Week 2: Chromosome disorders, aneuploidy, del/dup syndromes

Question 1

T/F: balanced translocations can present as a single gene disorder

Answer 1

True! Can present as single gene disorder if there is a partial gene loss due to breakage in middle of the gene (no great way to assess this with current technology)

Question 2

What are 3 possible outcomes of chromosomal rearrangements>

Answer 2

1. Infertility/recurrent miscarriage
2. Multiple congenital anomalies
3. Meiotic and mitotic errors

Question 3

What is Emmanuel syndrome and how does it occur

Answer 3

-Recurrent translocation that results in a supernumerary chromosome
-Results from parents with balanced 11;22 translocation
-Meiotic errors can result in a child with normal 11s and 22s (or balanced 11s and 22 translocation) PLUS one of the derivative 22s
-Results in dup of part of 22q cen-q11 and dup of part of 11q23-qter
-Overall chance of having an affected child is estimated to be 1.8-5.6% with miscarriage rate up to 37%

Question 4

How is Emmanuel syndrome different than other unbalanced translocations?

Answer 4

Different because typically expect deletion of one chromo and dup of another. This syndrome we end up with dup of each chromosome and the supernumerary chromosome

Question 5

Name some features of Emmanuel syndrome

Answer 5

-IUGR and postnatal growth deficiency
-Microcephaly
-Hypotonia
-Severe delays
-Dysmorphic features
-Other birth defects

Question 6

What are marker chromosomes? Are they typically inherited or de novo? Do they cause issues with development?

Answer 6

-Defined as structurally abnormal chromosomes smaller or equal to a length of chromosome 20
-Most are de novo but can be mosaic or inherited, most frequently chromo 15
-Most do not contain euchromatin, and may not interfere with development

Question 7

T/F we can tell what chromosome a marker chromosome is derived from.
If so, what test can be performed to determine chromosome of origin

Answer 7

True! CMA can detect chromo of origin, will show up as a duplication

Question 8

What are some special considerations related to X;autosome translocations?

Answer 8

-Have to account for random X inactivation
-Are balanced translocation carriers at risk for symptoms??
-Skewed X inactivations

Question 9

What is the other name for 5p- syndrome? Give info and features of this syndrome

Answer 9

-AKA Cri-du-chat syndrome
-Caused by recurrent deletion on 5p
-Most often de novo, but ~10% of cases inherited from parent with balanced translocation
-Mewing cry, microcephaly, low birth weight, hypotonia, DD, ID, up to 40% of affected individuals do not develop expressive language, heart defect, behavioral issues

Question 10

Wolf-Hirschhorn syndrome info

Answer 10

-Recurrent deletion of distal 4p
-~55% of individuals have a de novo deletion
-40-45% inherit the deletion from a parent with a balanced translocation
-Categorized by deletion size, largest deletion most severe
-Pre and postnatal poor growth, often IUGR
-feeding difficulties
-Microcephaly
-Hypotonia
-Delayed speech and language skills
-Mild to moderate ID
-Epilepsy
-Missing teeth and/or delayed eruption
-Cardiac defects, most often ASD

Question 11

How are mosaic chromosomal disorders detetced?

Answer 11

-Assess standard 20 cell metaphase count
-Any suspicion of mosaicism should be confirmed in cells from an additional slide and possibly an alternative tissue

Question 12

What are mosaic monogenic disorders? Why might a mosaic variant be clinically silent?

Answer 12

-Mosaic single nucleotide variant occur due to post-zygotic errors in DNA replication
-Might be silent because: variant is not pathogenic, tissue it has occurred in is not one where the gene is expressed, may have occurred after a critical time frame for gene function, the deleterious variant is selected against and/or selective pressure favors cells without the variant

Question 13

Pallister-Killian syndrome info

Answer 13

-Rare, prevalence unknown
-Caused by a confined mosaic tetrasomy of 12p, usually an extra isochromosome 12p
-The isochromosome is not typically detected in lymphocytes (skin biopsy or buccal swabs needed to make dx typically)
-ID (severe to profound), skin pigmentation anomalies, seizures, sparse hair at temples, congenital diaphragmatic hernia, less common features (HL, supernumerary nipples, genital abnormalities, heart defects, polydactyly)

Question 14

Describe Williams syndrome at each stage of life

Answer 14

-7q11.23 deletion syndrome
-Infancy: congenital heart disease (supravalvar aprtic stenosis), elfin features, poor weight gain/FTT
-Childhood: connective tissue dysfunction, learning differences (strength in language), “cocktail” personality
-Adolescence: early puberty, short stature as an adult, ID, premature grey hairs
-Adulthood: many live independent/semi-independently, cardiac complications, diabetes, joint pain

Question 15

Is Williams syndrome typically inherited or de novo? What gene is associated with this syndrome?

Answer 15

-Most de novo
-ELN gene

Question 16

Natural history of 7q11.23 duplication syndrome

Answer 16

-Infancy: many children not born with MCA, most children have normal growth
-Childhood: DD, speech delays, seizures, some children with aortic enlargement, behavioral concerns, learning differences
-Adulthood: duplication is inherited from a mildly affected children ~30% of time

Question 17

Match the type of non-allelic homologous recombination with it’s subtypes/outcome:
-Intrachromosomal recombination & interchromosomal recombination
-Deletions and paracentric inversions
-Deletions and duplications

Answer 17

Intrachromosomal recombination: Deletions and paracentric inversions

Interchromosomal recombination: Deletions and duplications

Question 18

Name the corresponding deletion and duplication syndromes for each of the following locations:
-17p12
-17p11.2
-5q35.3
-7q11.23

Answer 18

LISTED AS DEL/DUP SYNDROME

-17p12: PMP22: hereditary neuropathy and liability to pressure palsies/Charcot-Marie-Tooth disease type IA
-17p11.2: Smith-Magenis/Potocki-Lupski
-5q35.3: Sotos/Dup of 5q35
-7q11.23: Williams-Beuren/Dup 7q11.23

Question 19

Name 3 disorders associated with NHEJ issues

Answer 19

-Fanconi anemia
-Ataxia telangiectasia
-Retinoblastoma

Question 20

What is chromothripsis

Answer 20

-Single catastrophic event resulting from formation of clustered DNA ds breaks on one or few chromosomes
-Subsequent error-prone repair generates highly rearranged chromosome
-Direct results=deletions
-In germline there is bias toward paternal alleles

Question 21

What is chromoanasynthesis?

Answer 21

-Alternating copy number changes arising from defective replication, typically clustered on a single or few chromosomes
-Occurs through replication-based mechanisms: fork-stalling and template switching (FoSTes) and micro-homology-mediated break-induced replication (MMBIR)
-Results in dups, dels, triplications

Question 22

What is chromoplexy?

Answer 22

-Interdependent occurrence of multiple inter and intra translocations and deletions resulting from DSBs with precise junctions
-Progressive multistep process, fragments were reinserted in random orientation, breakpoints are widely spread across the genome but cluster within genes
-Results=deletions

Question 23

Name the 3 types of complex copy number rearrangements due to chromoanagenesis

Answer 23

1. Chromothripsis
2. Chromoanasynthesis
3. Chromoplexy

Question 24

Presently, DiGeorge syndrome is used to describe what?

Answer 24

Individuals who have features of 22q11.2 del syndrome but who don’t have a deletion in this region

Question 25

Tell me some things about 22q11.2 proximal microdeletion syndrome

Answer 25

-Most common microdeletion syndrome
-Infancy: congenital heart disease (conotruncal defects ToF, IAA), palatal defects, hypocalcemia (increased risk for seizures), immunodeficiency
-Childhood: expressive and receptive speech delays, learning differences
-Adulthood: psychiatric concerns (anxiety, depression, OCD, schizophrenia (25%))

Question 26

What is used to make a molecular diagnosis of 22q11.2 deletion syndrome?

Answer 26

-SNP microarray: will provide exact breakpoints
-FISH or qPCR: confirm if deletion is present, quick and dirty
-Chromosome analysis: typically too small to be seen on karyotype

Question 27

T/F: For 22q del syndrome, the larger the CNV, the more likely it is to be identified in a parent

Answer 27

False!

Question 28

Name and describe the 4 different deletion sizes for 22q11.2

Answer 28

-Typical del size: 30-40 genes, this size is typically de novo in 90% of affected individuals
-Atypical deletion size: 20-30 genes, this size is typically inherited from mildly or unaffected parent
-Distal deletion size: 25-40 genes, inheritance is dependent on size of deletion
-Tiny deletion: inherited from unaffected parent

Question 29

If a child has a tiny deletion but that deletion includes TBX1, how are they managed?

Answer 29

They are managed like they have a standard 3mB deletion because missing TBX1 is so variable

Question 30

Tell me some things about 22q11.2 distal microdeletion syndrome

Answer 30

-Similar concerns to 22q proximal deletion syndrome
-Infancy: many have congenital heart defect, feed/swallowing difficulties, poor growth, palate differences less likely
-Childhood: DD, speech delays, behavior concerns, ADHD, anxiety, learning differences
-Adulthood: nothing specific

Question 31

Things about Phelan-McDermid (PMS) 22q13 microdeletion syndrome

Answer 31

-SHANK3: thought to be causative gene, associated with ASD, mental health, and psychiatric diagnoses
-ARSA and RABL2B also associated with microdeletion, AR inheritance for ARSA for leukodystrophy and RABL2B thought to be involved with infertility but doesn’t contribute to PMS phenotype
-Infancy: feeding difficulties, GI abnormalities, hypotonia, congenital heart defects, accelerated growth (tall as adults), CNS abnormalities seizures, renal anomalies
-Childhood: significant DD, ASD
-Adult: cognitive deficits, mental health disorders (bipolar, catatonia), neuropsych decompensation and regression

Question 32

Tell me about Wolf Hirschhorn/4p- syndrome

Answer 32

-4p16.3 deletion
-Critical regions: WHSCR1, WHSCR2
-Clinical features: distinct craniofacial appearance (greek warrior helmet), microcephaly, poor growth overall, sizures (may become milder with age but is not well controlled early in life, are main cause or morbidity), DD, lifelong cognitive deficits
-Recurrence: majority are de novo many of which are paternal in origin, sometimes one parent is a balanced translocation carrier

Question 33

Tell me about Williams syndrome 7q11.23 deletion syndrome

Answer 33

-Genes: ELN (associated with supravalvular aortic stenosis), LIMK1 (possible association with cognitive profile
-Clinical features: congenital heart disease, elfin-like features, poor weight gain/FTT, short stature in adulthood
-Specific cocktail personality: very friendly, non-social anxiety
-Recurrence: most de novo

Question 34

Tell me about WAGRO

Answer 34

-11p13 deletion
-Genes: PAX6 (associated with aniridia), WT1 (associated with Wilms tumor)
-Clinical features
W: wilms tumor
A: aniridia, cataracts, nystagmus, ptosis, vision loss
G: genitalia, males with cryptorchidism, hypospadias, females with structural uterine anomalies
R: slow growth, range of DD
O: obesity
-Recurrence: typically de novo

Question 35

Tell me stuff about Angelman syndrome

Answer 35

-Gene: UBE3A
-Clinical features: microcephaly, hypopigmentation (specific to deletion), cognitive deficit, nonverbal, gross motor delay, ataxic gait, behavioral concerns, seizures
-Recurrence: typically de novo

Question 36

Tell me about Prader Willi syndrome

Answer 36

-Gene: MAGEL2
-Clinical features: severe neonatal hypotonia, feeding issues, excessive eating ~4yo, DD, cognitive deficit, short stature, morbid obesity, behavioral issues, high mortality rate
-Recurrence: low, typically de novo

Question 37

Tell me about Miller-Dieker syndrome

Answer 37

-17p13.3 del
-Genes: LIS1/PAFAH1B1 (associated with lissencephaly, complete agyria, pachygyria)
-Clinical features: microcephaly, FTT, CNS anomalies/seizures/spasticity, significant DD, profound cognitive deficit
-Demise by age 2yo
-Recurrence: always de novo

Question 38

Tell me about Smith-Magenis syndrome

Answer 38

-17p11.2 del syndrome
-Genes: RAI1 (craniofacial and behavior issues), FLCN (BHD), PMP22 (can cause HNPP/neuropathy)
-Clinical features: specific facial features, DD, cognitive deficit, inverted circadian rhythm, maladaptive and self injurious behavior, short stature, childhood onset obesity
-Recurrence: de novo

Question 39

Tell me about Kleefstra syndrome

Answer 39

-9q34.3 deletion syndrome
-Genes: EHMT1/KMT1D
-Features: DD, cognitive deficit, severe expressive speech delay, distinct face, behavioral concerns (ASD, psych dxs), CNS anomalies
-Recurrence: de novo

Question 40

Name a few features of DiGeorge syndrome

Answer 40

-Hypoplasia or absence (rare) of the thymus, causes low T cells and high rate of infection
-Congenital heart defects
-Hypoparathyroidism
-Problems with voicebox/noisy breathing

Question 41

Tell me about Cornelia-de Lange syndrome

Answer 41

-The “classic” chromatinopathy
-EXTREMELY variable phenotype
-Main features: synophyrys, feeding difficulties/small size, ID, dental problems, radius/limb anomalies, hearing loss, other dysmorphisms (long eyelashes, excessive hair growth), self injurious behavior, heart defects
-Most have dominant de novo variant in NIPBL, multiple other genes-most of which dominant but some X-linked

Question 42

Tell me about Kabuki syndrome

Answer 42

-Multiple genes, KMT2D, dominant de novo, rare cases X-linked
-Long palpebral fissures, fetal fat pads, ID, heart/palate/GI defects
-Poor growth, endocrine abnormalities, feeding problems, hearing loss, immunodeficiency

Question 43

Tell me about Rubinstein-Taybi

Answer 43

-Dominant, de novo (CREBBP, EP300)
-Beaked nose and grimacing smile, broad thumbs/big toes, undescended testes almost universal, heart defects
-Rare cases with normal intellect

Question 44

Tell me about CHARGE syndrome

Answer 44

-C: coloboma
-H: heart defect
-A: choanal atresia
-R: developmental differences, poor growth
-G: genital and/or urinary anomalies
-E: ear abnormalities
-Gene: CHD7, 98% of individuals with CHARGE have sequence variant in CHD7, if VUS in CHD7=no dx
-Many concerns associated with syndrome identified at birth, life expectancy dependent on severity of anomalies
-

Question 45

Tell me about VACTERL association

Answer 45

-V: vertebral anomalies
-A: anorectal malformations/anal atresia
-C: cardiac defects
-TE: tracheoesophageal fistula with or without esophageal atresia
-R: renal anomalies
-L: limb anomalies
-These findings occur together more frequently than would be expected by chance
-Currently no identified genetic etiology
-A clinical diagnosis, diagnosis of exclusion

Question 46

Tell me about Allagille syndrome

Answer 46

-AD inheritance, JAG1, NOTCH2
-Clinical features: hepatic manifestations (jaundice, elevated liver enzymes, chronic cholestasis, liver failure usually by 18yo), cardiac malformations (ToF, VSD, ASD, AS CoArc), posterior embryotoxon (eye thing), renal disease (structural and funcitonal), vertebral anomalies (butterfly vertebrae), characteristic facies

Question 47

Tell me about Coffin-Siris syndrome

Answer 47

-Super rare, AD usually de novo variants in several genes most common is ARID1B
-Clinical features: fifth digit nail hypoplasia, DD/ID, coarse facial features (coarsen over time), hypotonia, hirsutism/hypertrichosis, sparse scalp hair

Question 48

Tell me about OAV ( oculo-auriculo-vertebral) /Goldenhar syndrome

Answer 48

-Genetic causes: CNVs, single gene variants (MYT1, AMIGO2, ZYG11B, ZIC3), majority of individuals have no known genetic cause
-Minimal diagnostic criteria-controversial
-Etiology complex but include both familial and genetics- usually occurs sporadically
-Disorder primarily involving structures derived from 1st and 2nd pharyngeal arches during development
-O: oculo
-A: auriculo
-V: vertebral
-Craniofacial features: can be asymmetric, ear anomalies, with/without hearing loss, hemifacial microsomia, orofacial clefts, ocular (dermoids, microphthalamia, eyelid coloboma)
-Spectrum of phenotypic features and can have overlap with other syndromes

Question 49

Tell me about Treacher Collins syndrome

Answer 49

-Genes: TCOF1, POLR1D, POLR1B, POLR1C, unknown
-Variable expressivity
-Primarily a craniofacial disorder
-Downslanting palpebral fissures (bilateral, symmetric), malar hypoplasia, micrognathia, external hear abnormalities, significant feeding and respiratory difficulties, conductive hearing loss, cleft palate, choanal stenosis or atresia, intellect is typically normal