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Pediatric Genetics and
Genomics
April 28, 2020
Lab Testing and Genetic &
Metabolic Disease: Spotting
the "Red Flags"
1
Leah Burke, MD
University of Vermont
Mark Korson, MD
VMP Genetics, LLC
Get the Most Out of Your Experience
 Use the Q&A Button to submit questions
during today’s session
 Recording and slides will be sent by email
 For further information, contact
WeitzmanLearning@chc1.com
2
 Founding year: 1972
 Hubs/Locations: 15/210
 Patients per year: 100,000
The Weitzman Institute is a program of
3
4
The Weitzman Instituteworks to improve primary care and its delivery to medically
underserved and special populationsthrough research, innovation, and the education and
training of health professionals.
4Genetics | 2/18/204
New England Regional Genetics
Network
The NERGN project is supported by the Health Resources and
Services Administration (HRSA) of the U.S. Department of Health
and Human Services (HHS) under grant number UH7MC30778;
New England Regional Genetics Network; total award amount:
1.5 million; 100% from governmental sources. This information
or content and conclusions are those of the author and should
not be construed as the official position or policy of, nor should
any endorsements be inferred by HRSA, HHS or the U.S.
Government.
5
CME Credits Available
 CME credits available to live webinar
participants only
 A brief survey will be sent after this session to
those who registered and attended this webinar
 CME certificate will be sent to participants who
complete the survey
American Academy
Family Physicians
(AAFP)
6
Disclosures
No Disclosures
7
Today’s Presenters
Dr. Leah W. Burke, MD
Dr. Mark Korson, MD
8
Goals
• Review the genetic and genomic testing modalities
• Identify the clinical and family history findings that raise a
concern for a genetic disorder
• Review how simple biochemical tests that can determine
the competence of human metabolism
• Describe a few findings on routine biochemical testing that
can increase suspicion about an underlying metabolic
disease
Genetic Testing:
Screening vs. Diagnostic
• Testing done on a particular
population
• Individuals are asymptomatic
• Not designed to diagnose, simply
to identify individuals at a higher
risk
• May lead to diagnostic tests
• Testing done on individuals
• Individuals often symptomatic
• Individuals may have had a
positive screening test
• May lead to treatment options
Diagnostic Genetic Testing
Karyotype
FISH
Image
Fluorescence
In Situ
Hybridization
Microarray
Jax.com
Karyotype
Karyotype
Compare the Karyotype to published Idiograms
2q34
2q10
2p24
Diagnostic Genetic Testing
Karyotype
FISH
Image
Fluorescence
In Situ
Hybridization
Microarray
Jax.com
FISH: Fluorescence in situ Hybridization
Diagnostic Genetic Testing
Karyotype
FISH
Image
Fluorescence
In Situ
Hybridization
Microarray
Jax.com
What’s in a name?
A test by any other name…
• Microarray
• Chromosomal microarray
• Whole genome microarray
• Comparative Genomic Hybridization (CGH)
• Array CGH
Function is to determine copy number variants
Microarray
Duplication in patient
Deletion in patient
Normal copy number
20
Karyotype Individual
FISH test
Microarray
Can detect whole
chromosome
differences,
translocations, and
large deletions or
duplications
Only looks at
specific areas for
deletions or
duplications
Can detect very
small duplications
or deletions
What about sequencing?
21
Sanger Sequencing
• A massively parallel sequencing technology in which
millions of overlapping “reads” of DNA sequences are
done simultaneously
• Creates an enormous amount of data to be analyzed
• Can detect single gene mutations including nonsense,
missense, splice-site, and frame-shift mutations
23
Next Generation Sequencing
24
25
Whole Exome Sequencing (WES)
• Now being offered clinically
• Parallel sequencing of at least 98% of
the coding sequences
Whole Genome Sequencing (WGS)
• Parallel sequencing of the coding and
non-coding sequences
• Some conditions are caused by DNA
changes outside the “gene”
26
Both are being considered in rapid testing
of sick newborns in the NICU and other places
Lots of data…What happens next?
27
28
Variants of Uncertain Significance:
The Dreaded VUS
• With whole genome sequencing or whole exome
sequencing, the chance of VUS is even greater than with
microarray testing
• The reading of the variants can be different between
different labs and over time
29
Variants of Uncertain Significance:
The Dreaded VUS
So when should you refer for a
genetics/metabolism evaluation?
30
REMEMBER THE RULE OF “TWO/TOO” (when asking questions)
• TOO tall
• TOO short
• TOO early
• TOO many
• TOO young
• TOO different
• TWO tumors
• TWO generations
• TWO in the family
• TWO birth defects
Let’s start with the Too’s
• TOO tall
• TOO short
• TOO early
• TOO many
• TOO young
• TOO different
32
Acromelic Mesomelic Rhizomelic
Too tall
• Cerebral gigantism (Sotos syndrome)
• Marfan syndrome
• Beckwith-Weidemann syndrome
• Homocystinuria
• XYY males
• Other syndromes
• Prenatal onset overgrowth
• Cerebral gigantism
• Dolichocephaly
• Frontal bossing, prognathism, pointed chin,
downslating palpebral fissures
• High-arched palate
• Developmental delay, poor coordination, behavioral
problems, autism, seizures
• Ventriculomegaly, absent corpus callosum, persistent
cavum septum pellucidum
Sotos syndrome
Marfan Syndrome
• Tall stature with long
bone overgrowth
• Long narrow face
• High-arched palate
• Subluxation of lenses
• Spontaneous
pneumothoraces
• Arachnodactyly
• Aortic root dilation and
dissection
• Mitral regurgitation
• Scoliosis
• Pectus deformities
• Joint hypermobility
• Striae dystrophica
• Recurrent hernias
Usually due to a FBN1 (fibrillin 1) mutation
Also consider TGFBR1 and TGFBR2
Beckwith-Wiedemann
• LGA babies without maternal diabetes
• Macroglossia
• Hemi-hypertrophy
• Ear creases and or posterior pits
• Umbilical hernia or omphalocele
• Wilms tumor
Too short
• History of Growth deficiency
– Onset
• Prenatal – intrauterine growth retardation
• Postnatal
– Growth maturation
• Normal
• Delayed
– Proportional
• Proportions are normal
• Malproportion
Achondroplasia
• Short-limb dwarfism –
rhizomelic shortening
• Macrocephaly with frontal
bossing
• Midface hypoplasia
• Foramen magnum
stenosis
• Upper airway obstruction
• Kyphosis and lumbar
lordosis
• Trident hand
• Limited elbow extension
• Generalized joint hypermobility
• Bowing of legs
• Conductive hearing loss
• Delayed motor development
• Occasional hydrocephalus
• Mutations in FGFR3 gene (80%
de novo)
Too many
46
Too many
47
Skin Manifestations: Subcutaneous Neurofibromas
Too different
49
Eyes
Too close Normal Too wide
Short Normal Long
Upslanting Nl Downslanting
Ears
Too different
• Developmental delay
• Autism
51
Initial Genetics Evaluation: First Tier
• Three generation family history
• Medical history for clues about
birth/environmental causes
• Physical evaluation for signs of underlying
syndromes
– Targeted testing for a specific syndrome
– Metabolic and/or mitochondrial testing if indicated
• Chromosomal microarray
• Fragile X DNA testing
Fragile X physical features
• Macrocephaly
• Long face with
prominent jaw
and long ears
• Joint
hypermobility
• May not have any
striking features
Fragile X Syndrome
• Caused by a change in the FMR1 gene located
on the X chromosome
• A full mutation is expressed in 100% of males
and 50% of females
• Intellectual disability is a major feature in
affected males
• Must be tested for with a specific test that
determines the repeat size
Initial Genetics Evaluation: First Tier
• Three generation family history
• Medical history for clues about
birth/environmental causes
• Physical evaluation for signs of underlying
syndromes
– Targeted testing for a specific syndrome
– Metabolic and/or mitochondrial testing if indicated
• Chromosomal microarray
• Fragile X DNA testing
Chromosomal Microarray
An important part of the First Tier
• Numerous pathogenic copy number variants
(CNVs) have been identified in the etiology of
autism
• Yield is thought to be about 10%
• Several “hot spots” or recurrent CNVs have been
identified
• Often present in unaffected parents – variable
penetrance
Case
• 18 month old girl referred to genetics for gross motor delays
• Additional features
– Small VSD
– Epicanthal folds and puffy eyelids
– Upturned nose and wide mouth
– Difficulty gaining weight
• Facial features reminiscent of Williams syndrome but didn’t
completely fit
• Did the first tier of testing
57
Case
• Seen again at 5 ½ years and proposed doing exome sequencing
• Received approval from insurance, but parents decided to wait
• At 6 years of age, she was diagnosed with celiac disease
• Parents proceeded with testing
• A pathogenic variant was found in SETD5
58
SETD5
• Associated with an autosomal dominant neurodevelopmental
syndrome
• Found on the short arm of chromosome 3
• Deletions in this area have been known to cause a
neurodevelopmental syndrome
59
60
Rarechromo.org
REMEMBER THE RULE OF “TWO/TOO” (when asking questions)
• TOO tall
• TOO short
• TOO early
• TOO many
• TOO young
• TOO different
• TWO tumors
• TWO generations
• TWO in the family
• TWO birth defects
The Two’s
62
• Chief complaint
• Family History, if available:
– Include 3 generations if available
– Designate how each person is related
– Include developmental history
– Do not limit to symptoms found in patient
– Include causes of death, esp. in early deaths
– Include miscarriages & early infant deaths
– Include consanguinity and ethnicity
WHAT THE PCP SHOULD PROVIDE WITH THE REFERRAL
(35)
Breast Cancer @ 63
died @ 67 - heart
disease
Breast Cancer @ 58 post-menopausal
died at 63 - metastases
Breast cancer @ 80
died @ 83
Irish, English, ScottishIrish, German
(60)
(87)
(62)
Prostate cancer 70’s (84)
(62)
Russian Jewish
(35)
bre ca @ 42
died @ 48
bre ca @ 45
died @ 52
bil bre ca @ 45, 52
died @ 80
• SC – some concerns re: diseases in family
“Do you have any questions about diseases or conditions that run in your family?”
• R – reproduction problems
“Have there been any problems with pregnancy, infertility, or birth defects in your
family?”
• E – early disease, death, or disability
“Have any members of your family become sick or died at an early age?”
• E – ethnicity
“How would you describe your ancestry?” OR “What countries do your families
originate from?
• N – non-genetic factors
“Are there any other nonmedical conditions that run in your family?”
FAMILY HISTORY SCREEN MNEMONIC
Let’s take a
walk to the
Chemistry
Lab…
BASIC LAB TESTING: THE THEORY
• Can help assess the competence of metabolism of:
• Protein
• Carbohydrates
• Fat
BASIC LAB TESTING: THE THEORY
• Can help assess the competence of metabolism of:
• Protein
• Carbohydrates
• Fat
BASIC LAB TESTING: THE THEORY
- C - N
--
ANATOMY OF AN AMINO ACID
- C - N
--
UREA CYCLE
- C -
--
ORGANIC ACID
AMINO ACIDS
CHANGE
Krebs
cycle
Urea
cycle
ORGANIC
ACIDS
NH3
ATPELECTRON
TRANSPORT
CHAIN
PROTEIN
DEGRADATION
AMINO ACIDS
CHANGE
Krebs
cycle
Urea
cycle
ORGANIC
ACIDS
NH3
ATPELECTRON
TRANSPORT
CHAIN
PROTEIN
DEGRADATION
DEFECTS
Organic
acidemia
Urea cycle
disorder
AMINO ACIDS
CHANGE
Krebs
cycle
Urea
cycle
ORGANIC
ACIDS
NH3
ATPELECTRON
TRANSPORT
CHAIN
PROTEIN
DEGRADATION
TESTING
Organic
acidemia
Urea cycle
disorder
AMINO ACIDS
CHANGE
Krebs
cycle
Urea
cycle
ORGANIC
ACIDS
NH3
ATPELECTRON
TRANSPORT
CHAIN
PROTEIN
DEGRADATION
TESTING
- Ammonia
- Blood gases
- Electrolytes
- Anion gap
Organic
acidemia
Urea cycle
disorder
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Blood pH=7.4
Low pH  acidic
High pH  alkalotic
Blood HCO3=24
Low HCO3  acidic
High HCO3  alkalotic
TACHYPNEA  A WAY TO BLOW OFF ACID
pH pCO2 HCO3
H+ + HCO3
- H2CO3 H2O + CO2
TACHYPNEA  A WAY TO BLOW OFF ACID
pH pCO2 HCO3
Blood pH=7.4
Low pH  acidic
High pH  alkalotic
Blood pCO2=40
Low pCO2 rapid breathing
High pCO2 slower breathing
Blood HCO3=24
Low HCO3  acidic
High HCO3  alkalotic
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Organic
acidemias LOW LOW LOW
Urea cycle
disorders HIGH LOW LOW
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Organic
acidemias LOW LOW LOW
1° METABOLIC
ACIDOSIS
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Organic
acidemias LOW LOW LOW
1° METABOLIC
ACIDOSIS
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Organic
acidemias LOW LOW LOW
1° METABOLIC
ACIDOSIS
2° RESPIRATORY
ALKALOSIS
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Organic
acidemias LOW LOW LOW
1° METABOLIC
ACIDOSIS
2° RESPIRATORY
ALKALOSIS
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Organic
acidemias LOW LOW LOW
Urea cycle
disorders HIGH LOW LOW
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Urea cycle
disorders HIGH LOW LOW
2° RESPIRATORY
ALKALOSIS
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Urea cycle
disorders HIGH LOW LOW
2° RESPIRATORY
ALKALOSIS
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Urea cycle
disorders HIGH LOW LOW
2° RESPIRATORY
ALKALOSIS 1° METABOLIC
ACIDOSIS
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Urea cycle
disorders HIGH LOW LOW
1° RESPIRATORY
ALKALOSIS 2° METABOLIC
ACIDOSIS
THIS SLIDE HAS BEEN UPDATED POST
PRODUCTION. THE INFORMATION ON
THIS SLIDE IS CORRECT. THE
INFORMATION ON THE SLIDE SHOWN
ON THE RECORDING IS INCORRECT AS
POINTED OUT BY DR. KORSON
BLOOD GAS MEASUREMENT
pH pCO2 HCO3
Organic
acidemias LOW LOW LOW
Urea cycle
disorders HIGH LOW LOW
A CASE OF VOMITING & LETHARGY
A 10 month old girl presents to the ER with her second
bout of vomiting and dehydration. The first resolved with
IV fluids. She is now lethargic and tachypneic. Her blood
gases show- pH=7.54, pCO2=16, HCO3=17. Electrolytes
reveal Na=142, K=3.1, Cl=107, HCO3=18. Glucose
measures 62 mg/dL.
QUESTION
Which ONE of the following choices regarding the
patient’s presentation is the most diagnostically helpful?
A. The glucose level
B. This is the second episode of vomiting/dehydration
C. The respiratory alkalosis
D. The metabolic acidosis
E. The patient’s lethargy
QUESTION
Which ONE of the following choices regarding the
patient’s presentation is the most diagnostically helpful?
A. The glucose level
B. This is the second episode of vomiting/dehydration
C. The respiratory alkalosis
D. The metabolic acidosis
E. The patient’s lethargy
RESPIRATORY ALKALOSIS
Hyperventilation
Medications/drugs
Pain
Fever
Intracranial:
• Malformations
• Trauma
Hyperammonemia
Causes
THE ANION GAP
Difference between measured
anions and cations in the blood
Definition
Calculation Anion gap = Na - (Cl + HCO3)
Anion gap = 140 - (105 + 25)
Anion gap = 10
Normal anion gap = 10-15
NON-ANION GAP ACIDOSIS
Anion gap = Na - (Cl + HCO3)
Anion gap = 140 - (115 + 10)
Anion gap = 15
 Bicarbonate loss (urine or stool)
HIGH
NORMAL
LOW
ANION GAP ACIDOSIS
Anion gap = Na - (Cl + HCO3)
Anion gap = 140 - (105 + 10)
Anion gap = 25
 Anion accumulation
NORMAL
HIGH
LOW
AMINO ACIDS
CHANGE
Krebs
cycle
Urea
cycle
ORGANIC
ACIDS
NH3
ATPELECTRON
TRANSPORT
CHAIN
PROTEIN
DEGRADATION
DEFECTS:
Ammonia
Blood gases
Electrolytes
Anion gap
Organic
acidemia
Urea cycle
disorder
• Can help assess the competence of metabolism of:
• Protein
• Carbohydrates
• Fat
BASIC LAB TESTING: THE THEORY
CARBOHYDRATE
ANABOLISM
Krebs
cycle ATPELECTRON
TRANSPORT
CHAIN
LACTATE PYRUVATE
GLUCOSE
GLYCOGEN
GLYCOLYSIS
CARBOHYDRATE
CATABOLISM
LACTATE PYRUVATE
GLUCOSE
GLYCOGEN
GLUCONEOGENESIS
CARBOHYDRATE
CATABOLISM
GLYCOGEN
STORAGE
DISEASE
LACTATE PYRUVATE
GLUCOSE
GLUCONEOGENESIS
GLYCOGEN
CARBOHYDRATE
CATABOLISM
DEFECTS IN
GLUCO-
NEOGENESIS
LACTATE PYRUVATE
GLUCOSE
GLUCONEOGENESIS
GLYCOGEN
CARBOHYDRATE
CATABOLISM
TESTING
LACTATE PYRUVATE
GLUCOSE
GLUCONEOGENESIS
GLYCOGEN
CARBOHYDRATE
CATABOLISM
TESTING
- Glucose
- Lactate
LACTATE PYRUVATE
GLUCOSE
GLUCONEOGENESIS
GLYCOGEN
• Can help assess the competence of metabolism of:
• Protein
• Carbohydrates
• Fat
BASIC LAB TESTING: THE THEORY
Krebs
cycle ATPELECTRON
TRANSPORT
CHAIN
FATTY ACID
CATABOLISM
LIVER
FATTY ACIDS
KETONESACETYL CoA
Four-step
oxidative
cycle
Krebs
cycle ATPELECTRON
TRANSPORT
CHAIN
FATTY ACID
CATABOLISM
PERIPHERY
KETONESACETYL CoA
Krebs
cycle ATPELECTRON
TRANSPORT
CHAIN
FATTY ACID
OXIDATION
DEFECTSFATTY ACIDS
KETONESACETYL CoA
Four-step
oxidative
cycle
Krebs
cycle ATPELECTRON
TRANSPORT
CHAIN
FATTY ACID
OXIDATION
TESTINGFATTY ACIDS
KETONESACETYL CoA
Four-step
oxidative
cycle
Krebs
cycle ATPELECTRON
TRANSPORT
CHAIN
FATTY ACID
OXIDATION
TESTING
- Ketones
FATTY ACIDS
KETONESACETYL CoA
Four-step
oxidative
cycle
• Aketosis or hypoketosis is always an abnormal
response to hypoglycemia (or even very prolonged
fasting)
• Exception – newborns
HYPOGLYCEMIA
• Routine laboratory testing can be a good indicator
for assessing basic intermediary metabolism:
• Abnormalities might suggest an underlying acute
metabolic disorder
SUMMARY
• Blood gases
• Electrolytes, bicarb (anion gap)
• Ammonia
• Glucose
• Lactate
• Urinalysis
WHICH IS WHICH?
Which set of lab results most likely correlates with diarrhea and
which with a metabolic
disorder?
A
CASE 1 – diarrhea
CASE 2 – metabolic disorder
B
CASE 1 – metabolic disorder
CASE 2 – diarrhea
ANALYTE CASE 1 CASE 2 NORMALS
Sodium 141 135 133–146
Potassium 5 5 3.7-5.9
Chloride 116 103 98-107
Bicarbonate 10 10 21-31
Anion gap 15 22 8-15 (without K)
WHICH IS WHICH?
Which set of lab results most likely correlates with diarrhea and
which with a metabolic
disorder?
A
CASE 1 – diarrhea
CASE 2 – metabolic disorder
B
CASE 1 – metabolic disorder
CASE 2 – diarrhea
ANALYTE CASE 1 CASE 2 NORMALS
Sodium 141 135 133–146
Potassium 5 5 3.7-5.9
Chloride 116 103 98-107
Bicarbonate 10 10 21-31
Anion gap 15 22 8-15 (without K)
NON-ANION GAP ACIDOSIS
Anion gap = Na - (Cl + HCO3)
Anion gap = 140 - (115 + 10)
Anion gap = 15
 Bicarbonate loss (urine or stool)
HIGH
NORMAL
LOW
ANION GAP ACIDOSIS
Anion gap = Na - (Cl + HCO3)
Anion gap = 140 - (105 + 10)
Anion gap = 25
 Anion accumulation
NORMAL
HIGH
LOW
THE INFANT WITH LIVER DISEASE
A 6-month old infant male, product of a healthy
pregnancy/labor/delivery, was found to have a distended
belly at 3 months. By that time, he had lost 1 kg of
weight and was failing to thrive. He continues to feed
every 3-4 hours day and night. The liver was noted to be
enlarged at 5 months of age. He was evaluated in the ED
shortly after that for fever and upper respiratory
symptoms.
THE INFANT WITH LIVER DISEASE
Lab tests:
• Glucose=39 mg/dL
• Mild metabolic acidosis: HCO3=15
• ALT=118, AST=274
• Other liver functions normal
• Lactate=3.6 mmol/L (NL<2.2)
• Urinalysis: pH=6.5
Based on these
clinical/lab data, this
patient has liver disease.
Which other organ are
you worried about?
A. Brain
B. Kidneys
C. Distal extremities
D. Heart
E. Muscle
THE INFANT WITH LIVER DISEASE
Lab tests:
• Glucose=39 mg/dL
• Mild metabolic acidosis: HCO3=15
• ALT=118, AST=274
• Other liver functions normal
• Lactate=3.6 mmol/L (NL<2.2)
• Urinalysis: pH=6.5
Based on these
clinical/lab data, this
patient has liver disease.
Which other organ are
you worried about?
A. Brain
B. Kidneys
C. Distal extremities
D. Heart
E. Muscle
May be associated with:
• Pan-liver dysfunction
• Cholestasis
• Just hepatomegaly
Often associated with renal tubular dysfunction (renal
Fanconi syndrome)
METABOLIC LIVER DISEASE
A CASE OF HYPOGLYCEMIA
A 2 ½ year old boy develops a cough and cold symptoms.
His PCP diagnoses a pharyngitis; the patient takes only
smaller volumes than usual. On the third day, he is pale
and difficult to rouse. He is rushed to the ED and has a
seizure in the car. His blood glucose measures 25 mg/dL.
Blood gases – pH=7.29, pCO2=31, HCO3=15. Electrolytes
measure Na=131, K=4.4, Cl=99. His urinalysis shows -
pH=5.0, no glucose or protein, and 1+ ketones.
QUESTION
Which ONE of the following choices regarding the
patient’s presentation is the most diagnostically helpful?
A. Hypoglycemia
B. Metabolic acidosis
C. Hypoglycemia with seizure
D. Hypoglycemia with 1+ urine ketones
E. Hypoglycemia, hyponatremia, with seizures
QUESTION
Which ONE of the following choices regarding the
patient’s presentation is the most diagnostically helpful?
A. Hypoglycemia
B. Metabolic acidosis
C. Hypoglycemia with seizure
D. Hypoglycemia with 1+ urine ketones
E. Hypoglycemia, hyponatremia, with seizures
HYPOKETOTIC HYPOGLYCEMIA
HYPOKETOTIC HYPOGLYCEMIA
FAT FATTY
ACIDS
KETONES
HIGH Insulin State
HYPOKETOTIC HYPOGLYCEMIA
HIGH Insulin State
• Insulin tumor
• Infant of DM mother
• Beckwith-Wiedemann syndrome
• Iatrogenic
HYPOKETOTIC HYPOGLYCEMIA
FAT FATTY
ACIDS
KETONES
LOW Insulin State
HYPOKETOTIC HYPOGLYCEMIA
LOW Insulin State
• Fatty acid oxidation defect
• Glycogen storage disease
type I
• Aketosis or hypoketosis is always an abnormal
response to hypoglycemia (or even very prolonged
fasting)
• Exception – newborns
HYPOGLYCEMIA
THE CRITICALLY ILL INFANT
A male is the 5th child of non-consanguineous parents
following a normal pregnancy and delivery. Within 12
hours, he developed respiratory distress and lethargy,
requiring intubation and ventilation. Blood gases
showed: pH=7.21, pCO2=10, HCO3=4. Electrolytes:
Na=137, K=4.9, Cl=105, measured HCO3=4. Glucose=44
mg/dL. The patient was dehydrated; lactate measured 21
mmol/L (NL<2.2) but persisted despite rehydration.
Ammonia=105 μmol/L. Urinalysis: ketones=3+.
QUESTION
The most likely reason for the high lactic acid level in this
patient is dehydration leading to poor perfusion?
A. True
B. False
QUESTION
The most likely reason for the high lactic acid level in this
patient is dehydration leading to poor perfusion?
A. True
B. False
THE CRITICALLY ILL INFANT
A male is the 5th child of non-consanguineous parents
following a normal pregnancy and delivery. Within 12
hours, he developed respiratory distress and lethargy,
requiring intubation and ventilation. Blood gases
showed: pH=7.21, pCO2=10, HCO3=4. Electrolytes:
Na=137, K=4.9, Cl=105, measured HCO3=4. Glucose=44
mg/dL. The patient was dehydrated; lactate measured 21
mmol/L (NL<2.2) but persisted despite rehydration.
Ammonia=105 μmol/L. Urinalysis: ketones=3+.
Questions?
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Pediatric Genetics & Genomics

  • 1. Pediatric Genetics and Genomics April 28, 2020 Lab Testing and Genetic & Metabolic Disease: Spotting the "Red Flags" 1 Leah Burke, MD University of Vermont Mark Korson, MD VMP Genetics, LLC
  • 2. Get the Most Out of Your Experience  Use the Q&A Button to submit questions during today’s session  Recording and slides will be sent by email  For further information, contact WeitzmanLearning@chc1.com 2
  • 3.  Founding year: 1972  Hubs/Locations: 15/210  Patients per year: 100,000 The Weitzman Institute is a program of 3
  • 4. 4 The Weitzman Instituteworks to improve primary care and its delivery to medically underserved and special populationsthrough research, innovation, and the education and training of health professionals. 4Genetics | 2/18/204
  • 5. New England Regional Genetics Network The NERGN project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number UH7MC30778; New England Regional Genetics Network; total award amount: 1.5 million; 100% from governmental sources. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. 5
  • 6. CME Credits Available  CME credits available to live webinar participants only  A brief survey will be sent after this session to those who registered and attended this webinar  CME certificate will be sent to participants who complete the survey American Academy Family Physicians (AAFP) 6
  • 8. Today’s Presenters Dr. Leah W. Burke, MD Dr. Mark Korson, MD 8
  • 9. Goals • Review the genetic and genomic testing modalities • Identify the clinical and family history findings that raise a concern for a genetic disorder • Review how simple biochemical tests that can determine the competence of human metabolism • Describe a few findings on routine biochemical testing that can increase suspicion about an underlying metabolic disease
  • 10. Genetic Testing: Screening vs. Diagnostic • Testing done on a particular population • Individuals are asymptomatic • Not designed to diagnose, simply to identify individuals at a higher risk • May lead to diagnostic tests • Testing done on individuals • Individuals often symptomatic • Individuals may have had a positive screening test • May lead to treatment options
  • 12.
  • 14. Karyotype Compare the Karyotype to published Idiograms 2q34 2q10 2p24
  • 16. FISH: Fluorescence in situ Hybridization
  • 18. What’s in a name? A test by any other name… • Microarray • Chromosomal microarray • Whole genome microarray • Comparative Genomic Hybridization (CGH) • Array CGH Function is to determine copy number variants
  • 19. Microarray Duplication in patient Deletion in patient Normal copy number
  • 20. 20 Karyotype Individual FISH test Microarray Can detect whole chromosome differences, translocations, and large deletions or duplications Only looks at specific areas for deletions or duplications Can detect very small duplications or deletions
  • 23. • A massively parallel sequencing technology in which millions of overlapping “reads” of DNA sequences are done simultaneously • Creates an enormous amount of data to be analyzed • Can detect single gene mutations including nonsense, missense, splice-site, and frame-shift mutations 23 Next Generation Sequencing
  • 24. 24
  • 25. 25
  • 26. Whole Exome Sequencing (WES) • Now being offered clinically • Parallel sequencing of at least 98% of the coding sequences Whole Genome Sequencing (WGS) • Parallel sequencing of the coding and non-coding sequences • Some conditions are caused by DNA changes outside the “gene” 26 Both are being considered in rapid testing of sick newborns in the NICU and other places
  • 27. Lots of data…What happens next? 27
  • 28. 28 Variants of Uncertain Significance: The Dreaded VUS
  • 29. • With whole genome sequencing or whole exome sequencing, the chance of VUS is even greater than with microarray testing • The reading of the variants can be different between different labs and over time 29 Variants of Uncertain Significance: The Dreaded VUS
  • 30. So when should you refer for a genetics/metabolism evaluation? 30
  • 31. REMEMBER THE RULE OF “TWO/TOO” (when asking questions) • TOO tall • TOO short • TOO early • TOO many • TOO young • TOO different • TWO tumors • TWO generations • TWO in the family • TWO birth defects
  • 32. Let’s start with the Too’s • TOO tall • TOO short • TOO early • TOO many • TOO young • TOO different 32
  • 33.
  • 35. Too tall • Cerebral gigantism (Sotos syndrome) • Marfan syndrome • Beckwith-Weidemann syndrome • Homocystinuria • XYY males • Other syndromes
  • 36.
  • 37. • Prenatal onset overgrowth • Cerebral gigantism • Dolichocephaly • Frontal bossing, prognathism, pointed chin, downslating palpebral fissures • High-arched palate • Developmental delay, poor coordination, behavioral problems, autism, seizures • Ventriculomegaly, absent corpus callosum, persistent cavum septum pellucidum Sotos syndrome
  • 38.
  • 39. Marfan Syndrome • Tall stature with long bone overgrowth • Long narrow face • High-arched palate • Subluxation of lenses • Spontaneous pneumothoraces • Arachnodactyly • Aortic root dilation and dissection • Mitral regurgitation • Scoliosis • Pectus deformities • Joint hypermobility • Striae dystrophica • Recurrent hernias Usually due to a FBN1 (fibrillin 1) mutation Also consider TGFBR1 and TGFBR2
  • 40.
  • 41. Beckwith-Wiedemann • LGA babies without maternal diabetes • Macroglossia • Hemi-hypertrophy • Ear creases and or posterior pits • Umbilical hernia or omphalocele • Wilms tumor
  • 42. Too short • History of Growth deficiency – Onset • Prenatal – intrauterine growth retardation • Postnatal – Growth maturation • Normal • Delayed – Proportional • Proportions are normal • Malproportion
  • 43.
  • 44.
  • 45. Achondroplasia • Short-limb dwarfism – rhizomelic shortening • Macrocephaly with frontal bossing • Midface hypoplasia • Foramen magnum stenosis • Upper airway obstruction • Kyphosis and lumbar lordosis • Trident hand • Limited elbow extension • Generalized joint hypermobility • Bowing of legs • Conductive hearing loss • Delayed motor development • Occasional hydrocephalus • Mutations in FGFR3 gene (80% de novo)
  • 50. Eyes Too close Normal Too wide Short Normal Long Upslanting Nl Downslanting Ears
  • 51. Too different • Developmental delay • Autism 51
  • 52. Initial Genetics Evaluation: First Tier • Three generation family history • Medical history for clues about birth/environmental causes • Physical evaluation for signs of underlying syndromes – Targeted testing for a specific syndrome – Metabolic and/or mitochondrial testing if indicated • Chromosomal microarray • Fragile X DNA testing
  • 53. Fragile X physical features • Macrocephaly • Long face with prominent jaw and long ears • Joint hypermobility • May not have any striking features
  • 54. Fragile X Syndrome • Caused by a change in the FMR1 gene located on the X chromosome • A full mutation is expressed in 100% of males and 50% of females • Intellectual disability is a major feature in affected males • Must be tested for with a specific test that determines the repeat size
  • 55. Initial Genetics Evaluation: First Tier • Three generation family history • Medical history for clues about birth/environmental causes • Physical evaluation for signs of underlying syndromes – Targeted testing for a specific syndrome – Metabolic and/or mitochondrial testing if indicated • Chromosomal microarray • Fragile X DNA testing
  • 56. Chromosomal Microarray An important part of the First Tier • Numerous pathogenic copy number variants (CNVs) have been identified in the etiology of autism • Yield is thought to be about 10% • Several “hot spots” or recurrent CNVs have been identified • Often present in unaffected parents – variable penetrance
  • 57. Case • 18 month old girl referred to genetics for gross motor delays • Additional features – Small VSD – Epicanthal folds and puffy eyelids – Upturned nose and wide mouth – Difficulty gaining weight • Facial features reminiscent of Williams syndrome but didn’t completely fit • Did the first tier of testing 57
  • 58. Case • Seen again at 5 ½ years and proposed doing exome sequencing • Received approval from insurance, but parents decided to wait • At 6 years of age, she was diagnosed with celiac disease • Parents proceeded with testing • A pathogenic variant was found in SETD5 58
  • 59. SETD5 • Associated with an autosomal dominant neurodevelopmental syndrome • Found on the short arm of chromosome 3 • Deletions in this area have been known to cause a neurodevelopmental syndrome 59
  • 61. REMEMBER THE RULE OF “TWO/TOO” (when asking questions) • TOO tall • TOO short • TOO early • TOO many • TOO young • TOO different • TWO tumors • TWO generations • TWO in the family • TWO birth defects
  • 63. • Chief complaint • Family History, if available: – Include 3 generations if available – Designate how each person is related – Include developmental history – Do not limit to symptoms found in patient – Include causes of death, esp. in early deaths – Include miscarriages & early infant deaths – Include consanguinity and ethnicity WHAT THE PCP SHOULD PROVIDE WITH THE REFERRAL
  • 64. (35) Breast Cancer @ 63 died @ 67 - heart disease Breast Cancer @ 58 post-menopausal died at 63 - metastases Breast cancer @ 80 died @ 83 Irish, English, ScottishIrish, German (60) (87) (62) Prostate cancer 70’s (84) (62)
  • 65. Russian Jewish (35) bre ca @ 42 died @ 48 bre ca @ 45 died @ 52 bil bre ca @ 45, 52 died @ 80
  • 66. • SC – some concerns re: diseases in family “Do you have any questions about diseases or conditions that run in your family?” • R – reproduction problems “Have there been any problems with pregnancy, infertility, or birth defects in your family?” • E – early disease, death, or disability “Have any members of your family become sick or died at an early age?” • E – ethnicity “How would you describe your ancestry?” OR “What countries do your families originate from? • N – non-genetic factors “Are there any other nonmedical conditions that run in your family?” FAMILY HISTORY SCREEN MNEMONIC
  • 67.
  • 68. Let’s take a walk to the Chemistry Lab…
  • 69. BASIC LAB TESTING: THE THEORY
  • 70. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
  • 71. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
  • 72. - C - N -- ANATOMY OF AN AMINO ACID
  • 73. - C - N -- UREA CYCLE
  • 80. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Blood pH=7.4 Low pH  acidic High pH  alkalotic Blood HCO3=24 Low HCO3  acidic High HCO3  alkalotic
  • 81. TACHYPNEA  A WAY TO BLOW OFF ACID pH pCO2 HCO3 H+ + HCO3 - H2CO3 H2O + CO2
  • 82. TACHYPNEA  A WAY TO BLOW OFF ACID pH pCO2 HCO3 Blood pH=7.4 Low pH  acidic High pH  alkalotic Blood pCO2=40 Low pCO2 rapid breathing High pCO2 slower breathing Blood HCO3=24 Low HCO3  acidic High HCO3  alkalotic
  • 83. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW Urea cycle disorders HIGH LOW LOW
  • 84. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS
  • 85. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS
  • 86. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS 2° RESPIRATORY ALKALOSIS
  • 87. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW 1° METABOLIC ACIDOSIS 2° RESPIRATORY ALKALOSIS
  • 88. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW Urea cycle disorders HIGH LOW LOW
  • 89. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 2° RESPIRATORY ALKALOSIS
  • 90. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 2° RESPIRATORY ALKALOSIS
  • 91. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 2° RESPIRATORY ALKALOSIS 1° METABOLIC ACIDOSIS
  • 92. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Urea cycle disorders HIGH LOW LOW 1° RESPIRATORY ALKALOSIS 2° METABOLIC ACIDOSIS THIS SLIDE HAS BEEN UPDATED POST PRODUCTION. THE INFORMATION ON THIS SLIDE IS CORRECT. THE INFORMATION ON THE SLIDE SHOWN ON THE RECORDING IS INCORRECT AS POINTED OUT BY DR. KORSON
  • 93. BLOOD GAS MEASUREMENT pH pCO2 HCO3 Organic acidemias LOW LOW LOW Urea cycle disorders HIGH LOW LOW
  • 94. A CASE OF VOMITING & LETHARGY A 10 month old girl presents to the ER with her second bout of vomiting and dehydration. The first resolved with IV fluids. She is now lethargic and tachypneic. Her blood gases show- pH=7.54, pCO2=16, HCO3=17. Electrolytes reveal Na=142, K=3.1, Cl=107, HCO3=18. Glucose measures 62 mg/dL.
  • 95. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. The glucose level B. This is the second episode of vomiting/dehydration C. The respiratory alkalosis D. The metabolic acidosis E. The patient’s lethargy
  • 96. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. The glucose level B. This is the second episode of vomiting/dehydration C. The respiratory alkalosis D. The metabolic acidosis E. The patient’s lethargy
  • 98. THE ANION GAP Difference between measured anions and cations in the blood Definition Calculation Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 25) Anion gap = 10 Normal anion gap = 10-15
  • 99. NON-ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (115 + 10) Anion gap = 15  Bicarbonate loss (urine or stool) HIGH NORMAL LOW
  • 100. ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 10) Anion gap = 25  Anion accumulation NORMAL HIGH LOW
  • 102. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
  • 108. CARBOHYDRATE CATABOLISM TESTING - Glucose - Lactate LACTATE PYRUVATE GLUCOSE GLUCONEOGENESIS GLYCOGEN
  • 109. • Can help assess the competence of metabolism of: • Protein • Carbohydrates • Fat BASIC LAB TESTING: THE THEORY
  • 110. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID CATABOLISM LIVER FATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
  • 112. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID OXIDATION DEFECTSFATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
  • 113. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID OXIDATION TESTINGFATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
  • 114. Krebs cycle ATPELECTRON TRANSPORT CHAIN FATTY ACID OXIDATION TESTING - Ketones FATTY ACIDS KETONESACETYL CoA Four-step oxidative cycle
  • 115. • Aketosis or hypoketosis is always an abnormal response to hypoglycemia (or even very prolonged fasting) • Exception – newborns HYPOGLYCEMIA
  • 116. • Routine laboratory testing can be a good indicator for assessing basic intermediary metabolism: • Abnormalities might suggest an underlying acute metabolic disorder SUMMARY • Blood gases • Electrolytes, bicarb (anion gap) • Ammonia • Glucose • Lactate • Urinalysis
  • 117. WHICH IS WHICH? Which set of lab results most likely correlates with diarrhea and which with a metabolic disorder? A CASE 1 – diarrhea CASE 2 – metabolic disorder B CASE 1 – metabolic disorder CASE 2 – diarrhea ANALYTE CASE 1 CASE 2 NORMALS Sodium 141 135 133–146 Potassium 5 5 3.7-5.9 Chloride 116 103 98-107 Bicarbonate 10 10 21-31 Anion gap 15 22 8-15 (without K)
  • 118. WHICH IS WHICH? Which set of lab results most likely correlates with diarrhea and which with a metabolic disorder? A CASE 1 – diarrhea CASE 2 – metabolic disorder B CASE 1 – metabolic disorder CASE 2 – diarrhea ANALYTE CASE 1 CASE 2 NORMALS Sodium 141 135 133–146 Potassium 5 5 3.7-5.9 Chloride 116 103 98-107 Bicarbonate 10 10 21-31 Anion gap 15 22 8-15 (without K)
  • 119. NON-ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (115 + 10) Anion gap = 15  Bicarbonate loss (urine or stool) HIGH NORMAL LOW
  • 120. ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 10) Anion gap = 25  Anion accumulation NORMAL HIGH LOW
  • 121. THE INFANT WITH LIVER DISEASE A 6-month old infant male, product of a healthy pregnancy/labor/delivery, was found to have a distended belly at 3 months. By that time, he had lost 1 kg of weight and was failing to thrive. He continues to feed every 3-4 hours day and night. The liver was noted to be enlarged at 5 months of age. He was evaluated in the ED shortly after that for fever and upper respiratory symptoms.
  • 122. THE INFANT WITH LIVER DISEASE Lab tests: • Glucose=39 mg/dL • Mild metabolic acidosis: HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 Based on these clinical/lab data, this patient has liver disease. Which other organ are you worried about? A. Brain B. Kidneys C. Distal extremities D. Heart E. Muscle
  • 123. THE INFANT WITH LIVER DISEASE Lab tests: • Glucose=39 mg/dL • Mild metabolic acidosis: HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 Based on these clinical/lab data, this patient has liver disease. Which other organ are you worried about? A. Brain B. Kidneys C. Distal extremities D. Heart E. Muscle
  • 124. May be associated with: • Pan-liver dysfunction • Cholestasis • Just hepatomegaly Often associated with renal tubular dysfunction (renal Fanconi syndrome) METABOLIC LIVER DISEASE
  • 125. A CASE OF HYPOGLYCEMIA A 2 ½ year old boy develops a cough and cold symptoms. His PCP diagnoses a pharyngitis; the patient takes only smaller volumes than usual. On the third day, he is pale and difficult to rouse. He is rushed to the ED and has a seizure in the car. His blood glucose measures 25 mg/dL. Blood gases – pH=7.29, pCO2=31, HCO3=15. Electrolytes measure Na=131, K=4.4, Cl=99. His urinalysis shows - pH=5.0, no glucose or protein, and 1+ ketones.
  • 126. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. Hypoglycemia B. Metabolic acidosis C. Hypoglycemia with seizure D. Hypoglycemia with 1+ urine ketones E. Hypoglycemia, hyponatremia, with seizures
  • 127. QUESTION Which ONE of the following choices regarding the patient’s presentation is the most diagnostically helpful? A. Hypoglycemia B. Metabolic acidosis C. Hypoglycemia with seizure D. Hypoglycemia with 1+ urine ketones E. Hypoglycemia, hyponatremia, with seizures
  • 130. HYPOKETOTIC HYPOGLYCEMIA HIGH Insulin State • Insulin tumor • Infant of DM mother • Beckwith-Wiedemann syndrome • Iatrogenic
  • 132. HYPOKETOTIC HYPOGLYCEMIA LOW Insulin State • Fatty acid oxidation defect • Glycogen storage disease type I
  • 133. • Aketosis or hypoketosis is always an abnormal response to hypoglycemia (or even very prolonged fasting) • Exception – newborns HYPOGLYCEMIA
  • 134. THE CRITICALLY ILL INFANT A male is the 5th child of non-consanguineous parents following a normal pregnancy and delivery. Within 12 hours, he developed respiratory distress and lethargy, requiring intubation and ventilation. Blood gases showed: pH=7.21, pCO2=10, HCO3=4. Electrolytes: Na=137, K=4.9, Cl=105, measured HCO3=4. Glucose=44 mg/dL. The patient was dehydrated; lactate measured 21 mmol/L (NL<2.2) but persisted despite rehydration. Ammonia=105 μmol/L. Urinalysis: ketones=3+.
  • 135. QUESTION The most likely reason for the high lactic acid level in this patient is dehydration leading to poor perfusion? A. True B. False
  • 136. QUESTION The most likely reason for the high lactic acid level in this patient is dehydration leading to poor perfusion? A. True B. False
  • 137. THE CRITICALLY ILL INFANT A male is the 5th child of non-consanguineous parents following a normal pregnancy and delivery. Within 12 hours, he developed respiratory distress and lethargy, requiring intubation and ventilation. Blood gases showed: pH=7.21, pCO2=10, HCO3=4. Electrolytes: Na=137, K=4.9, Cl=105, measured HCO3=4. Glucose=44 mg/dL. The patient was dehydrated; lactate measured 21 mmol/L (NL<2.2) but persisted despite rehydration. Ammonia=105 μmol/L. Urinalysis: ketones=3+.
  • 138. Questions? Call Genetics! We like answering your questions! THANK YOU FOR PARTICIPATING TODAY.