Genetics Flashcards
What type of defect is cleft palate?
Déformation
What type of defect is potters sequence?
Primary defect malformation (renal issues)
Then deformation from oligohydramnios
Definition of major anomaly? Examples?
• MAJOR ANOMALY: a congenital anomaly severe enough to need
surgical intervention, increased morbidity and/or mortality,
potentially has a long-term impact medically and/or psychologically.
• Examples: cleft lip and palate, spina bifida / myelomeningocele, omphalocele,
duodenal atresia, congenital heart disease
Définition of Minor Anomaly ?
Examples?
- MINOR ANOMALY: a congenital anomaly that requires no treatment at all or can be easily corrected, do not cause increased morbidity or mortality, often common in population.
- Examples: postaxial polydactyly, abnormal palmar creases, low-set ears, preauricular tag
What complications can patients with 22q11 Deletion Sequence have?
• CHD (64%),
conotruncal, e.g., VSD, TOF, IAA type B, truncus, aberrant subclavian
• Palatal abnormalities (67%): velopharyngeal insufficiency, submucosal cleft, cleft palate, dysphagia
Airway/related: vascular ring, laryngeal web, subglottic stenosis
Gl: anteriorly placed/imperforate anus, esophageal atresia, umbilical / inguinal hernia
• Immune deficiency (77%) e.g., frequent infections, thymic hypoplasia
Craniofacial: prominent nasal bridge, micrognathia, asymmetric crying facies
• Hearing loss (sensorineural / conductive)
Developmental delay / learning difficulties (70%-90%)
Psychiatric: autism spectrum (20% of children), schizophrenia (25% of adults), ADD, anxiety
Skeletal: scoliosis, rib / vertebral anomalies, clubfoot
Genitourinary: hydronephrosis, renal anomalies, cryptorchidism, hypospadias
• Laboratory: hypoCa, hypoparathyroidism (50%), GH deficiency, cytopenias (lymphopenia)
Features of T18
- Trisomy 18 aka Edward’s syndrome
- Majority (95%) of trisomy 18 conceptuses spontaneously aborted
- Incidence 1/7500 livebirths
Clinical features:
• Physical: prominent occiput, low set ears, micrognathia, small mouth, high arched palate, clenched fists (2nd and 5th fingers overlapping 3rd and 4th), rockerbottom feet, hypoplastic nails (especially 5th fingernail), short sternum, hypertonia
• Other / major anomalies: CHD (VSD, PDA, ASD, poly-valvular disease) in 80-100%,
central apnea - respiratory failure, horseshoe kidneys
- Postnatal survival poor: 50% die in 1st week, most do not live past 1st year
- Severe intellectual disability in survivors
Describe Potters sequence
• Potter sequence (deformation)
• External and internal abnormalities caused by
oligohydramnios
• Primary defect a malformation: posterior urethral valves, renal
agenesis, multicystic dysplastic kidneys
• Lack of fetal urine > oligohydramnios > fetus has a flat face due to compression of the face against the uterine wall, club foot due to no room for significant movement, and associated lung hypoplasia
• “Potter facies”: wrinkly skin, low-set ears, flat nose & chin, widely
spaced, epicanthal folds.
T21 is most at risk for
A. Intestinal atresia
B. Congenital hypothyroidism
C. Transient myeloproliferative disorder (TMD)
D. Hirschsprung’s disease
A. Intestinal atresia (Duodenal atresia)
Features of 22q11 deletion syndrome
• CHD (64%), especially conotruncal, e.g., VSD, TOF, IAA type B, truncus, aberrant subclavian
Palatal abnormalities (67%): velopharyngeal insufficiency, submucosal cleft, cleft palate, dysphagia
Airway/related: vascular ring, laryngeal web, subglottic stenosis
Gl: anteriorly placed/imperforate anus, esophageal atresia, umbilical / inguinal hernia
• Immune deficiency (77%) e.g., frequent infections, thymic hypoplasia
Craniofacial: prominent nasal bridge, micrognathia, asymmetric crying facies
Hearing loss (sensorineural / conductive)
Developmental delay / learning difficulties (70%-90%)
Psychiatric: autism spectrum (20% of children), schizophrenia (25% of adults), ADD, anxiety
• Skeletal: scoliosis, rib / vertebral anomalies, clubfoot
Genitourinary: hydronephrosis, renal anomalies, cryptorchidism, hypospadias
Laboratory: hypoCa, hypoparathyroidism (50%),
GH deficiency, cytopenias (lymphopenia)
Feature of Noonan
• Autosomal dominant
Multiple genes: most common PTPN11 in 50%, other genes include SOS1, RAF1, RIT1,
KRAS
- CHD: most common pulmonary valve stenosis (PS), hypertrophic cardiomyopathy
- Broad/ webbed neck
Characteristic faces
• Low-set posteriorly rotated ears, blue-green irises, widely-spaced downslanting eyes, ptosis.
Chest wall abnormalities: superior pectus carinatum, inferior pectus excavatum
Widely spaced nipples
• Short stature
• Cryptorchidism
Developmental delay (variable degree)
Coagulation defects, e.g., PT, PTT, platelet count may show abnormalities.
• Lymphatic dysplasias of the lungs, intestines, and/or lower extremities
How do you confirm T21
Routine Karyotype
Robertsoniam translocation - can increase risk for future pregnancies up to 15%
When to order microarray ?
It is the first-line test recommended by the American
College of Medical Genetics (ACMG) for multiple congenital anomalies that do not fit a specific pattern of diagnosis
How to test for CF?
Single gene sequencing: CFTR gene for cystic fibrosis.
**The majority of infants with meconium ileus end up having cystic fibrosis. 20% of
CF patients present in the neonatal period with meconium ileus.
How to test for BWS
• DNA Methylation studies
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome
that should be suspected if a neonate has one or more of the
following major/minor findings.
• Major findings: macrosomia, macroglossia, hemihyperplasia,
omphalocele, embryonal tumor (e.g., Wilms tumor, hepatoblastoma),
visceromegaly, anterior linear ear lobe creases and/or posterior
helical ear pits, large placenta
• Minor findings (relatively common in population): polyhydramnios,
prematurity, neonatal hypoglycemia, vascular lesions e.g. nevus
simplex (forehead, back of the neck)
Most common gene imprinting error during in vitro fertilization
Beckwidth wiedemann syndrome
What does dysostosis refer to?
Abnormalities in early patterning events during skeletal development
Occurs GA 3-6 weeks
Ie: spondylocostal dysostosis (AR, mutation in notch ligand DLL3)
What is the genetic defect associated with trnasient neonatal diabetes mellitus? Chromosome?
Genomic imprinting
Chromosome 6
Manifests with IUGR, FTT, hyperglycemia and dehydration 4-6 weeks
3 year old girl with developmental delay, hand foot sucking and cheerful disposition. Dx and chromosomal location?
Angelman syndrome
Deletion of maternal inherited gene UBE3A on Chromosome 15q11
What diagnostic test do you send to diagnose uniparental disomy?
Single nucleotide polymorphism microarray
Comparative genomic hybridization refers to which test?
Fancy way of saying Microarray
Can detect deletions or duplications
Takes longer than karyotype
Beckwidth wiedemann is associated with (gain or deletion)?
Gain of methylation of maternal chromosome or paternal duplication
Overgrowth, think double
Supravalvular subaortic stenosis is associate with which syndrome?
Williams
7q11 deletion
Can also have peripheral pulmonic stenosis, hypoplastic nails, prominent lips, hoarse voice, stellate iris pattern, mental deficiency
Cell free fetal DNA is usually _______ than are maternally derived cfDNA
Shorter
Most commin presenting clinical manifestation klinefelter syndrome?
Infertility from azoospermia
Iugr, microcephaly, short sternum, camptylodactlyly, clenched hand, multicystic dysplastic kidney. Dx?
Trisomy 18
Triangular face, IUGR, 5th finger clinodactyly, leg length asymmetric, cryptoorchidism. Dx?
Silver Russell Syndrome
Remember this is a genomic imprinting disorder
Large polycystic kidneys, post axial polydactyly, occipital encephalocele. Dx?
Meckel Gruber syndrome (AR)
Chromostome 17
How is mRNA formed?
From transcription of DNA
Primary mRNA is formed first, undergoes splicing (removal of introns) to form mature mRNA
Ribosomal RNA
RNA that is part of ribosome and helps bind mRNa and tRNA to ribosome
Transfer RNA
RNA that transports amino acids and assists in translation of mature mRNA
The anticodon portion of tRNA (contains specific AA at 3’ end) binds to complementary mRNA codon
Transcription
MRNA is synthesized from DNA template
DNA polymerase
Enzyme important in DNA replication by utilizing complementary DNA strands as a template to synthesize new strand
RNA polymerase
Enzyme that binds to promoter region and synthesizes mRNA from a DNA template
Reverse transcriptase
Enzyme that transcribes RNA into DNA (reverses transcription)
Intron
Dna sequence of a gene located between 2 exons that is transcribed into mRNA but spliced out during formation of mature mRNA
Exon
DNA sequence of gene located between 2 introns that is transcribed into mRNA and retained after primary mRNA is spliced
Contains introns and exons
Genome
Exome
Coding region of genome (~1.5% of genome)
Promoter
DNA sequence located 5’ to a specific gene
RNA polymerase binds to this region so that transcription (DNA to mRNA) can occur
Enhancer
Dna sequence that interacts with specific transcription factors and leads to increased transcription of gene
Polyadenylation sequence
Important for mRNA stabilization
100-200 adenibe nucleotides locared at the 3’ end of primary mRNA
Translation
Process by which an aminoacid sequence is assembled utilizing mature mRNA
tRNA is required for translation
Difference of southern, northern and western analysis
Southern analysis-DNA is digested and exposed to DNA probe
Northern analysis-labeled DNA probe to digested RNA
Western analysis- used to identify protein of interest
How many newborns have a minor malformation?
13% have 1 minor
- 8% 2 minor
- 5% 3 minor
2-3% major malformation
Remember malformation is abnormal tissue formation (CHD, cleft palate, micrognathia, renal agenesis)
Arthrogryposis is what type of abnormal morphogenesis?
Deformation
Associated with altered mechanical forces on normal tissue
What type of abnormal morphogenesis is amniotic band?
Disruption
Breakdown of normal tissue
What type of abnormal morphigenesis is a hemangioma?
Dysplasia
Abnormal organization of cellular formation into tissue.
Ectodermal dysplasia is another example
What type of Abnormal morphogenesis is pierre robin?
Sequence
Primary mandibular development with secondary findings of micrognathia, cleft palate and glossoptosis
Match the mutation with disease (point mutation, frameshift, splice cite ir triple repeat mutation)
CF Thalassemia Fragile X Sickle cell Myotonic dystrophy
CF- nonsense point mutation (stop codon, shorter protein)
Thalassemia-splice site muration (intron isnt removed)
Fragile X-trinucleotide repeat CGG>50
Sickle cell-missense point mutation glutamic acid to valine at Ch 6
Myotonic dystrophy CTG> 100 severe
Most common single gene disorder in the Caucasian population
Cystic fibrosis
Diseases associated with advanced paternal age
Achondroplasia Apert syndrome Crouzon syndrome Neurofibromatosis Osteogenesis imperfecta Thanatophoric dysplasia Klinefelter syndrome and Trisomy 21-possible slightly increased risk
Genetic disorders associated with advanced maternal age
Klinefelter syndrome
Trisomy 13
Trisomy 18
Trisomy 21
What does massive parallel shotgun sequencing detect (MPPS)?
Highly sensitive in the detection of fetal aneuploidy (including Turner’s)
This is one of the types of NIPT
How does newborn screen detect disease?
Mass spectrometry
Analysis of allele ratios in cfDNA is useful to detect
Aneuplodies
Most commonly used biomarker for oxidative stress
Ratio of reduced to oxidized glutathione
DNA methylation of cytosine of a Cpg dinucleotide is an example of which type of gene regulation?
Epigenetic modification
Clenched fists, scalp defect, holoprosencephaly, cleft lip and palate. Dx?
T13
What is a major diagnostic criterion with the highest frequency in CHARGE syndrome
Major: Coloboma (80-90%) Cranial nerve dysfunction (75-95%) Choanal atresia/stenosis (50-60%) Ear anomalies (90%)
Minor:
Genital hypoplasia
Cardiac
Developmental delay
What are the 3 epigenetic modifications?
Dna methylation
Histone modification
Imprinting and x inactivation
Name some multifactorial disorders
Cleft lip palate Anencephaly Spina bifida Clubfoot Congential hip dysplasia Pyloric stenosis
Usually w unaffected parents. Greates risk with increasing #affected family members, closeless or relatedness
Whats the recurrence risk for Cardiac defect Cleft lip Cleft palate Club foot Developmental hip dysplasia Hirschprungs NTD Pyloric stenosis T21
Cardiac defect Cleft lip Cleft palate Club foot Developmental hip dysplasia Hirschprungs NTD
All between 3-5% if one affected prior child
If parent affected 10% Risk for CHD and cleft lip and 25% for club foot.
Pyloric stenosis 3% risk sibling, mother 19% risk if boy 7% girl, dad affected 5.5% if boy and 2.4% if girl
T21- 1% sibling, mom w balanced translocation 10–15% and dad w balanced translocation 5%
Broad thrumbs and 1st toes, beaked nose . Dx?
Rubenstein Taybi Syndrome
Also have microcephaly, cryptorchidism, postnatal growth deficiency
Name the syndrome associated with supravalvular aortic stenosis
Williams syndrome
7q11 deletion of an elastin gene
After supravalvular aortic stenosis next most common is peripheral pulmonic stenosis
Trident hands, megalocephaly with small foramen magnum, short limbs. Dx? And gene affected?
Achondroplasia, AD
Fibroblast growth factor receptor 3 gene
Midface hypoplasia, craniosynostosis, broad distal phalanx of thumb/bigtoe. Dx?
Maxillary hypoplasia, premature craniosynostosis, less risk of mental deficiency. Dx?
Apert syndrome=acrocephalosyndactyly
Crouzon=Craniofacial dyostosis
Both mutations in fibroblast growth factor 2 gene
Absent hypoplastic or abnormally shaped thumbs, ASD and narrow shoulders. Dx?
Holt oram syndrome
Flat facies, mid facial/mandibular hypoplasia and spondyloeouphyseal dysplasia. Dx?
Stickler syndrome
Clover leaf skull, large cranium to body size, bowed humerii, short limbs, narrow thorax. Dx?
Thanatophoric dysplasia
Mutation in fibroblast growth factor receptor 3
White forelock, partial albinism, deafness. Dx? Associated instestinal anomaly?
Waardenburg
Hirshprungs
Most common mechanism of altered imprinting in beckwith wiedeman syndrome
Loss of methylation of imprinting control region 2 on the maternal chromosome
Deletion of elastin gene, broad forehead, periorbital fullness, long philtrum, wide mouth. Dx and associsted cardiac anomaly
Williams syndrome
Supravalvular aortic stenosis
Also has hypercalcemia
Oligohydramnios, FGr, hydrops, multiple congenital anomalies (including renal). Which disorder?
Triploidy
69XXX
What marker will help differentiate hypophosphatasia from other lethal skeletal dysplasias. What is treatment?
Alkaline phosphatase
Enzyme replacement: asfotase alfa
Cleft palate
Polydactyl
Ambiguous genitalia
Deficiency of 7 dehydro cholesterol
Smith Lemli opitz
AR
MCC of adrenal insufficiency in the newborn
CYP21 gene mutation
CAH
Syndactyly especially of the 3rd and 4th fingers is a characteristic feature of which genetic abnormality?
Triploidy
Think of this if cffDNA is reported as non-informative or negative with other anomalies similar to T18/13
If cffDNa is performed it might be reported as non-informatice because there is an insufficient fetal fraction of cfDNA (esp w very small placentas)
Condition associated eith DHCR7 gene
Smith Lemli Opitz
Condition associated transcription factor TBX5?
Holt Oram
Preterm renal characteristics vs term
Lower GFR
Lower urine osmolarity (term 800 mOsm/L vs 500 in preterm)
Lower abilitt to reabsorn Na+ H20
Decreased ability acidify urine
Small / narrowing of the foramen magnum is associated with _____.
Achondroplasia
AD
Fibroblast growth factor receptor 3 gene
Trident hands
Transmission from females
All offspring of affected females will be affected
Male offspring does not pass disease
Mitochondrial
Mom transmits to boys and daufhters
Boys are affected
Girls are cariers
X linked recessive
More common in females (2x more common than in males)
Father passes to girls
Father cannot pass to sons
Both parents can pass it on
X linked Dominant
Incidence of major malformation?
Incidence of minor malformation?
2-3% of newborns with major malformation
13% of newborns with 1 minor malformation
- 8% with 2 minor malformation
- 5% with 3 minor malformation
What is assoc’d with fibroblast growth factor 3?
What is assoc’d with fibroblast growth factor 2?
FGF3 - thanatrophic. Achondroplasia
FGF2 - Apert, Crouzon, Pfeiffer
Neonates hypotonia cardiomegaly and macroglossia. What is elevated un these neonates?
Pompes diseases (alpha glucosidase deficiency)
Very high CPK
Mitchell-Riley syndrome (MRS)
autosomal recessive disorder characterized by neonatal diabetes with congenital gastrointestinal and hepatobiliary anomalies. It is caused by mutations of the RFX6 gene, which is located on chromosome 6q22 adjacent to genes implicated in transient neonatal diabetes mellitus. RFX6 encodes regulatory factor X6, a member of the RFX family of transcription factors that is expressed in the proximal intestine, pancreas, and liver. Manifestations associated with MRS include intrauterine growth restriction, duodenal atresia, neonatal diabetes, pancreatic insufficiency, anemia, hepatic siderosis, and biliary atresias.
Most common mechanism for prader Willi and angelman syndromes
Micro deletion 70% of the paternally inherited chromosome 15 (prader willi ) and maternal for angelman
Uniparental disomy 20%
Imprinting error <5%
Skeletal Dysplasia vs
Skeletal dystoses
Dysplasia = abnormal organization
Dysostoses = bone malformation
