Genetics Flashcards
What is germline mosaicism?
Parent cares AD gene mutation in their gonadal tissue and germline cells, but NOT in somatic cells–so they don’t show signs of disease.
Suspect when “normal” parent has more than 1 child affected with AD or X-linked condition.
What are some keys to look for on AR pedigree?
- will see disorders in 1 or more siblings but NOT in other generations
- males and females equally affected
- consanguinity increases risk of having offspring with disorder
What is genomic imprinting?
What are examples?
Genomic imprinting refers to difference in gene expression, depending on whether the disease allele is inherited from the mother or father.
Deletion of 2-4Mb portion of chromosome 15 inherited from father–> Prader-Willi syndrome = severe hypotonia, obesity, small hands and feet, MR
Deletion of 2-4Mb portion of chromosome 15 inherited from mother--> Angelman syndrome = normal until 6-12mo, then develop seizures, MR, hand flapping, ataxia, uncontrolled laughter (“happy puppet”)
Name the syndrome:
LGA, macrocephaly, prominent forehead, hypertelorism (increased distance b/t eyes), MR, large hands and feet
Sotos syndrome (AR)
Name the syndrome:
Coarse facies, macroglossia, ear lobe creases, posterior auricular pits, omphalocele, Wilms tumor, cryptorchidism, hemihypertrophy
Beckwith-Wiedemann syndrome (AD)
Name the syndrome:
Macrodactyly, soft tissue hypertrophy, hemihypertrophy, nevi, lipomas, hemangiomas, accelerated growth
Proteus syndrome
What are keys to look for in X-linked recessive pedigree?
- affected fathers transmit disease allele to all daughters (they are obligate carriers and usually unaffected) and no sons
- carrier females have 50% chance of transmitting disease to their sons
- there is no male-male transmission!
Common presentations for mitochondrial disorders include:
- metabolic encephalopathy
- lactic acidosis
- cardiac failure
- liver failure
What is this mitochondrial d/o that presents in infancy with anemia, neutropenia, pancreatic dysfunction, and myopathy?
Pearson syndrome
What is the mitochondrial d/o that presents with basal ganglia defects, hypotonia, and optic atrophy in infancy or early childhood?
Leigh syndrome
L
E ye problems
I nfancy/childhood
G anglia defects
H ypotonia
How is fragile X inherited?
What is the genetic abnormality?
X-linked inheritance; however 30% of carrier females have similar clinical phenotype to that of affected males
Caused by unstable CGG repeats on the FMR1 gene on the X chromosome
Normal = 6 to 50 repeats
Premutation = 55 to 200 repeats
Full mutation = > 200 repeats
What are common clinical findings of Fragile X?
- Large head
- MR
- Long face with large ears
- Large hands and feet
- Macroorchidism
- Hyperextensible joints
Think X-tra large!
Name 3 clinical disorders seen in premutation carriers of Fragile X (55 to 200 repeats).
- Mild cognitive and/or behavioral delays
- Premature ovarian failure
- FXTAS (fragile X associated tremor/ataxia syndrome) seen in older adult carriers who are mostly male and usually >50yo; clinical criteria includes intention tremor, gait ataxia, parkinsonism
What maternal serum results may indicate increased risk of Trisomy 21?
(high or low alpha, inhibin, hCG, estriol)
LOW alpha-fetoprotein
LOW unconjugated estriol
HIGH hCG
HIGH inHibin
What is the ratio or girls:boys in Edward’s syndrome (Trisomy 18)
4:1
Which syndrome is this?
- IUGR
- Rocker bottom feet
- Clubfoot
- Clenched fist with overlapping fingers
- Heart defects (90%), most with VSD and multiple dysplastic valves
Edward’s syndrome (Trisomy 18)
(Edward the vampire is 18yo)
What syndrome is this?
- Orofacial cleft (usually with midline cleft lip)
- Postaxial polydactyly of limbs
- Hypoplastic or absent ribs
- Genital anomalies
- Abdominal wall defects
Trisomy 13 (Patau syndrome)
Think midline defects! (3 looks like vertical m)
What syndrome consists of long face, high forehead, thick lower lip, deep palmar and sole creases (very characteristic)
What are they at increased risk of in adulthood?
Mosaic Trisomy 8
AML
What syndrome has these features:
- most common in girls
- “Greek helmet” facies with ocular hypertelorism, frontal bossing, prominent glabella
- “Beaked” nose
- Seizures (90%)
Wolf-Hirschhorn syndrome = 4p deletion
What syndrome has these features:
- “Moon face” with telecanthus (increased distance between the medial canthi of the eyes, while the inter-pupillary distance is normal)
- Wide and flat nasal bridge
- Down-slanting palpebral fissures
- MR
- “cat’s cry” from anatomic change in larynx
Cri-du-chat syndrome = 5p deletion
What sydrome has these features:
- Microcephaly
- Developmental delay
- Atretic or narrowed ear canals
- “Frog-like’ position of legs
- Protruding mandible
- Deep set eyes
De Grouchy syndrome = 18q deletion
(Grouchy doesn’t want to listen anymore!)
What sydrome has these features:
- Jerky, ataxic movements
- Hypotonia
- Fair hair
- Severe MR
- Seizures
Angelman Syndrome : 15q11-13 microdeletion paternally derived
(“happy puppet”)
What sydrome has these features:
- Obesity (after initial FTT)
- Severe hypotonia at birth
- Short stature
- Small hands and feet
- Hypogonadism
- Mild MR
Prader-Willi Syndrome: 15q11-13 deletion maternally derived
What sydrome has these features:
- Periorbital fullness with down-turned lower lip
- Friendly, outgoing personality
- Stellate pattern of iris
- Supravalvular aortic stenosis
- MR
- Hypercalcemia
Williams Syndrome = 7q11.23 deletion
FISH will detect absence of elastin gene
What sydrome has these features:
- Wilms tumor (in up to 50%, most by 3yo)
- Aniridia
- Male genital hypoplasia
- MR (wide range)
- Gonadoblastoma
WAGR syndrome = 11p13 deletion
W ilm’s tumor
A niridia
G enitourinary malformation
R etardation
What sydrome has these features:
- Triangular facies with pointed chin
- Skeletal deformities: butterfly vertebrae
- Bile duct paucity with cholestasis
- Ocular defects (posterior embryotoxon–developmental abnormality
- Long nose with broad mid-nose
Alagille Syndrome = 20p12 deletion
Ocular defects = posterior embryotoxon–developmental abnormality marked by a prominent white ring of Schwalbe and iris strands that partially obscure the chamber angle
What syndrome has these features:
- Brachial arch defects (small chin, cleft palate, abnormal ears)
- Thymus agenesis or hypoplasia (immune deficiency)
- Parathyroid gland agenesis or hypoplasia (hypocalcemia)
- Cardiac abnormalites: TOF, interrupted aortic arch, VSD, truncus arteriosis
22q11.2 deletion = DiGeorge syndrome
This is a developmental defect of derivatives of the 3rd and 4th pharyngeal pouches
~66% of patient have nonverbal learning disability
20-30% have MR
What syndrome has these features:
- Tall male with gynecomastia
- Delayed secondary sex characteristics
- Small testes
- Almost all have azoospermia and are infertile
47, XXY = Klinefelter syndrome
What syndrome has these features
seen at birth:
- Broad, webbed neck
- Posteriorly rotated ears
- 50% with cardiac abnormalities: bicuspid aortic valves, coarc
later in life:
- Female with short stature
- Ovarian failure/gonadal dysgenesis
- Lack of secondary sex characteristics
Turner syndrome = 45, X
Other common associated disorders in childhood or adulthood include:
- Hashimoto thyroiditis
- alopecia
- vitiligo
- GI disorders
- carbohydrate intolerance
Generally, when do you surgically repair cleft lip?
Cleft palate?
Cleft lip: 1st 5 months of life
Cleft palate: 6-12 months
What is the clinical criteria for NF-1?
Need 2 of 7 for diagnosis:
- >6 cafe-au-lait spots >0.5cm in prepubertal children, >1.5cm in postpubertal
- >2 neurofibromas or 1 plexiform neurofibroma
- freckling in the axillary or inguinal area
- optic glioma
- >2 Lisch nodules (iris hamartomas)
- 1st degree relative with NF-1
- Sphenoid dysplasia or thinning of long bone cortex
What is inheritance pattern of NF-1 and NF-2?
AD
What are the diagnostic criteria for NF-2?
- presence of either bilateral acoustic neuromas
or
- 1st degree relative with NF-2 and either unilateral acoustic neuroma, CNS tumors, or lens opacity (cataracts)
What CNS tumors are associated with NF-2?
- Vestibular schwannomas: cause hearing loss, tinnitus, imbalance, facial weakness
- Intracranial meningiomas
- Spinal schwannomas
- Cranial nerve schwannomas
- Ependymomas
What syndrome has these features:
- Ash leaf hypopigmented macules (enhance with a Woods lamp)
- Shagreen patches on trunk or lower back
- Cardiac rhabdomyomas
- Infantile spasms
Tuberous Sclerosis (AD)
What do you use to treat infantile spasms?
Vigabatrin (Sabril)
