Chromosome Disorders Flashcards
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.
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.
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)
4
Q
1p32-p31 deletion syndrome
A
Haploinsufficiency of NFIA Size Features: Corpus Callosum dysgenesis Ventriculomegaly Dev Delay Seizures
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)
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
7
Q
1q21 Microduplication syndrome
A
Rare Mirrors 1q21 deletion syndrome Incomplete penetrance and variable expressivity Macrocephaly TOF
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)
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)
10
Q
1q41q42 deletions
A
Very rare Variable phenotype including: Dev delay Seizures Cleft palate Club feet DISP1 haploinsufficiency (craniofacial/neuro features)
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
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
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
14
Q
UPD2
A
6 reported cases
Maternal
No associated imprinting effects
15
Q
Inversion 2
A
Large blocks of segmental duplications
Common Variant inv(2)(p11.2q13)
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)
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
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
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
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
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
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
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
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
25
Trisomy 3
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.
26
UPD3
single case reported.
| Dev del - homozygous for rare cytogenetic polymorphism carried by one parent.
27
Ring Chromosome 3
Supernumerary ring - few cases reported
Non-supernumerary ring (with partial del):
10 patients in literature
Delayed psychomotor development + growth failure similar to 3p monosomy.
28
3pter-3p25 deletion syndrome
```
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
```
29
3p26 deletion
Similar to 3p25 deletions
Incomplete penetrance
Reported inh from normal parents
30
3p14 Waardenburg Syndrome type 2
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
31
3p14 Waardenburg Syndrome type 2
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
32
3p25-26 Von Hippel -Lindau
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
33
3q13.31 deletion syndrome
```
Hypotonia
above av. growth
Dev delay
Facies - short philtrum, high palate
Abnormal male genitalia
```
34
3q22.3 Blepharophimosis, ptosis and epicanthus inversus (BPES)
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
35
3q29 microdeletion syndrome
```
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
```
36
3q29 microduplication syndrome
```
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
```
37
Wolf-Hirschhorn Syndrome (WHS) chr. 4
```
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
```
38
Wolf-Hirschhorn Syndrome Etiology
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.
39
WHS Genotype-Phenotype correlations
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
40
4q21 microdeletion syndrome
```
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
```
41
Mosaic Trisomy 4
Very rare; may be seen at CVS.
1 case of liveborn reported.
UPD4 possible by trisomy rescue.
Poor outcome.
42
4p duplications
```
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
```
43
Facioscapulohumeral Muscular Dystrophy (FSHD) 4q35
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).
44
Cri du Chat Syndrome (5p) Clinical Features
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.
45
Cri du Chat Syndrome (5p) Aetiology
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
46
Cri du Chat Syndrome (5p) Critical Regions
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
47
Sotos Syndrome (5q35 deletion syndrome)
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
48
5q14.3 deletion
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
49
Cornelia de Lange Syndrome 5q13.2
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
50
Trisomy 6
Full trisomy not viable.
Several prenatally reported cases of mosaicism.
PM with +6 in 13% amnio and 40% cord blood had multiple congential anomalies
51
UPD6 paternal
Neonatal benign transient diabetes
Low birth weight
Overexpression of paternally expressed imprinted genes at 6q24.
(also diabetes from mat hypomethylation/paternal duplication)
52
UPD6 maternal
Only a couple of cases reported
| IUGR
53
Subtelomeric 6p24-q25 deletion
```
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
```
54
Interstitial 6p22-24 deletions
```
Features:
Orofacial clefting
Clinodactyly/Syndactyly
Brain defects
Heart defects
Kidney defects
```
55
6q11-14 deletion
```
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)
```
56
Interstitial 6q24-25 deletion
```
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
```
57
Subtelomeric 6q27 deletion
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.
58
Disorders with genes on chromosome 6
```
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
```
59
Ring Chromosome 6
```
Rare; typically de novo
Variable phenotypes:
ID
Microcephaly
Prenatal growth failure
retarded bone age
Prenatally: hydrocephalus, cortical atrophy, ventriculomegaly
```
60
Mosaic trisomy 8 (Warkany syndrome)
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
61
8p23.1 region
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
62
inv dup del (8p)
```
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
```
63
8p23.1 microdeletion/microduplication
```
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
```
64
Roberts Syndrome (Pseudothalidomide Syndrome; 8p21.1)
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
65
Key Disorders on chromosome 8
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
66
Trichorhinophalangeal syndrome type II (8q23.3)
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
67
Langer-Giedion Syndrome (8q24.11)
Contiguous microdeletion syndrome with TPS syndrome (TRPS1)
Phenotype:
Multiple cartilaginous exostoses (formation of new bone on the surface of a bone).
68
Trisomy 9
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
69
Mosaic Trisomy 9
```
>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
```
70
Trisomy 9p
```
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
```
71
Tetrasomy 9p
```
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
```
72
9p deletion syndrome (Alfi's syndrome)
```
>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
```
73
9p24 and XY gonadal dysgenesis
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
74
Kleefstra Syndrome
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
Chromosome 9 ring
```
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
Trisomy 7
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
Silver Russell Syndrome (mat UPD7)
```
~10% of cases of RSS
Clinical features:
severe IUGR
Postnatal short stature
Retarded bone age
Relative macrocephaly
Prominent bossed forehead
Micrognathia
```
78
Greig Cephalosyndactyly (7p13 deletion)
```
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
Saethre-Chotzen Syndrome (7p21.1 deletion)
```
Mutns and microdeletions
TWIST gene
Craniosynostosis
Normal intelligence
Larger deletions can include ID.
Incomplete Penetrance
```
80
7p21.1 duplication
Underdevelopment of cranial bones
81
7q11.22 deletion/gene disruption
```
AUTS2
Deletion or interruption of gene by small dup
Clinical Features:
ID
Behavioural issues
ASD
Dev delay
```
82
7q11.23 Williams Beuren Syndrome
```
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
7q11.23 duplication Syndrome
```
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
7q21.3 deletion Ectrodactyly Plus syndrome
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
Holoprosencephaly Plus syndrome (7q32-qter)
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
Other genes on chromosome 7
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
BRAF (7q34)
```
Oncogene
Cardiofaciocutaneious syndrome
Multiple letigines syndrome (LEOPARD)
Noonan syndrome
Langerhans cell histiocytosis
Melanoma and astiocytomas
```
88
DLD (7q31-32) Maple Syrup Urine Disease
Mutations in DLD lead to lactic acidosis
| Prevents BCKD enzyme complex breaking down valine, isoleucine and leucine - build up of byproducts.
89
Ring 7
46, r(7): Microcephaly and ID
| 47, +r(7): language acquisition difficulty, ?STX1A and LIMK1
90
10p13 deletion DiGeorge Syndrome 2
```
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
Barakat Syndrome/HDR syndrome (10p14 deletion)
Haploinsufficiency of GATA3 gene; AD
H - Hypoparathyroidism (results in low calcium level)
D - deafness
R - Renal abnormalities
92
10q22.3q23.2 microdeletion syndrome
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
Duplications of 10q22q23
```
v. rare
Variable phenotypic penetrance
Features:
Dev delay
Speech delay
Microcephaly
```
94
10q25q26 Deletion Syndrome
```
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
Proximal 10q duplications (10q11-10q22)
```
Clinical Features:
Short stature
Microcephaly
Dev delay
LD
Eye defects
Heart defects
Facies: prominent forehead, iris coloboma
```
96
10q24-q26 duplication
```
Mild Clinical Features:
Dev Delay
LD
Delayed speech
Slightly dysmorphic face
```
97
10q25-26 duplcations
Similar to 10q24-26 duplications but milder includes:
Feeding difficulties
Dysmorphic face: round, flat face, narrowed eyes, ptosis
Dev delay
LD
98
RIng chromosome 10
```
~20 cases reported
Features (dependent on BP):
LD
Short stature
Microcephaly
Growth retardation
Cardiac
Renal
Undescended testes + hypoplastic scrotum
```
99
FGFR2 Crouzon Syndrome (10q26.13)
Premature fusion of skull bones (craniosynostosis)
| Cleft lip and palate
100
WAGR Syndrome (11p13 deletion syndrome)
```
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
Potocki-Shaffer Syndrome (11p11.2-11p12)
```
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
Jacobsen Syndrome (11q23.3-11qter)
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
Chromosome 11 disorders
```
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
Mosaic trisomy 12
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
UPD12
No apparent UPD syndrome or phenotype
106
Ring 12
Varying phenotypes
Growth retardation
ID
107
Pallister-Killian Syndrome/Mosaic Tetrasomy 12p/+i(12p)
```
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
12q14 microdeletion syndrome
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
12p13.33 microdeletion
```
V. rare ~4 case reports
Speech delay (childhood Apraxia of speech CAS) ELKS/ERC1 candidates for CAS
ID
Non-specific dysmorphism
Variable expressivity
```
110
Other genes on chromosome 12
```
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
Patau Syndrome Trisomy 13
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
Mosaic Trisomy 13
May be CPM or may reflect foetus.
High risk of ab if found at AF.
Phenotype very variable from 'normal' to full T13.
113
13q14 deletion syndrome
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
13q22-33 deletion
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
Genes on chromosome 13
CX26/DFNB1A (13q12.11)
CX30/DFNB1B (13q12.11)
FLT3 (13q12.2)
BRCA2 (13q13.1)
116
Mosaic Trisomy 14
```
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
UPD14 Maternal (TEMPLE syndrome)
Generally mild phenotype; may be undiagnosed.
Pre/Postnatal GR
mild ID
Subtle dysmorphism
118
UPD14 Paternal (WANG syndrome)
```
More severe phenotype than mat
Obstetric complications - polyhydramnios + premature labour
Low birth weight
THoracic and ab wall defects
Subtle dysmorphism
```
119
Imprinted region 14q32
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
Ring chromosome 14
```
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
14q11-22 deletion syndrome
```
Very rare; half of q arm!
Phenotype:
Dev delay
Dysmorphism - hypertelorism, epicanthic folds
Partial agenesis of CC
Blindness
Hearing impairment
Seizures
Apnoea
```
122
14q22-23 deletion syndrome
```
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
14q32.3-32.3 deletion
```
Terminal 14q deletion
Critical region of 250kb; CRIP2, MTA1 and TMEM121
Features:
Hypotonia
Single palmar crease
Feeding difficulties
Eyesight problems
ID
```
124
Genes on chromosome 14
alpha-1 antitrypsin deficiency SERPINA1
```
FOXG1 syndrome (14q12); mutations or microdeletion.
Features: GR, severe brain ab, severe ID.
```
125
15q11.2 Deletion syndrome (BP1/BP2)
Susceptibility loci
300-500kb;
TUBGCP5, NIPA1, NIPA2 and CYFIP1
Increase in susceptibility to neuropsychiatric or neurodevelopmental problems
126
15q11.2 Duplication syndrome (BP1/BP2)
CNV not sufficient for phenotype; increase in susceptibility.
TUBGCP5, NIPA1, NIPA2 and CYFIP1
127
15q13.3 microdeletion syndrome (BP4/BP5)
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
Homozygous deletion of 15q13.3
More severely affected with significant global dev delay, severe hypotonia and seizures
129
15q13.3 duplications (BP3/BP5)
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
Distal 15q deletion: 15q15-22
```
Growth delay
Truncal obesity
Scoliosis
Craniosynostosis
Seizures
Motor delay
```
131
15q22-q26 (pale section of 15q)
Feeding difficulties
Dev delay
IUGR
Diaphragmatic hernia
132
15q24 microdeletion syndrome
```
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
15q26 deletion
```
Pale tip of 15q; IGFR1 gene
Features:
IUGR (IGFR1 gene)
Micrognathia
Triangular face
Low set ears
Feeding difficulties
```
134
15q21/q22 duplication
```
Central dark band of 15q.
Dev delay
LD
Seizures
CLP
Scoliosis
```
135
BP between 15q15 and 15q24 with terminal duplication
```
Dev delay
LD
Unusual fingers
Born normal weight/height but growth slows
CHD
Microcephaly
Hypotonia
Scoliosis
```
136
BP at 15q25 (distal dark band) or 15q26 (pale tip) and terminal duplication
```
Involved IGFR1 gene (insulin growth receptor type 1)
Opposite phenotype to deletion
Large at birth
Macrocephaly
Overgrowth
ID
```
137
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-)
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
Important genes on Chromosome 15
```
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
Down Syndrome Trisomy 21
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
Trisomy 16
```
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
16p11.2 Microdeletion syndrome
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
16p11.2 Microduplication syndrome
```
NAHR mediated common recurrent dup (600kb)
Variable features:
Motor delay
ADHD
Congenital anomalies
Seizures
Microcephaly
```
143
16p11.2 duplication syndrome
```
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
16p11.2-p12.2 Microdeletion syndrome
```
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
16p11.2 Distal deletion
```
220kb
SH2B1 gene
Features:
Obesity
Dev delay
Behavioural problems
```
146
16p12.1 Microdeletions
```
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
Rubinstein-Taybi syndrome (16p13.3)
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
16p13.3 Contiguous deletion syndrome
```
Severe form of Rubinstein-Taybi syndrome
40kb to >3Mb;
Include 5' CREBBP gene + DNAse1 TRAP1
Add features:
FTT
Seizures
Intractable infections
```
149
16p13.11 Deletions
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
Duplication of 16p13.3
```
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
21q22 Deletion
```
Includes RUNX1 gene -thrombocytopenia + predisposition to myeloid leukemia
Features:
Behavioural problems
No speech
Microcephaly
Feeding problems
Obesity
VSD
Epilepsy
Thinned CC
```
152
Trisomy 21 (Down Syndrome) Aetiology
```
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
Partial Monosomy 21
21cen to 21q22.11: Severe; CHD, psychomotor delay
| 21q22.11 to 21q22.13
154
Smith Magenis Syndrome (17p11.2)
```
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
Miller Dieker Syndrome (microdeletion 17p13.3)
```
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
HNPP (Hereditary Neuropathy with liability to pressure palsies) 17p12 microdeletion
```
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
NF1 microdeletion syndrome (17q11.2)
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
Koolen de Vries syndrome (17q21.31 recurrent microdel)
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
Renal Cysts and Diabetes syndrome (RCAD)/Maturity onset diabetes of the young (MODY5)
17q12 microdeletion
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
Potocki-Lupski Syndrome (microduplication 17p11.2)
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
Charcot Marie Tooth Disease (CMT1A)
| 17p12 microduplication
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
Reciprocal NF1 Microduplication syndrome (17q11.2 microduplication)
Few cases reported
Variable ID
1.5Mb duplication corresponding to Type 1 NF microdeletion (NAHR mediated)
163
Trisomy 18 (Edward Syndrome)
```
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
Tetrasomy 18p/Isochromosome 18p
```
~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
18p deletion syndrome
```
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
Proximal 18q deletion
```
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
18q11.2 deletion
Features:
CHD
Kidney defects
GATA6 Candidate gene
168
Pitt Hopkins Syndrome
```
HI of TCF4
Most seq mutations but some genomic dels obs.
Features:
Severe epileptic encephalopathy
Psychomotor retardation
Breathing abnormalities
```
169
Genes on chromosome 18
SMAD4 (18q21.2)
Associated with Juvenille Polyposiss and Hereditary Hemorrhagic Telangiectasia syndrome
Inactivated in ~50% pancreatic cancer.
170
Microdeletion of 19p13.2
```
Variation in size of microdeletion
"Sotos syndrome 2" or "Malan syndrome"
Candidate gene NFIX
Features:
Macrocephaly
Delayed speech
ID
```
171
Microduplication of 19p13.2
Variable neuro-cognitive disability, overgrowth
172
19p13.13 Microdeletion/duplication
```
Contiguous gene deletion syndrome
Candidate genes: MAST1, NFIX, CALR
Microdeletion Features:
Dev delay, overgrowth, GI findings, eye findings
Microduplication Features:
Growth delay, microcephaly
```
173
Microdeletion 19q13.11
```
Candidate genes: 5 zinc finger genes
Features:
Growth deficiency
Microcephaly
Dev delay
Speech disturbance
Genital malformations (hypospadias) in males (WIPT1 in larger deletions)
```
174
20p12.3 microdeletion syndrome (Wolff-Parkinson-White syndrome)
Specific EKG findings - Tachycardia
| Hemizygosity of BMP2 gene
175
Alagille-Watson syndrome orarteriohepatic dysplasia
```
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
Ring 20 syndrome
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
22q11 Region
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
22q11.2 deletion syndrome Phenotypes
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
22q11.2 deletion syndrome
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
22q11.2 duplications
Freq ~half that of reciprocal deletions
Phenotype:
Milder than deletions; very variable
May have no discernable phenotypic effect
181
Distal 22q11.2 deletions
```
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
Cat Eye syndrome + invdup(22)(pter-q11.2)
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
Phelan-McDermid Syndrome (distal 22q13 deletion)
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
Emanuel Syndrome der(22)t(11;22)(q23.3;q11.2)
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
