males (WIPT1 in larger deletions)
174
Q

20p12.3 microdeletion syndrome (Wolff-Parkinson-White syndrome)

A

Specific EKG findings - Tachycardia

Hemizygosity of BMP2 gene

175
Q

Alagille-Watson syndrome orarteriohepatic dysplasia

A 
AD; reduced penetrance + variable expression
60% de novo
Mosaicism relatively frequent (up to 8%)
HI of JAG1 gene
90% mutations in JAG1
5-7% deletion
1% NOTCH2 (1p13)
Features:
Jaundice (conjugated hyperbilirubinaemia)
Facies
CHD
Axial skeleton anomalies
Eye defects
176
Q

Ring 20 syndrome

A

Childhood onset seizures
Frequent daytime complex partial seizures and nocturnal tonic seizures
Seizures are refractory to treatment
May also have: Dysmorphism, regression + ID (more common with deletions)
Ring replaces one of the normal chr. 20 copies
2 forms of ring syndrome:

Postzygotic telomere-telomere fusion - mosaic
No detectable deletions of chromosome 20
? effect due to positional effect of the telomere following rearrangement.

Deletion of p, q or both subtelomeric regions.

177
Q

22q11 Region

A

Several LCRs - LCR22-A to LCR22-H
LCR22-A and LCR22-D - 3Mb del(22)(q11.2q11.2) +dup
LCR22-A and LCR22-B - Smaller 1.5Mb del
LCR22-B - site of t(11;22) BP
LCR22-A - Cat Eye syndrome type 1
LCR22-D (and LCR22-A) Cat Eye syndrome type II
LCR22-D to H - distal 22q11.2 syndrome

178
Q

22q11.2 deletion syndrome Phenotypes

A

Velo-cardio-facial syndrome
Nasal speech due to palatal insufficiency, dysmorphism and CHD
DiGeorge Syndrome
Hypocalcaemia (from parathyroid hypoplasia)
Recurrent infections (deficient T cells)
CHD - Outflow tract defects e.g. TOF
Palatal ab
LD
Conotruncal anomaly face or Takao syndrome

179
Q

22q11.2 deletion syndrome

A

90% have common 3Mb deletion (LCR22-A and LCR22-D)
7% have smaller nested recurrent del (LCR22-A and LCR22-B)
Point mutations in TBX1 - same phenotype
90% cases de novo
Recurrence ~1%

180
Q

22q11.2 duplications

A

Freq ~half that of reciprocal deletions
Phenotype:
Milder than deletions; very variable
May have no discernable phenotypic effect

181
Q

Distal 22q11.2 deletions

A 
NAHR mediated
80% de novo
Between 700kb and 3Mb
Type I: Typical featuers
Type II: Milder phenotype
Type III: rhabdoid tumours (include MAPK1)
Phenotype:
Dev delay
Short stature
Premature birth
Dysmorphism
Very distal deletions including LCR22-F to LCR22-G encompass SMARCB1 gene - increased risk of rhabdoid tumours
182
Q

Cat Eye syndrome + invdup(22)(pter-q11.2)

A

Supernumerary bisatellited dicentric marker chromosome - tetrasomy 22q11
Incl 2 copies of 22 p arm and variable portion of 22q.
Type I CES: symmetrical proximal LCR22-A
Type II CES: One proximal + one distal BP (IIa) or two distal (IIb)

Phenotype:
Ocular coloboma (55-60%)
Preauricular skin tags and pits
CHD
Dev delay (some 47% within normal range)
183
Q

Phelan-McDermid Syndrome (distal 22q13 deletion)

A

rare; ~1200 cases reported
Both mosaic and non mosaic forms
Most common terminal deletion after 1p36 leading to a clinically significant chr disorder

Variable deletion size 100kb to 9Mb
75% of cases de novo
20% result of unbalanced structural rearrangements
<1% mutn in SHANK3
SHANK3 = post-synaptic density
HI of SHANK3 results in neurological features

Features:
Dev delay
Hypotonia (75%)
Dysmorphism
Autism (30%)
184
Q

Emanuel Syndrome der(22)t(11;22)(q23.3;q11.2)

A

Aetiology via recurrent translocation
3:1 malseg (tertiary trisomy) of t(11;22)(q23.3;q11.2)
BP within palindromic AT-rich repeats
Recurrence risk:
Stengel-Rutkowski 3.7% for females and <0.7% males
Zackai and Emanuel female risk ~10%

Phenotype:
Multiple congenital anomalies - CHD, CLP, GU, renal, GI
Dysmorphism
Sig dev delay

FRCPath Part 1 Genetics (4 decks)

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