Chromosome Disorders Flashcards
1p36 deletions (contiguous gene disorder)
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.
Proximal Interstitial 1p36 deletion
Features: Dev delay, Hypotonia, characteristic facies (microcephaly, frontal bossing…), Hirsutism, Structural heart defects.
Multiples candidate genes including KCNAB2 for epilepsy.
1p36 duplication
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)
1p32-p31 deletion syndrome
Haploinsufficiency of NFIA Size Features: Corpus Callosum dysgenesis Ventriculomegaly Dev Delay Seizures
1q21 region
complex
4 blocks of LCR - NAHR
Class I: distal 1q21.1 del/dup 1.8Mb
Class II: larger ~2.7Mb (includes TAR + distal region)
Distal 1q21 microdeletion syndrome
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
1q21 Microduplication syndrome
Rare Mirrors 1q21 deletion syndrome Incomplete penetrance and variable expressivity Macrocephaly TOF
Thrombocytopenia Absent Radius Syndrome (TAR)
Proximal 1q21 deletion
“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)
1q43q44 deletions
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)
1q41q42 deletions
Very rare Variable phenotype including: Dev delay Seizures Cleft palate Club feet DISP1 haploinsufficiency (craniofacial/neuro features)
1q duplications
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
Supernumerary ring chromosome 1
Mostly de novo (can be inh - mostly mat) Varying size of ring therefore pheno Features: Dev del Hypotonia Sacral dimple
Trisomy 2
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
UPD2
6 reported cases
Maternal
No associated imprinting effects
Inversion 2
Large blocks of segmental duplications
Common Variant inv(2)(p11.2q13)
2p15-2p16.1 deletion syndrome
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)
2p16.3 deletion
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
2q13 deletion
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
2q13 duplication
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
Mowat Wilson 2q22 deletion
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
2q23.1 deletion syndrome
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
2q32q33 deletion syndrome
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
2q37 deletion syndrome (also called Albright-like syndrome, Brachydactyly Mental Retardation syndrome (BDMR)
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
Disorders with genes on chromosome 2
Alport syndrome
Classical Ehlers Danlos syndrome (COL5A2) 2q31
Vascular Ehlers Danlos syndrome (COL3A1) 2q32.2
Waardenburg syndrome (PAX3) 2q36.1
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.
UPD3
single case reported.
Dev del - homozygous for rare cytogenetic polymorphism carried by one parent.
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.
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
3p26 deletion
Similar to 3p25 deletions
Incomplete penetrance
Reported inh from normal parents
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
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
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
3q13.31 deletion syndrome
Hypotonia above av. growth Dev delay Facies - short philtrum, high palate Abnormal male genitalia
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
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
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
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
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.
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
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
Mosaic Trisomy 4
Very rare; may be seen at CVS.
1 case of liveborn reported.
UPD4 possible by trisomy rescue.
Poor outcome.
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
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).
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.
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
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
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
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
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
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
UPD6 paternal
Neonatal benign transient diabetes
Low birth weight
Overexpression of paternally expressed imprinted genes at 6q24.
(also diabetes from mat hypomethylation/paternal duplication)
UPD6 maternal
Only a couple of cases reported
IUGR
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
Interstitial 6p22-24 deletions
Features: Orofacial clefting Clinodactyly/Syndactyly Brain defects Heart defects Kidney defects
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)
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
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.
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
Ring Chromosome 6
Rare; typically de novo Variable phenotypes: ID Microcephaly Prenatal growth failure retarded bone age Prenatally: hydrocephalus, cortical atrophy, ventriculomegaly
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
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
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
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
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
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
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
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).
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
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
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
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
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
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
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
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
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.
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
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
Saethre-Chotzen Syndrome (7p21.1 deletion)
Mutns and microdeletions TWIST gene Craniosynostosis Normal intelligence Larger deletions can include ID. Incomplete Penetrance
7p21.1 duplication
Underdevelopment of cranial bones
7q11.22 deletion/gene disruption
AUTS2 Deletion or interruption of gene by small dup Clinical Features: ID Behavioural issues ASD Dev delay
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
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
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.
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.
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
BRAF (7q34)
Oncogene Cardiofaciocutaneious syndrome Multiple letigines syndrome (LEOPARD) Noonan syndrome Langerhans cell histiocytosis Melanoma and astiocytomas
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.
Ring 7
46, r(7): Microcephaly and ID
47, +r(7): language acquisition difficulty, ?STX1A and LIMK1
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
Barakat Syndrome/HDR syndrome (10p14 deletion)
Haploinsufficiency of GATA3 gene; AD
H - Hypoparathyroidism (results in low calcium level)
D - deafness
R - Renal abnormalities
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
Duplications of 10q22q23
v. rare Variable phenotypic penetrance Features: Dev delay Speech delay Microcephaly
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)
Proximal 10q duplications (10q11-10q22)
Clinical Features: Short stature Microcephaly Dev delay LD Eye defects Heart defects Facies: prominent forehead, iris coloboma
10q24-q26 duplication
Mild Clinical Features: Dev Delay LD Delayed speech Slightly dysmorphic face
10q25-26 duplcations
Similar to 10q24-26 duplications but milder includes:
Feeding difficulties
Dysmorphic face: round, flat face, narrowed eyes, ptosis
Dev delay
LD
RIng chromosome 10
~20 cases reported Features (dependent on BP): LD Short stature Microcephaly Growth retardation Cardiac Renal Undescended testes + hypoplastic scrotum
FGFR2 Crouzon Syndrome (10q26.13)
Premature fusion of skull bones (craniosynostosis)
Cleft lip and palate
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)
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
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.
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
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.
UPD12
No apparent UPD syndrome or phenotype
Ring 12
Varying phenotypes
Growth retardation
ID
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
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)
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
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)
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.
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.
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.
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
Genes on chromosome 13
CX26/DFNB1A (13q12.11)
CX30/DFNB1B (13q12.11)
FLT3 (13q12.2)
BRCA2 (13q13.1)
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
UPD14 Maternal (TEMPLE syndrome)
Generally mild phenotype; may be undiagnosed.
Pre/Postnatal GR
mild ID
Subtle dysmorphism
UPD14 Paternal (WANG syndrome)
More severe phenotype than mat Obstetric complications - polyhydramnios + premature labour Low birth weight THoracic and ab wall defects Subtle dysmorphism
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
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
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
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.
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
Genes on chromosome 14
alpha-1 antitrypsin deficiency SERPINA1
FOXG1 syndrome (14q12); mutations or microdeletion. Features: GR, severe brain ab, severe ID.
15q11.2 Deletion syndrome (BP1/BP2)
Susceptibility loci
300-500kb;
TUBGCP5, NIPA1, NIPA2 and CYFIP1
Increase in susceptibility to neuropsychiatric or neurodevelopmental problems
15q11.2 Duplication syndrome (BP1/BP2)
CNV not sufficient for phenotype; increase in susceptibility.
TUBGCP5, NIPA1, NIPA2 and CYFIP1
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
Homozygous deletion of 15q13.3
More severely affected with significant global dev delay, severe hypotonia and seizures
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.
Distal 15q deletion: 15q15-22
Growth delay Truncal obesity Scoliosis Craniosynostosis Seizures Motor delay
15q22-q26 (pale section of 15q)
Feeding difficulties
Dev delay
IUGR
Diaphragmatic hernia
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
15q26 deletion
Pale tip of 15q; IGFR1 gene Features: IUGR (IGFR1 gene) Micrognathia Triangular face Low set ears Feeding difficulties
15q21/q22 duplication
Central dark band of 15q. Dev delay LD Seizures CLP Scoliosis
BP between 15q15 and 15q24 with terminal duplication
Dev delay LD Unusual fingers Born normal weight/height but growth slows CHD Microcephaly Hypotonia Scoliosis
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
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.
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.
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.
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
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
16p11.2 Microduplication syndrome
NAHR mediated common recurrent dup (600kb) Variable features: Motor delay ADHD Congenital anomalies Seizures Microcephaly
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
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
16p11.2 Distal deletion
220kb SH2B1 gene Features: Obesity Dev delay Behavioural problems
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
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,
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
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…)
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
21q22 Deletion
Includes RUNX1 gene -thrombocytopenia + predisposition to myeloid leukemia Features: Behavioural problems No speech Microcephaly Feeding problems Obesity VSD Epilepsy Thinned CC
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)
Partial Monosomy 21
21cen to 21q22.11: Severe; CHD, psychomotor delay
21q22.11 to 21q22.13
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
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
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
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.
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.
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
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
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
Reciprocal NF1 Microduplication syndrome (17q11.2 microduplication)
Few cases reported
Variable ID
1.5Mb duplication corresponding to Type 1 NF microdeletion (NAHR mediated)
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)
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
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)
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
18q11.2 deletion
Features:
CHD
Kidney defects
GATA6 Candidate gene
Pitt Hopkins Syndrome
HI of TCF4 Most seq mutations but some genomic dels obs. Features: Severe epileptic encephalopathy Psychomotor retardation Breathing abnormalities
Genes on chromosome 18
SMAD4 (18q21.2)
Associated with Juvenille Polyposiss and Hereditary Hemorrhagic Telangiectasia syndrome
Inactivated in ~50% pancreatic cancer.
Microdeletion of 19p13.2
Variation in size of microdeletion "Sotos syndrome 2" or "Malan syndrome" Candidate gene NFIX Features: Macrocephaly Delayed speech ID
Microduplication of 19p13.2
Variable neuro-cognitive disability, overgrowth
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
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)
20p12.3 microdeletion syndrome (Wolff-Parkinson-White syndrome)
Specific EKG findings - Tachycardia
Hemizygosity of BMP2 gene
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
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.
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
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
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%
22q11.2 duplications
Freq ~half that of reciprocal deletions
Phenotype:
Milder than deletions; very variable
May have no discernable phenotypic effect
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
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)
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%)
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
